FOOD AND CHEMICAL TOXICOLOGY CONTENTS Food and (PDFDrive)

Volume 48, Supplement 4, July 2010 ISSN 0278-6915
48/S4
FOOD AND CHEMICAL TOXICOLOGY
VOLUME 48 (2010) SUPPLEMENT 4 Editors
Food and
CONTENTS

J F Borzelleca
A Safety Assessment of Saturated Branched Chain Alcohols when used as
Fragrance Ingredients
A R Boobis
D. Belsito, D. Bickers, M. Bruze,

P. Calow, H. Greim, J. M. Hanifin,
A. E. Rogers, J. H. Saurat, I. G. Sipes,
S1–S46 A safety assessment of branched chain saturated alcohols when used as
fragrance ingredients Chemical
Toxicology
H. Tagami, and The RIFM Expert
Panel
D. McGinty, J. Scognamiglio, S47–S50 Fragrance material review on 3,5,5-trimethyl-1-hexanol
C. S. Letizia and A. M. Api
D. McGinty, J. Scognamiglio, S51–S54 Fragrance material review on 3,7-dimethyl-7-methoxyoctan-2-ol
Vol. 48/S4 (2010) S1–S130

D. McGinty, J. Scognamiglio, S55–S59 Fragrance material review on 4-methyl-2-pentanol
D. McGinty, J. Scognamiglio, S60–S62 Fragrance material review on 2-methylundecanol
D. McGinty, J. Scognamiglio, S63–S66 Fragrance material review on 3,4,5,6,6-pentamethylheptan-2-ol
C. S. Letizia and A. M. Api A Safety Assessment of Saturated Branched Chain
D. McGinty, J. Scognamiglio, S67–S69 Fragrance material review on isodecyl alcohol
Alcohols when used as Fragrance Ingredients
D. McGinty, J. Scognamiglio, S70–S72 Fragrance material review on isooctan-1-ol
D. McGinty, S. P. Bhatia, S73–S78 Fragrance material review on isotridecan-1-ol (isomeric mixture)
J. Scognamiglio, C. S. Letizia and
A. M. Api
D. McGinty, J. Scognamiglio, S79–S81 Fragrance material review on isononyl alcohol
D. McGinty, J. Scognamiglio, S82–S84 Fragrance material review on 6,8-dimethylnonan-2-ol
D. McGinty, C. S. Letizia and S85–S88 Fragrance material review on 2-ethyl-1-butanol
A. M. Api
D. McGinty, J. Scognamiglio, S89–S92 Fragrance material review on 2,6-dimethyl-4-heptanol
(Contents continued on inside back cover)
Available online at www.sciencedirect.com
http://www.elsevier.com/locate/foodchemtox
Fd Chem. Toxic. is indexed/abstracted in Analyt. Abstr., Aqua. Abstr.,
Biosis Data., CAB Inter., CABS (Current Awareness in Biological Sciences),
Cam. Sci. Abstr., Chem. Abstr. Serv., Chem. Haz. in Indus.,
Curr. Cont. ISI/BIOMED Database, Curr. Cont. Sci. Cit. Ind.,
Curr. Cont. SCISEARCH Data., Excerp. Med., Health & Saf. Sci. Abstr.,
Ind. Med., Int. Pack., MEDLINE, Res. Alert, Tox. Abstr.
ELSEVIER
ISSN 0278-6915
48(S4) S1–S130 (2010)
Printed by Polestar Wheatons Ltd, Exeter, UK 237
CYAN MAGENTA YELLOW BLACK

FOOD AND CHEMICAL TOXICOLOGY (Contents continued from outside back cover)
Founding Editor
The late Leon Golberg
Editors D. McGinty, J. Scognamiglio, S97–S101 Fragrance material review on 2-methylbutanol
JOSEPH F. BORZELLECA AL A N R. BO O B I S C. S. Letizia and A. M. Api
Department of Pharmacology and Section of Experimental Medicine and Toxicology, D. McGinty, A. Lapczynski, S102–S109 Fragrance materials review on isoamyl alcohol
Toxicology, Medical College of Virginia, Division of Medicine, Imperial College, Hammersmith Campus, J. Scognamiglio, C. S. Letizia and
Richmond, VA 23298-0613, USA Ducane Road, London W12 0NN, UK
A. M. Api
Review Editor D. McGinty, J. Scognamiglio, S110–S114 Fragrance material review on 2,6-dimethyl-2-heptanol
SU S A N M. BA R L O W C. S. Letizia and A. M. Api
Harrington House, 8 Harrington Road, D. McGinty, J. Scognamiglio, S115–S129 Fragrance material review on 2-ethyl-1-hexanol
Brighton, East Sussex BN1 6RE, UK C. S. Letizia and A. M. Api
Associate Editors
JO H N CH R I S T I A N LA R S E N IV O N N E RI E T J E N S
National Food Institute, Technical University of Denmark, AFSG/Division of Toxicology, Wageningen University, PO Box 8000,
19 Mørkhøj Bygade, DK-2860 Søborg, Denmark 6700 EA Wageningen, The Netherlands
B R Y A N DE L A N E Y
DA V I D J. BR U S I C K
Senior Research Scientist – Toxicology, Pioneer Hi-Bred International,
Brusick Consultancy, 123 Moody Creek Road, VA 23024, Bumpass,
2450 SE Oak Tree Court Ankeny, IA 50021-7102, USA
Virginia, USA
GA R Y WI L L I A M S
Department of Pathology, New York Medical College, Basic Science MI C H A E L W. PA R I Z A
Building, Room 413, Valhalla, NY 10595, USA Department of Food Microbiology and Toxicology, University of
SA M U E L M. CO H E N Wisconsin at Madison, 176 Microbial Sciences Building,
Department of Pathology and Microbiology, University of Nebraska 1550 Linden Drive Madison, WI 53706, USA
Medical Center, 983135 Nebraska Medical Center,
Omaha, NE 68198-3135
International Editorial Board
P. BA L D R I C K , UK I. KI M B E R , UK R. C. SH A N K , USA
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T. F. X. CO L L I N S , USA B. LA K E , UK Y.-J. SU R H , South Korea
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A Safety Assessment of Saturated Branched Chain
Food and Chemical Toxicology 48 (2010) S1–S46
Contents lists available at ScienceDirect
Food and Chemical Toxicology

journal homepage: www.elsevier.com/locate/foodchemtox
Review
A safety assessment of branched chain saturated alcohols when used

as fragrance ingredients q
D. Belsito a, D. Bickers b, M. Bruze c, P. Calow d, H. Greim e, J.M. Hanifin f, A.E. Rogers g, J.H. Saurat h,
I.G. Sipes i, H. Tagami j, The RIFM Expert Panel
a
University of Missouri (Kansas City), c/o American Dermatology Associates, LLC, 6333 Long Avenue, Third Floor, Shawnee, KS 66216, USA
b
Columbia University Medical Center, Department of Dermatology, 161 Fort Washington Ave., New York, NY 10032, USA
c
Malmo University Hospital, Department of Occupational and Environmental Dermatology, Sodra Forstadsgatan 101, Entrance 47, Malmo SE-20502, Sweden
d
Roskilde University, Department of Environmental, Social and Spatial Change, Isafjordvej 66, Roskilde, Denmark
e
Technical University of Munich, Institute for Toxicology and Environmental Hygiene, Hohenbachernstrasse 15-17, Freising-Weihenstephan D-85354, Germany
f
Oregon Health Sciences University, Department of Dermatology L468, 3181 SW Sam Jackson Park Rd., Portland, OR 97201-3098, USA
g
Boston University School of Medicine, Department of Pathology and Laboratory Medicine, 715 Albany Street, L-804, Boston, MA 02118-2526, USA
h
Dermatotoxicology Swiss Centre for Applied Human Toxicology, University Medical Center, Rue Michel Servet, 1211 Genève 4, Switzerland
i
Department of Pharmacology, University of Arizona, College of Medicine, 1501 North Campbell Avenue, P.O. Box 245050, Tucson, AZ 85724-5050, USA
j
3-27-1 Kaigamori, Aoba-ku, Sendai 981-0942, Japan
a r t i c l e i n f o a b s t r a c t
Keywords: The Branched Chain Saturated Alcohol (BCSA) group of fragrance ingredients was evaluated for safety. In
Review humans, no evidence of skin irritation was found at concentrations of 2–10%. Undiluted, 11 materials
Safety evaluated caused moderate to severe eye irritation. As current end product use levels are between
Fragrance ingredients
0.001% and 1.7%, eye irritation is not a concern. The materials have no or low sensitizing potential. For
Branched chain saturated alcohols
individuals who are already sensitized, an elicitation reaction is possible. Due to lack of UVA/UVB
light-absorbing structures, and review of phototoxic/photoallergy data, the BCSA are not expected to eli-
cit phototoxicity or photoallergy. The 15 materials tested have a low order of acute toxicity. Following
repeated application, seven BCSA tested were of low systemic toxicity. Studies performed on eight BCSA
and three metabolites show no in vivo or in vitro genotoxicity. A valid carcinogenicity study showed that
2-ethyl-1-hexanol is a weak inducer of liver tumors in female mice, however, the relevance of this effect
and mode of action to humans is still a matter of debate. The Panel is of the opinion that there are no
safety concerns regarding BCSA under the present levels of use and exposure.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S2
2. Chemical identity, regulatory status, and exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S2
2.1. Rationale for grouping branched chain saturated alcohols together . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S2
2.2. Occurrence and use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S7
2.3. Estimated consumer exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S7
3. Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S8
3.1. Primary alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S8
3.2. Secondary alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S8
3.3. Tertiary alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S8
4. Pharmacokinetics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S8
4.1. Dermal route of exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S8
4.2. Oral route of exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S8
q
All correspondence should be addressed to: A.M. Api, RIFM, 50 Tice Blvd, Woodcliff Lake, NJ 07677, USA. Tel.: +1 201 689 8089; fax: +1 201 689 8090. E-mail address:
amapi@rifm.org.
0278-6915/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.fct.2010.05.046
S2 D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46
4.3. Respiratory route of exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S9

4.4. Parenteral route of exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S9
5. Toxicological studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S9
5.1. Acute toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S9
5.2. Repeated dose toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S9
5.2.1. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S9
5.2.2. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S10
5.2.3. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S11
5.3. Mutagenicity and genotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S13
5.3.1. In vitro mutagenicity studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S13
5.3.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S18
5.4. Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S18
5.4.1. Cell transformation assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S18
5.4.2. Carcinogenicity studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S18
5.5. Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S20
5.5.1. Fertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S20
5.5.2. Developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S20
5.6. Skin irritation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S32
5.6.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S32
5.6.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S32
5.7. Mucous membrane irritation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S32
5.7.1. Sensory irritation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S32
5.7.2. Eye irritation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S33
5.8. Skin sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S33
5.8.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S33
5.8.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S33
5.9. Phototoxicity and photoallergenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S33
5.10. Miscellaneous studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S36
6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S36
Conflict of interest statement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S41
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S42
1. Introduction shown in Table 1.1 In addition, several noncyclic branched chain

alcohols used as examples here have been reviewed in other recent
In 2006 complete literature searches were conducted on the RIFM publications. Information on previously reviewed substances
branched chain saturated alcohol group of fragrance ingredients. of this group is not presented again unless it is new or required to
This document provides a risk assessment of these materials as fra- evaluate remaining fragrance ingredients. The common characteris-
grance ingredients and is a critical evaluation of the pertinent data. tic structural elements of the alcohols with saturated branched chain
The scientific evaluation focuses on dermal exposure, which is con- are one hydroxyl group per molecule, a C4–C12 carbon chain with
sidered to be the primary route for fragrance materials. Where rel- one or several methyl side chains. Two members of the group, 2-
evant, toxicity, metabolism and biological fate data from other ethyl-1-butanol and 2-ethyl-1-hexanol, contain an ethyl side chain.
exposures have been considered. One member contains a methoxy group. Metabolism studies are
The current format includes a group summary evaluation pa- lacking for this compound, however, a methoxy group is enzymati-
per and individual Fragrance Material Reviews on discrete chem- cally not readily cleaved and if it were so, another primary alcohol
icals. The group summary is an evaluation of relevant data group would be formed.
selected from the large bibliography of studies and reports on As the database for the alcohols under review is limited, addi-
the individual chemicals. The selected data were deemed to be tional data for some metabolites of these alcohols have been used.
relevant based on the currency of protocols, quality of the data, It was demonstrated that 4-methyl-2-pentanol, a group member, is
statistical significance and appropriate exposure. These are iden- metabolized to 4-methyl-2-pentanone and 4-hydroxy-4-methyl-2-
tified in tabular form in the group summary. Details that are pentanone is a metabolite of both substances (Gingell et al.,
provided in the tables are not always discussed in the text of 2003). It can also be expected that 2,6-dimethyl-4-heptanol is
the group summary. The Fragrance Material Reviews contain a metabolized to 2,6-dimethylheptan-4-one. Therefore, studies on
comprehensive summary of all published reports including com- pharmacokinetics, metabolism, genotoxicity and systemic toxicity
plete bibliographies (McGinty et al., 2010a,b,c,d,e,f,g,h,i,j,k,l,m,n, of 4-methyl-2-pentanone, 4-hydroxy-4-methyl-2-pentanone and 2,6-
o,p,q). dimethylheptan-4-one have been added to the database. These
materials are not used as fragrance ingredients. Due to their struc-
tural similarity, these alcohols also share common metabolic path-
2. Chemical identity, regulatory status, and exposure ways (see below). As metabolism is crucial for pharmacokinetics
and toxicity, these alcohols or their metabolites are expected to
2.1. Rationale for grouping branched chain saturated alcohols together have the same primary target organs (liver, kidney, and blood) as
was shown for 2-ethyl-1-hexanol, isoamyl alcohol, isotridecan-1-
The group consists of 12 primary, 5 secondary and 3 tertiary
alcohols. Of these materials, three have been previously reviewed 1
Isooctan-1-ol, isononyl alcohol, isodecyl alcohol and Isotridecan-1-ol (isomeric
in RIFM’s Safety Assessment on Terpene Alcohols (Belsito et al., mixture) are generic names for mixtures of isomers of primary branched alcohols
2008). The names and structures of the materials reviewed are with an average C-number of 8, 9, 10, or 13, respectively.
Table 1
Material identification, summary of volume of use, and dermal exposure.
Material Synonyms Structure Worldwide metric Dermal systemic exposure Maximum skin
tons (annual)a in cosmetic products (mg/ level (%)b
kg/day)
Subgroup: primary
3,7-Dimethyl-1-octanolc
C10H22O
CAS# 106-21-8 Dihydrocitronellol 100–1000 0.0005d 0.02
Henry’s Law: 0.0000547 atm m3/mol 25 °C 1-Octanol, 3,7-dimethyl-
Log Kow: 3.9 at 35 °C Pelargol
Molecular weight: 158.29 Tetrahydrogeraniol
Vapor pressure: 0.06 mm Hg 20 °C
Water solubility: 175.4 mg/l at 25 °C
2-Ethyl-1-butanol
C6H14O
CAS# 97-95-0 1-Butanol,2-ethyl- <0.01 0.0005d 0.02
Henry’s Law: 0.0000176 atm m3/mol 25 °C 2-Ethylbutyl alcohol
Log Kow: 1.75 calc 2-Ethylbutan-1-ol
Molecular weight: 102.18
Water solubility: 11,950 mg/l at 25 °C
2-Ethyl-1-hexanol
C8H18O
CAS# 104-76-7 2-Ethylhexanol 0.1–1 0.0005 0.008
Henry’s Law: 0.000031 atm m3/mol 25 °C 1-Hexanol,2-ethyl-
Log Kow: 2.73 calc 2-Ethylhexan-1-ol
Water solubility: 1379 mg/l at 25 °C
Isoamyl alcohol 0.1–1 0.0002 0.01
C5H12O
CAS# 123-51-3 1-Butanol,3-methyl-
Henry’s Law: 0.0000133 atm m3/mol at 25 °C Isobutyl carbinol
Log Kow: 1.16 Isopentanol
Molecular weight: 88.15 Isopentyl alcohol
Vapor pressure: 3.84 mm Hg 25 °C 3-Methyl-1-butanol
D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46
Water solubility: 41,580 mg/l at 25 °C 3-Methylbutan-1-ol

Isodecyl alcohol
C10H22O
CAS# 25339-17-7 Isodecanol 0.1–1 0.0005d 0.02
Henry’s Law: 0.0000547 atm m3/mol 25 °C 8-Methylnonan-1-ol
Log Kow: 3.71 calc
Isononyl alcohol (isomer unspecified)

C9H20O
CAS# 27458-94-2 Isononanol <0.01 0.11 0.3
Henry’s Law: 0.0000412 atm m3/mol 25 °C 7-Methyloctan-1-ol
Log Kow: 3.22 calc
S3
(continued on next page)

S4
Table 1 (continued)
kg/day)
Isooctan-1-ol
C8H18O
CAS# 26952-21-6 Isooctanol <0.01 0.0005d 0.02
Henry’s Law: 0.000031 atm m3/mol 25 C 6-Methylheptan-1-ol
Log Kow: 2.73 calc
Vapor pressure: 0.151 mm Hg 25 C
Isotridecan-1-ol (isomeric mixture)
C13H28O
CAS# 27458-92-0 Isotridecanol 10–100 0.04 0.7
Henry’s Law: 0.000128 atm m3/mol 25 °C 11-Methyldodecan-1-ol
Log Kow: 5.19 calc
2-Methylbutanol
C5H12O
CAS# 137-32-6 Active amyl alcohol 0.01–0.1 0.0002 0.001
Henry’s Law: 0.0000133 atm m3/mol 25 °C 1-Butanol,2-methyl-
Log Kow: 1.26 calc sec-Butylcarbinol
Molecular weight: 88.15 (+/) 2-Methyl-1-butanol
Vapor pressure: 2.5 mm Hg 20 °C 2-Methylbutyl alcohol
Water solubility: 32200 mg/l at 25 °C 2-Methylbutan-1-ol
3-Methyl-1-pentanol
C6H14O
CAS# 589-35-5 2-Ethyl-4-butanol <0.01 0.0005d 0.02
Henry’s Law: 0.0000176 atm m3/mol 25 °C 1-Pentanol,3-methyl-
Log Kow: 1.75 calc 3-Methylpentan-1-ol
Molecular weight: 102.18 Methyl Pentanol-3
2-Methylundecanol
C12H26O
CAS# 10522-26-6 1-Undecanol,2-methyl- <0.01 0.01 0.04
Henry’s Law: 0.0000963 atm m3/mol 25 °C 2-Methylundecan-1-ol
Log Kow: 4.7 calc
3,5,5-Trimethyl-1-hexanol
C9H20O 1-Hexanol,3,5,5-trimethyl- 1–10 0.004 0.7
CAS# 3452-97-9 i-Nonyl alcohol
Henry’s Law: 0.0000412 atm m3/mol 25 °C Nonylol
Log Kow: 3.11 calc Trimethylhexanol
Molecular weight: 144.26 3,5,5-Trimethylhexanol
Vapor pressure: 0.2 mm Hg 20 °C 3,5,5-Trimethylhexan-1-ol
Water solubility: 572 mg/l at 25 °C 3,5,5-Trimethylhexyl alcohol
Subgroup: secondary
2,6-Dimethyl-4-heptanol
C9H20O
CAS# 108-82-7 Diisobutylcarbinol 10–100 0.0005d 0.02
Henry’s Law: 0.0000412 atm m3/mol 25 °C 4-Heptanol,2,6-dimethyl-
Log Kow 3.08 calc 2,6-Dimethylheptan-4-ol
3,7-Dimethyl-7-methoxyoctan-2-ol
C11H24O2
CAS# 41890-92-0 7-Methoxy-3,7-dimethyloctan-2-ol 1–10 0.09 1.3
Henry’s Law: 0.000000404 atm m3/mol 25 °C 2-Octanol,7-methoxy-3,7-dimethyl-
Log Kow: 2.76 calc Osirol
Molecular weight: 188.31 Osyrol
6,8-Dimethylnonan-2-ol
C11H24O
CAS# 70214-77-6 2-Nonanol,6,8-dimethyl- 1–10 0.001 0.009
Log Kow: 4.06 calc Nonadyl
4-Methyl-2-pentanol
C6H14O
CAS# 108-11-2 Isobutyl methyl carbinol 0.01–0.1 0.0005d 0.02
Henry’s Law: 0.0000176 atm m3/mol 25 °C Methyl isobutyl carbinol
Log Kow: 1.68 calc MIC
Molecular weight: 102.18 2-Pentanol,4-methyl-
Vapor pressure: 3.7 mm Hg 20 °C 4-Methylpentan-2-ol
3,4,5,6,6-Pentamethylheptan-2-ol
C12H26O
CAS# 87118-95-4 2-Heptanol,3,4,5,6,6-pentamethyl- 10–100 0.14 1.7
Log Kow: 4.36 calc Koavol DH
Subgroup: tertiary
C9H20O
CAS# 13254-34-7 Dimetol 10–100 0.0614 1.4
Henry’s Law: 0.0000412 atm m3/mol 25 °C Freesiol
Log Kow 3.0 at 45 °C 2-Heptanol,2-6-dimethyl-
Molecular weight: 144.26 Lolitol
Vapor pressure: 0.2 mm Hg 20 °C 2,6-Dimethylheptan-2-ol

S5
S6
Table 1 (continued)
kg/day)
3,6-Dimethyl-3-octanol
C10H22O
CAS# 151-19-9 3-Octanol,3,6-dimethyl- 0.1–1 0.0005d 0.02
Henry’s Law: 0.0000547 atm m3/mol 25 °C 3,6-Dimethyloctan-3-ol
Log Kow: 3.6 calc
Tetrahydrolinaloolc
C10H22O
CAS# 78-69-3 2,6-Dimethyl-6-octanol >1000 0.0005d 0.02
Henry’s Law: 0.0000547 atm m3/mol 25 C 3,7-Dimethyloctan-3-ol
Log Kow: 3.6 at 45 °C 3-Octanol, 3,7-dimethyl-
Tetrahydromyrcenolc
C10H22O
CAS# 18479-57-7 2,6-Dimethyloctan-2-ol 100–1000 0.06 0.7
Henry’s Law: 0.0000547 atm m3/mol 25 C 2,6-Dimethyl-2-octanol
Log Kow: 3.6 calc 2-Octanol, 2,6-dimethyl

a
2007 Volume of use survey.
b
Skin levels were based on the assumption that the fragrance mixture is used at 20% in a consumer product.
c
Materials have been previously reviewed by in RIFM’s Safety Assessment of Terpene Alcohols.
d
A default value of 0.02% was used to calculate dermal systemic exposure.
D. Belsito et al. / Food and Chemical Toxicology 48 (2010) S1–S46 S7
ol (isomeric mixture), 3,5,5-trimethyl-1-hexanol, 2,6-dimethylhep- through the dermal and inhalation routes of exposure. Worst-case
tan-4-one, 4-hydroxy-4-methyl-2-pentanone, 4-methyl-2-pentanol, scenario calculations indicate that depositions on the surface of the
and 4-methyl-2-pentanone. skin following use of cosmetics represents the major route of expo-
Data for 2-ethyl-1-hexanol, 2-ethylbutanol, 4-methyl-2-penta- sure to fragrance ingredients when conservative estimates for
nol, isoamyl alcohol, 2-methylbutanol and 4-methyl-2-pentanone evaporation, rinsing and other forms of product removal are em-
show that the alcohols share common metabolic pathways. The ployed (Cadby et al., 2002). Therefore, the dermal route was the
major pathways of metabolism and fate are: major route in assessing the safety of these compounds.
The fragrance industry has developed three types of approaches
– conjugation of the alcohol group with glucuronic acid; to estimate potential exposure for consumers to fragrance materials.
– oxidation of the alcohol group; All three types of exposure are summarized in Table 1. The first is vol-
– side-chain oxidation yielding polar metabolites, which may be ume of use. The total worldwide volume of use for fragrance materi-
conjugated and excreted – or further oxidized to an aldehyde, als in the branched chain saturated alcohols ranges from <0.01 to
a carboxylic acid, and to CO2; >1000 metric tons per year (IFRA, 2004). The reported volume is
– excretion of the unchanged parent compound. for the fragrance ingredient as used in fragrance compounds (mix-
tures) in all finished consumer product categories. The volume of
In most cases, metabolism yields innocuous metabolites. Inter- use is determined by IFRA approximately every 4 years through a
mediary reactive products of oxidation of primary alcohols are comprehensive survey of IFRA and RIFM member companies. As such
aldehydes, which are toxic and possibly genotoxic, although no rel- the volume of use data from this survey provides volume of use of
evant genotoxicity was shown with the primary alcohols tested. fragrance ingredients for the majority of the fragrance industry.
The alcohols under review are summarized in Table 1. CAS No. The second method estimates the potential percutaneous (total
and synonyms for the alcohols considered in this review are shown skin exposure) absorption from the entire body based on the use of
in Table 1. The structural formulas are provided in Table 1. multiple consumer personal care products containing the same fra-
grance ingredient. The dermal systemic exposure in cosmetic prod-
2.2. Occurrence and use ucts is calculated based on the concentrations in 10 types of the
most frequently used personal care and cosmetic products (anti-
The alcohols under review are used as fragrance ingredients. perspirant, bath products, body lotion, eau de toilette, face cream,
They may be found in fragrances used in decorative cosmetics, fine fragrance cream, hair spray, shampoo, shower gel, and toilet soap).
fragrances, shampoos, toilet soaps, and other toiletries as well as in The concentration of the fragrance ingredient in fine fragrances is
non-cosmetic products such as household cleaners and detergents. obtained from examination of several thousand commercial for-
This report summarizes and synthesizes animal and human data, mulations. The upper 97.5 percentile concentration is calculated
including studies by various routes of exposure, and emphasizes from the data obtained. This upper 97.5 percentile concentration
the risk assessment for use as fragrance ingredients. The scientific is then used for all 10 consumer products. These concentrations
evaluation focuses on dermal exposure, which is considered the are multiplied by the amount of product applied, the number of
primary exposure route for fragrance materials. Where relevant applications per day for each product type, and a ‘‘retention factor”
the metabolism, toxicity, and biological fate data of other routes (ranging from 0.001 to 1.0) to account for the length of time a
of exposure have also been considered. product may remain on the skin and/or likelihood of the fragrance
The selected data from published and unpublished reports were ingredient being removed by washing. The resultant calculation
deemed relevant based on the nature of the protocols, quality of represents the total consumer exposure (mg/kg/day) (Cadby
the data, and appropriate exposure. These data are presented in et al., 2002; Ford et al., 2000). In view of all of the above assump-
tabular form. tions, the total calculated consumer exposure is conservative; it is
Some of the alcohols assessed in this report have been evaluated unlikely that a consumer will consistently use a number of differ-
and approved for use as flavor ingredients in foodstuffs. In the Uni- ent consumer products which are all perfumed with the upper 97.5
ted States, 2-ethyl-1-hexanol, isoamyl alcohol, and 3-methyl-1- percentile level of the fragrance ingredient from a fine fragrance
pentanol have been approved for use as food additives or in food type of product (Cadby et al., 2002; Ford et al., 2000). The total con-
contact materials by the Food and Drug Administration (FDA). In sumer exposures to fragrance ingredients range from 0.0002 to
addition, 2,6-dimethyl-4-heptanol, 2-methylbutanol, and 3,5,5-tri- 0.11 mg/kg/body weight (bw)/day for the branched chain satu-
methyl-1-hexanol are listed as food additives (FDA, 2007). rated alcohols fragrance ingredients in high-end users of cosmetic
The International Joint FAO/WHO Expert Committee on Food products containing these materials (see Table 1) (IFRA, 2004).
Additives (JECFA) has evaluated alicyclic ketones, secondary alco- The third method provides maximum skin levels. For consider-
hols and related esters including 2,6-dimethyl-4-heptanol from ation of potential sensitization, the exposure is calculated as the
the group under review and its metabolite 2,6-dimethylheptan-4- percent concentration of the fragrance ingredient applied to the
one (JECFA, 1999). JECFA also evaluated aliphatic, branched chain skin based on the use of 20% of the fragrance mixture in the fine
saturated and unsaturated alcohols, aldehydes, acids, and related fragrance consumer product (IFRA, 2007). The maximum skin
esters including 2-methylbutanol (JECFA, 2004). These materials exposure levels of the branched chain saturated alcohol com-
were judged by this Committee not to present a safety concern pounds that form part of the formulae of fine fragrances vary
at the current estimated intake levels. widely and have been report to range from 0.008% to 1.7%. The
The annual worldwide use of the individual alcohols reviewed maximum skin exposure for branched chain saturated alcohols in
herein varies greatly and ranges from <0.01 to 100 metric tons. fine fragrance products are listed in Table 1 (IFRA, 2007).
Compounds with a use volume of >10 metric tons are 2,6-di- In assessing safety, the calculated dermal systemic exposure in
methyl-2-heptanol, 2,6-dimethyl-4-heptanol, isotricedan-1-ol, cosmetic products can then be compared to the indices of systemic
and 3,4,5,6,6-pentamethylheptan-2-ol (IFRA, 2007; Table 1). toxicity such as NOAEL and LOAEL that are obtained from the re-
peat dose subchronic, chronic and reproductive toxicity studies
2.3. Estimated consumer exposure to derive a margin of exposure (MOE). Systemic exposures (i.e.,
the dose absorbed through the skin and available to the systemic
Exposure data have been provided by the fragrance industry. circulation) were estimated based on dermal absorption rates.
Potential consumer exposure to fragrance materials occurs Where such data were lacking, as a conservative measure, dermal
absorption was considered to be 100% (i.e., the maximum skin 3.2. Secondary alcohols
exposure value was considered as the estimate of systemic
exposure). After application of 4-methyl-2-pentanol (methyl isobutyl car-
All exposure data were provided by the fragrance industry. Fur- binol in Fig. 2) to rabbits 33.7% of the dose was excreted as the glu-
ther explanation of how the data were obtained and of how expo- curonide (Kamil et al., 1953a). In mammals, the metabolism of
sures were determined has been previously reported by Cadby secondary alcohols proceeds primarily through their respective ke-
et al. (2002) and Ford et al. (2000). tones. 4-Methyl-2-pentanol is metabolized to 4-methyl-2-penta-
none (methyl isobutyl ketone in Fig. 2) and further to 4-hydroxy-4-
methyl-2-pentanone in rats (Fig. 2; OECD/SIDS, 2007).
3. Metabolism Plasma levels of 4-methyl-2-pentanol, 4-methyl-2-pentanone,
and 4-hydroxy-4-methyl-2-pentanone were determined up to 12 h
3.1. Primary alcohols after oral gavage administration of 5 mmol/kg of 4-methyl-2-pent-
anol or 4-methyl-2-pentanone to male rats. After dosing rats by ga-
When 25 mmoles (2.55 g) of 2-ethyl-1-butanol were adminis- vage with 4-methyl-2-pentanol or 4-methyl-2-pentanone, the
tered by gavage to rabbits, 40% of the dose was excreted in the ur- major material in the plasma for both compounds was 4-hydro-
ine as the glucuronide conjugate. The excretion of glucuronide was xy-4-methyl-2-pentanone. No other metabolites were detected in
completed within 24 h (Kamil et al., 1953a). A rabbit was given the plasma. The extent of metabolism of 4-methyl-2-pentanol to
3.1 ml (2.55 g) 2-ethyl-1-butanol and the 24-h urine was collected. 4-methyl-2-pentanone was at least 73%. The reduction of 4-
2-Ethyl-1-butanol was excreted mainly as diethylacetylglucuro- methyl-2-pentanone to 4-methyl-2-pentanol was insignificant
nide and a minor amount of methyl n-propyl ketone was also (Gingell et al., 2003; Hirota, 1991a).
found (Kamil et al., 1953b). Similar results were obtained with intraperitoneal application
Main metabolites of 2-ethyl-1-hexanol identified in the urine of of 4-methyl-2-pentanol and 4-methyl-2-pentanone in mice. After
rats after oral or dermal application were 2-ethylhexanoic acid, 5- intraperitoneal administration of 4-hydroxy-4-methyl-2-pentanone,
hydroxy-2-ethylhexanoic acid, 5-keto-2-ethylhexanoic acid, 2- neither 4-methyl-2-pentanol nor 4-methyl-2-pentanone could be
ethyl-1,6-hexanedioic acid and 6-hydroxy-2-ethylhexanoic acid, detected in the blood and in the brain (Fig. 2; Granvil et al.,
mainly as their glucuronides, and expired carbon dioxide. Potential 1994). This result shows that in rats and mice 4-methyl-2-pentanol
metabolites not detected in each study were 2-ethylhexanoic acid, is predominantly oxidized to 4-methyl-2-pentanone and both com-
4- and 2-heptanone. One to three percent 2-ethyl-1-hexanol was pounds share the same principal metabolite, namely 4-hydroxy-4-
excreted unchanged or as glucuronide. Metabolic saturation was methyl-2-pentanone.
seen with 500 mg/kg body weight applied (Kamil et al., 1953a,b). In workers exposed to mixed solvents including 4-methyl-2-
This metabolite pattern demonstrates the well-known metabolic pentanone and 4-methyl-2-pentanol was identified by GC–MS in
pathways of primary alcohols: oxidation of the alcohol group and the urine. In a subject exposed to 42.3 ml pure 4-methyl-2-penta-
oxidation of the side chain at various positions, glucuronidation none/m3 for 6 h, 0.42 mg 4-methyl-2-pentanol/g creatinine was ex-
of the oxidation products, and decarboxylation (Fig. 1; Albro, creted (Hirota, 1991b). This result confirms, that in humans as well,
1975; Deisinger et al., 1993, 1994). Induction of metabolism was the reduction of 4-methyl-2-pentanone is insignificant (6 h 42 ml/
not seen with repeated oral dosing (Deisinger et al., 1994). In rab- m3 4-methyl-2-pentanone corresponds to about 320 mg at 66%
bits the glucuronide of 2-ethylhexanoic acid was identified as the retention in the lung and a minute volume of 8 l).
main metabolite (87%) after oral application of 2-ethyl-1-hexanol
(Kamil et al., 1953a,b). In vitro incubation with mammalian alcohol
3.3. Tertiary alcohols
dehydrogenase resulted in a Vmax of 0.30 lmol/min/mg protein and
a Km value of 0.74 mM (Albro, 1975).
Data on the tertiary alcohols under review are not available. A
Only about 9% of the administered dose was found in the form
tertiary alcohol group cannot be oxidized. Tertiary alcohols are ex-
of the glucuronide when isoamyl alcohol (3-methylbutanol) or 2-
pected to be excreted either via conjugation or unchanged or un-
methylbutanol was given to rabbits. Other metabolites were not
dergo hydroxylation of the carbon chain, which in turn may give
identified (Kamil et al., 1953a). Age-dependent glucuronidation
rise to a metabolite which can be easily excreted.
activity was demonstrated in vitro in the olfactory mucosa of rats
with isoamyl alcohol (Leclerc et al., 2002). The glucuronidation of
isoamyl alcohol and other short-chained aliphatic alcohols was
4. Pharmacokinetics
investigated in vitro with human liver microsomes. The Vmax value
was 3.3 nmol/min/mg protein and the Km was determined as
4.1. Dermal route of exposure
13.3 mM. The glucuronidation increased with chain length (C2–
C5) of the alcohols studied (Jurowich et al., 2004).
In vitro absorption rates for 2-ethyl-1-hexanol were 0.22 ± 0.09
Oxidation to the aldehyde and glucuronidation was demon-
and 0.038 ± 0.014 mg/cm2/h for rat and human skin, respectively,
strated for isoamyl alcohol and 2-methylbutanol with microsomes
giving a rat/human ratio of 5.78. The permeability constants were
from rats pretreated with ethanol (Iwersen and Schmoldt, 1995).
2.59 ± 1.10 104 cm/h for rats and 4.54 ± 1.66 105 cm/h for
The rate of oxidative metabolism of isoamyl alcohol was about
humans (Barber et al., 1992).
0.1 mmol/g liver in rat liver homogenate and about 0.05 mM/g per-
The dermal absorption in the rat was determined to be 5.2% of a
fused rat liver (Hedlund and Kiessling, 1969). The rate of oxidation
dose of 1000 mg 2-ethyl-1-hexanol/kg body weight applied for 6 h;
of isoamyl alcohol by human skin alcohol dehydrogenase was
the absorption rate was calculated to be 0.57 mg/cm2/h. The termi-
183.3 nM/mg protein per minute (Wilkin and Stewart, 1987). The
nal half-life was calculated to be 77 h (Deisinger et al., 1994).
Km-values of isoamyl alcohol with alcohol dehydrogenase from hu-
man and horse liver were 0.07 and 0.08 mM, respectively (Pie-
truszko et al., 1973). After intraperitoneal application of 1000 mg 4.2. Oral route of exposure
isoamyl alcohol or 2-methylbutanol/kg body weight, the corre-
sponding aldehydes could not be detected in expired air of rats In rats, oral administration of 2000 mg isoamyl alcohol/kg body
(Haggard et al., 1945). weight led to a peak concentration of 170 mg/l blood 1 h later. The
authors calculated an oxidation rate of 5 mg/kg body weight/h

(Gaillard and Derache, 1965).
After oral administration to rats, 69–75% of a dose of 500 mg
14
C-labeled 2-ethyl-1-hexanol/kg body weight was excreted in
the urine within 96 h. About 13–15% of the dose was excreted in
the feces and about the same amount was exhaled. More than
50% of the dose was excreted within 24 h (Deisinger et al., 1993,
1994).
Plasma levels of 4-methyl-2-pentanol, 4-methyl-2-pentanone,
and 4-hydroxy-4-methyl-2-pentanone were determined up to 12 h
after oral gavage administration of 5 mmol/kg of 4-methyl-2-pent-
anol or 4-methyl-2-pentanone to male rats. The major material in
the plasma for both compounds was 4-hydroxy-4-methyl-2-penta-
none, with similar areas under the curve (AUCs) and Cmax at 9 h
after dosing for both 4-methyl-2-pentanol and 4-methyl-2-penta-
none. 4-Methyl-2-pentanone plasma levels and AUC were also sim-
ilar after 4-methyl-2-pentanone or 4-methyl-2-pentanol
administration. 4-Methyl-2-pentanol AUC was only about 6% of
the total material in the blood following 4-methyl-2-pentanol
administration, and insignificant after 4-methyl-2-pentanone
administration (Gingell et al., 2003).
4.3. Respiratory route of exposure
Respiratory uptake of isoamyl alcohol was investigated in four Fig. 1. Metabolism of 2-ethyl-1-hexanol in the rat (from Albro, 1975). Metabolites
marked with asterisks were detected.
healthy volunteers. Air concentration was 25–200 ppm and expo-
sure duration was 10 min. The mean uptake for the last 5 min of
exposure was 63% and the mean respiratory rate was 15.3 min1 tion, and irritation of the skin after dermal administration. Signs
(Kumagai et al., 1998). of gastrointestinal irritation were noted at necropsy in acute oral
toxicity tests.
4.4. Parenteral route of exposure In inhalation tests with five primary and two secondary alco-
hols, no mortality was observed in rats exposed to air saturated
After intravenous administration to rats, about 74% of a dose of with alcohol vapor at room temperature for as long as 8 h. LC50 val-
1 mg 14C-labeled 2-ethyl-1-hexanol/kg body weight was excreted ues were not determined. Local ocular and upper respiratory tract
in the urine within 96 h. About 4% of the dose was excreted in irritation was seen with 2-ethyl-1-hexanol. However, 4-methyl-2-
the feces and 23% was exhaled. More than 50% of the dose was ex- pentanol exposure at 2000 ml/m3 for 8 h resulted in death at
creted within 8 h. The terminal half-life was estimated to be 60 h 14 days of 5/6 rats, and exposure to saturated air at 20 °C resulted
(Deisinger et al., 1993, 1994). in anesthesia at 4 h and death of 6/10 mice after 10 h.
The concentration of isoamyl alcohol in blood declined within Acute toxicity data obtained from studies with other than oral
5 h to non-detectable levels after intraperitoneal administration or dermal exposure are summarized in Table 2-3.
of 1000 mg isoamyl alcohol/kg body weight. Similar values were
found for 2-methylbutanol administered at the same dose. An 5.2. Repeated dose toxicity
elimination half-life was not calculated. For isoamyl alcohol and
2-methylbutanol, 1.2% and 7.6%, respectively, were excreted via ur- The evaluation of repeated dose systemic toxicity is based on
ine and expired air. Compared to other amyl alcohols tested by the several oral studies with mainly primary alcohols and only one sec-
authors, primary alcohols were eliminated from the blood more ondary alcohol. The metabolic pathways with all the materials in
quickly than secondary and tertiary alcohols (Haggard et al., 1945). this group yield innocuous metabolites. The database could be
strengthened by an evaluation of the systemic toxicity of a second-
5. Toxicological studies ary and tertiary alcohol. Other studies can be found in Section 5.10.
5.1. Acute toxicity 5.2.1. Dermal studies

Dermal studies with branched chain saturated alcohols are
Acute dermal toxicity studies have been performed with six pri- summarized in Table 3-1.
mary, three secondary, and three tertiary alcohols, all but one in
rabbits. The dermal LD50 values in rabbits and the one in rats are 5.2.1.1. Primary alcohols. Over a period of 12 days, rats were treated
in the range of 1000–>5000 mg/kg body weight. In summary all with undiluted 2-ethyl-1-hexanol (2 ml/kg body weight/day, about
the compounds are of low acute toxicity by the dermal route (Ta- 1600 mg/kg body weight/day) on their shaved backs. At necropsy,
ble 2-1). the treated animals had decreased absolute and relative thymus
Eight primary alcohols, four secondary, and three tertiary alco- weights, liver granulomas, bronchiectasis in the lung, renal tubular
hols have been tested for oral acute toxicity. The oral LD50 values in epithelial necrosis in the kidneys, edema in heart and testes, de-
rats, mice, and rabbits are in the range of 1000–>5000 mg/kg body creased spermatogenesis, and an increase in lipids in adrenals were
weight, and therefore, all the compounds exhibit a low toxicity found on day 17. These effects were reversed on day 30 (Schmidt
when administered via the oral route (Table 2-2). et al., 1973).
Lethargy was the most often reported clinical sign after oral or 2-Ethyl-1-hexanol was applied topically under occlusion to
dermal administration, diarrhea and ataxia after oral administra- Fischer 344 rats for 5 days, followed by 2 days untreated, 4 days
OECD TG 408, isoamyl alcohol was administered in the drinking

water in concentrations of 0, 1000 ppm (about 80 mg/kg/d),
4000 ppm (about 340 mg/kg/d), and 16,000 ppm (about 1250 mg/
kg/d). The NOAEL of isoamyl alcohol was concluded to be
4000 ppm in males (340 mg/kg/d) by the authors because the in-
crease of erythrocyte counts at this dose fell within the historical
control range. The NOAEL for females was 16,000 ppm (1250 mg/
kg/d) because the increase in prothrombin time was only seen in fe-
males and fell within the historical control range (Schilling et al.,
1997). Isoamyl alcohol was tested in a 17-week toxicity study with
Ash/CSE rats. The test substance was administered by gavage to 15
male and 15 female rats per group at dose levels of 0 (vehicle), 150,
500, or 1000 mg/kg body weight/day in corn oil. Observations
included mortality, behavior, body weight, food and water con-
sumption, hematology, serum analysis, urinalysis, renal concentra-
tion, organ weights, and gross pathology; microscopic pathology
of 25 organs or tissues on control and top dose only. The only ob-
served effect was a statistically significant reduced body weight
in males at the highest dose level; food intake was reduced, but
not statistically. The NOAEL was 500 mg/kg body weight/day for
males and 1000 mg/kg body weight/day for females (Carpanini
and Gaunt, 1973). Finally, isoamyl alcohol was administered to
male and female Wistar rats as a 2% solution in drinking water
Fig. 2. Metabolism of 4-methyl-2-pentanol in the rat and mouse (OECD/SIDS, (about 2000 mg/kg body weight/day) for 56 weeks. No treatment-
2007).
related effects on body weight, liver weight, ADH, GOT, GPT
activity, and protein content of the liver were found. Histological
treated with 0, 500, or 1000 mg/kg body weight/day. Treatment-
examinations of the livers, hearts, spleens, kidneys, and lungs did
related clinical signs of toxicity were restricted to the skin at the
not show any significant abnormalities (Johannsen and Purchase,
treatment site and included exfoliation (minimal severity) at both
1969).
doses and transient erythema at the high dose. Serum triglycerides
Several studies in mice (gavage, RIFM, 1992a,b) and rats (ga-
were increased in females at both doses. In high-dose females,
vage, RIFM, 1988; Weaver et al., 1989), given 2-ethyl-1-hexanol
peripheral blood lymphocytes and absolute spleen weight were re-
by gavage or drinking water (RIFM, 1988; Weaver et al., 1989),
duced (RIFM, 1988; Weaver et al., 1989).
or feed (RIFM, 1992c) for periods of 9–11 days yielded NOAELs in
Albino rabbits (2/sex/dose) were treated by dermal occluded
the range of 100–150 mg/kg body weight/day. Doses of 330 mg/
application with 0, 400, or 2000 mg/kg body weight/day of isooct-
kg body weight/day and higher resulted in CNS depression, lacri-
anol (alcohols C7–9, branched CAS No. 68526-83-0) for 12 days
mation, decreased food consumption, and body weights. 2-Ethyl-
with 10 applications, lasting 18–24 h each. Control animals re-
1-hexanol was administered by gavage to F344 rats and B6C3F1
ceived isopropyl alcohol. No relevant changes in appearance,
mice of both sexes as an aqueous solution (0, 25, 125, 250, or
behavior, body weight, hematology, and urinalysis were noted in
500 mg/kg body weight/day) for 13 weeks. Histopathology was
treated animals. Necropsy and microscopic evaluation demon-
undertaken on tissues recommended in US EPA guidelines. The
strated no treatment-related findings. Moderate to severe skin irri-
NOAEL was 125 mg/kg body weight/day for rats and mice (Astill
tation at the application site was noted in treated animals with
et al., 1996a). In a carcinogenicity study (see Section 5.4) 2-ethyl-
necrosis in high-dose animals. The systemic NOAEL was
1-hexanol was given to male and female rats and mice by gavage
2000 mg/kg body weight/day (Esso, 1961a, as cited in ExxonMobil
5 times a week in 0.005% aqueous Cremophor EL (rats: 0 (water),
Chemical Company, 2001a).
0 (vehicle), 50, 150, or 500 mg/kg body weight/day, 2 months;
mice: 0 (water), 0 (vehicle), 50, 200, or 750 mg/kg body weight/
5.2.1.2. Secondary alcohols. New Zealand White rabbits (5/sex/dose) day, 18 months). The NOAEL for systemic toxicity for mice was
were treated topically by occlusive application of 0 or 1000 mg/kg 200 mg/kg body weight/day. In rats, the NOAEL for systemic toxic-
body weight/day of 3,4,5,6,6-pentamethylheptan-2-ol for 28 con- ity was 50 mg/kg body weight/day (Astill et al., 1996b).
secutive days at the same site according to OECD test guideline An oral study according to OECD TG 422 (combined repeated
(TG) 410. Severe skin irritation was induced in rabbits receiving dose and reproductive/developmental toxicity screening test) was
1000 mg/kg body weight/day of 3,4,5,6,6-pentamethylheptan-2- conducted with 3,5,5-trimethyl-1-hexanol. Twelve SD (Crj:CD) rats
ol. However, no alterations in general health, hematology, bio- per sex and dose group were gavaged with 0 (vehicle: olive oil), 12,
chemistry, major organ weights, or histopathology were observed. 60, or 300 mg/kg body weight/day. Exposure duration in males was
For systemic effects the NOAEL was 1000 mg/kg body weight/day 46 days and in females from day 14 before mating to day 3 of lacta-
(RIFM, 1985c). tion. Males of all dose groups showed alpha-2u-globulin nephropa-
thy. In males and females dosed with 60 or 300 mg/kg body weight/
5.2.1.3. Tertiary alcohols. No studies are available for the members day, systemic effects were seen, including reduced body weight and
of this subgroup. food consumption. On the basis of these findings, the NOAEL for re-
peated dose toxicity was 12 mg/kg body weight/day for male and
5.2.2. Oral studies female rats (MHW, Japan, 1997b as cited in OECD/SIDS, 2003).
Oral toxicity studies with branched chain saturated alcohols are In a 90-day study according to OECD TG 408 isotridecanol(iso
summarized in Table 3-2. alcohols C11–14, C13 rich, CAS No. 68526-86-3) was administered
orogastrically (gavage) to Sprague–Dawley rats in doses of 0, 100,
5.2.2.1. Primary alcohols. Three repeated dose oral toxicity studies 500, or 1000 mg/kg body weight/day. No effects were observed
were done with isoamyl alcohol. In a 90-day study according to only at the lowest dose. The NOAEL for systemic toxicity was
100 mg/kg body weight/day (Exxon Biomedical Sciences Inc., 1986 cannot be deduced because of the reduction in body weight gain.
as cited in ExxonMobil Chemical Company, 2001b). For males the NOAEL is 11 mg/kg body weight/day.
5.2.2.2. Secondary alcohols. A combined repeated dose and repro- 5.2.2.3. Tertiary alcohols. No data available.
ductive/developmental screening study according to OECD TG
422 is available with 4-hydroxy-4-methyl-2-pentanone,a metabolite 5.2.3. Inhalation studies
of 4-methyl-2-pentanol. Ten rats per sex and group were dosed by Inhalation studies with branched chain saturated alcohols are
gavage with 0, 30, 100, 300, or 1000 mg 4-hydroxy-4-methyl-2- summarized in Table 3-3.
pentanone/kg body weight/day in distilled water. Males were
dosed for 44 days and females from day 14 before mating to day 5.2.3.1. Primary alcohols. Male and female Wistar rats (10/group/
3 of lactation (approximately for 45 days). No effects were noted sex) were exposed 6 h daily on 5 days per week for 90 days to 2-
at 30 mg/kg body weight/day. Males treated with at least ethyl-1-hexanol (purity 99.9%) in concentrations of 15, 40, or
100 mg/kg body weight/day showed male rat-specific alpha-2u- 120 ml/m3 (highest vapor concentration at room temperature).
nephropathy. At both 300 and 1000 mg/kg body weight/day, dele- Neither local nor systemic effects were found. The NOAEL is
terious effects were observed, including dilatation of the distal tu- 120 ml/m3 (Klimisch et al., 1998).
bules and fatty degeneration of the proximal tubular epithelium in Three female Alderly-Park rats exposed in whole body exposure
kidneys in females (300 mg/kg body weight/day) (MHW, Japan chambers for 13 six-hour exposure periods to saturated vapor of a
1997, as cited in OECD/SIDS, 2007). The NOAEL was 100 mg/kg mixture of branched chain alcohols designated isooctan-1-ol
body weight/day due to kidney effects in females at 300 mg/kg (180 ml/m3) showed no adverse effects (Gage, 1970).
body weight/day. The kidney effects in males at 100 mg/kg body
weight are not relevant for humans. 5.2.3.2. Secondary alcohols. A 9-day study in rats (10/sex/group, 5 h/
2,6-Dimethyl-4-heptanol was tested in a 13-week toxicity day, 5 days/week) exposed to 98, 300, or 905 ml/m3 2,6-dimethyl-
study in rats. Male and female animals were fed a diet containing heptan-4-one demonstrated increased liver weights from 300 ml/
the test substance mixed with five parts of microcrystalline cellu- m3 as well as alpha-2u-globulin accumulation in the kidneys of
lose (16/sex/group). The daily intake of the test material was males (Dodd et al., 1987). Considering the increased liver weights
11 mg/kg body weight/day for males and females. Female rats as a sign of enzyme induction, the NOAEL is 98 ml/m3.
showed a statistically significantly lower (12.1%) body weight In a 6-week inhalation study with 2,6-dimethylheptan-4-one,
gain and reduced food efficiency. The authors concluded that the groups of 30 rats (15/sex) were exposed to 0, 125, 252, 534, 925,
reduction in body weight gain was most probably of no toxicolog- or 1654 ml/m3 of 2,6-dimethylheptan-4-one, 7 h/day, 5 days/week
ical significance since the reduction was not associated with other for 6 weeks. Liver and kidney weights were increased at 252 ml/
toxicologically significant differences between test and control ani- m3 in females. At 925 ml/m3 ‘‘increased incidence of minor patho-
mals (Posternak and Vodoz, 1975). Because only the range of body logical change” was reported. At 1654 ml/m3 all females died dur-
weights at the start of the study is given, it is unclear whether the ing the first exposure whereas 12/15 males survived all exposures
animals were adequately randomized to control and test groups at this concentration. Among surviving males at 1654 ml/m3 there
based on body weight. Only one dose was tested, therefore, it can- were no major histopathological changes; ‘‘cloudy swelling” in the
not be judged whether the body weight gain reduction is a sub- liver and the convoluted tubules in the kidneys and lung conges-
stance-induced effect. A NOAEL for this study for the females tion were observed in some surviving males (Carpenter et al.,
Table 2-1
Acute dermal toxicity studies.
Material Species No./dose LD50 mg/kg body weightb References

Subgroup: primary
2-Ethyl-1-butanol Rabbit 4 1260 (95% C.I. 850–1870) Smyth et al. (1954)
Rabbit n.f.i. 2000 Draize et al. (1944)
2-Ethyl-1-hexanol Rabbit 10 >5000 RIFM (1977a)
Rabbit 4 (males) 2380 (95% C.I. 1700–3340) Smyth et al. (1969)
Rabbit 4 >2600 Scala and Burtis (1973)
Isoamyl alcohol Rabbit 10 >5000 RIFM (1976a)
Rabbit 6 4000 RIFM (1979c)
Rabbit 4 (males) 3970 (95% C.I. 2930–5370) Smyth et al. (1969)
Isotridecan-1-ol (isomeric mixture) Rabbit 4 (males) 7070 Smyth et al. (1962)
Rabbit 4 >2600 Scala and Burtis (1973)
2-Methylbutanol Rabbit 4 (males) 3540 Smyth et al. (1962)
Rabbit n.f.i. 3540 RIFM (1979b)
3,5,5-Trimethyl-1-hexanol Rabbit 10 >5000 RIFM (1977a)
Subgroup: secondary
2,6-Dimethyl-4-heptanol Rabbit 20 (males) 4591 (95% C.I. 2036–10,383) Smyth et al. (1949)
4-Methyl-2-pentanol Rabbit 5 3560 (2720–4760) Smyth et al. (1951)
3,4,5,6,6-Pentamethylheptan-2-ol Rat 10 (5/sex) >2000 RIFM (1985a)
Subgroup: tertiary
2,6-Dimethyl-2-heptanol Rabbit 10 >5000 RIFM (1976a)
3,6-Dimethyl-3-octanola Rabbit 8 >5000 RIFM (1973a)
3-Methyloctan-3-ola Rabbit 10 >5000 RIFM (1978c)
n.f.i.: no further information.

a
No relevant use was reported.
b
Units have been converted to make easier comparisons; original units are in the Fragrance Material Reviews.
1953). Considering the increased liver weights as a sign of enzyme There were no exposure-related histopathological effects in the
induction at 250 ml/m3, the NOAEL is 125 ml/m3. kidneys or other organs. The increases in ketone bodies, kidney
Wistar rats were whole body exposed to 0, 211, 825, or 3700 mg weight, and alkaline phosphatase were not considered adverse tox-
4-methyl-2 pentanol/m3 (0, 50.5, 198, or 886 ml/m3) (purity > 98%) icological effects. Therefore, the NOAEL was assessed to be
6 h per day and 5 days per week for 6 weeks, 12 animals per sex 3700 mg/m3 (886 ml/m3) by OECD/SIDs (Blair, 1982 as cited in
and group. In females of all concentration groups and in males OECD/SIDS, 2007). However, since the increase in alkaline phos-
treated with 198 ml/m3 or more, increased levels of ketone bodies phatase in high-concentration females was significantly elevated
in urine were noted. At the highest concentration, absolute kidney the NOAEL is judged to be 198 ml/m3.
weights increased in males and proteinuria was detected; an in- A 14-week inhalation study (equivalent to OECD TG 413) was
crease in serum alkaline phosphatase in females was observed. performed with the metabolite of 4-methyl-2-pentanol and
Table 2-2
Acute oral toxicity studies.
Material Species No./dose LD50 mg/kg body weightb References

Subgroup: primary
2-Ethyl-1-butanol Rat 5 1850 (95% C.I. 1520–2240) Smyth et al. (1954)
Rat n.f.i. 1850 Nishimura et al. (1994) and Bar and
Griepentrog (1967)
Rabbit n.f.i. 1200 Draize et al. (1944)
2-Ethyl-1-hexanol Rat n.f.i. 2049 Nishimura et al. (1994)
Rat 5 2460 (1820–3330) Smyth et al. (1969)
Rat 5-15 3200 Hodge (1943)
Rat males, n.f.i. 7100 (95% C.I. 5500–9199) Shaffer et al. (1945)
Rat 36 total 3290 (95% C.I. 2870–3790) Schmidt et al. (1973)
Rat n.f.i. 3290 (95% C.I. 2870–3790) Bar and Griepentrog (1967) and Dave and
Lidman (1978)
Rat 5 3730 Scala and Burtis (1973)
Isoamyl alcohol Mouse 4 (2/sex) >2000 (pre-screen for micronucleus RIFM (2008)
test)
Rat 5 males 7100 (4820–10400) Smyth et al. (1969)
Rat 4/sex males: 1300 (95% C.I. 670–2410) Purchase (1969)
females: 4000 (95% C.I. 2450–6170)
Rat n.f.i. 4360 Golovinskaia (1976)
Rat n.f.i. 1300 Nishimura et al. (1994)
Rat n.f.i. >5000 RIFM (1979c)
Rabbit 10–35 3438 Munch (1972)
Isodecyl alcohol Rat n.f.i. 6500 Nishimura et al. (1994)
Isotridecan-1-ol (isomeric mixture) Rat 5 males 17,200 Smyth et al. (1962); Nishimura et al. (1994)
Rat 5 4750 (ca) Scala and Burtis (1973)
Rat 3 2000 RIFM (2002a)
Rat n.f.i. >2000 (50% branched, 50% linear ECB (1995) as cited in Greim (2000)
form)
Mouse n.f.i. 6500 RIFM (1963a)
Mouse n.f.i. 7257 (mixture of branched saturated ECB (1995) and Hoechst (1961a) as cited in
primary isomers, purity > 99.7%) Greim (2000)
2-Methylbutanol Rat 5 males 4920 (95% C.I. 3750–6460) Smyth et al. (1962)
Rat n.f.i. 4010 Rowe and McCollister (1982)
Rat 10 (5/sex) 4170 RIFM (1979b)
Rat 10 (5/sex) >5000 RIFM (1985e)
3-Methyl-1-pentanol Mouse 10 >2000 RIFM (1982a)
3,5,5-Trimethyl-1-hexanol Rat 10 2300 (95% C.I. 1700–3100) RIFM (1977a)
Rat n.f.i. >2000 MHW, Japan (1997a) as cited in OECD/SIDS
(2003)
Subgroup: secondary
2,6-Dimethyl-4-heptanol Rat 20 males (5/dose) 3560 (95% C.I. 1430–8860) Smyth et al. (1949)
Rat 32 total (16/sex) 4350 Posternak and Vodoz (1975)
Rat 5–11 6500 McOmie and Anderson (1949)
Mouse 6–14 5000 (95% C.I. 2500–7500) McOmie and Anderson (1949)
3,7-Dimethyl-7-methoxyoctan-2-ol Rat 5/sex 5000 RIFM (1976a)
4-Methyl-2-pentanol Rat n.f.i. 2950 Bar and Griepentrog (1967)
Rat 5 2590 (2260–2970) Smyth et al. (1951)
3,4,5,6,6-Pentamethylheptan-2-ol Rat 10 (5/sex) 5845 (95% C.I. 5360–6375) RIFM (1984a)
Subgroup: tertiary
2,6-Dimethyl-2-heptanol Rat 10 >5000 RIFM (1976a)
Rat n.f.i. 6800 RIFM (1979a)
a
3,6-Dimethyl-3-octanol Rat 10 >5000 RIFM (1973a)
3-Methyloctan-3-ola Rat 10 3400 (95% C.I: 2500–4700) RIFM (1978c)

a
b
Units have been converted to make easier comparisons; original units are in the Fragrance Material Reviews.
4-methyl-2-pentanone. Male and female rats and mice (14 per spe- adults to 1000 and 2000 ml/m3. The systemic NOAEL was 500 ml/m3 in
cies/sex/group) were exposed to 0, 50, 250, or 1000 ml 4-methyl-2- this study. Signs of irritation were not reported (Nemec et al., 2004).
pentanone/m3 (0, 204, 1020, or 4090 mg/m3) 6 h per day and 5 days
per week. Slight, but statistically significant, increases in absolute 5.2.3.3. Tertiary alcohols. No data available.
and relative liver weight were observed in males of both species at
the highest concentration. As there were no histopathological 5.3. Mutagenicity and genotoxicity
changes in the livers observed, the changes were considered to be
of no toxicological relevance. Male rats demonstrated alpha-2u- 5.3.1. In vitro mutagenicity studies
globulin ephropathy. The NOAEL was considered to be 1000 ml/m3 The available studies are summarized in Table 4-1.
(4090 mg/m3) for both species (Phillips et al., 1987).
In a two-generation study with rats with 4-methyl-2-pentanone clin-
5.3.1.1. Indicator studies. In a study of the cytotoxic and genotoxic
ical signs in the form of CNS depression were noted during exposures of
effects of a number of alcohols and ketones, 2-methylbutanol
Table 2-3
Acute inhalation and miscellaneous toxicity studies in animals.
Material Dose route Species No./dose LD50 and/or clinical signs References
Subgroup: primary
2-Ethyl-1-butanol Inhalation, exposure to Rat 6 Maximum time for no death: 8 h Smyth et al. (1954)
concentrated vapors
2-Ethyl-1-hexanol Inhalation, exposure to Rat 6 Maximum time for no death: 8 h Smyth et al. (1969)
concentrated vapors
Whole body exposure for 6 h to Rat, mouse, 10/species No mortality, irritation of eyes, Scala and Burtis (1973)
air bubbled through 2-ethyl-1- guinea pig nose, throat, and respiratory
hexanol to yield a nominal passages, blinking, lacrimation,
chamber concentration of preening, nasal discharge,
227 ml/m3 salivation, gasping, and chewing
movements
Intraperitoneal Rat 5–15 LD50 650 mg/kg body weight Hodge (1943)
Intraperitoneal Rat 5/sex LD50 500–1000 mg/kg body Dave and Lidman (1978)
weight
Intraperitoneal Mouse 5–15 LD50 780 mg/kg body weight Hodge (1943)
Isoamyl alcohol i.v. Mouse Not reported LD50 2.64 mmol/kg body weight Chvapil et al. (1962)
(233 mg/kg body weight)
Isotridecan-1-ol Inhalation, exposure to air Rat 6 rats/14 days No effects RIFM (1963c) and Smyth
(isomeric mixture) saturated with alcohol vapor at et al. (1962)
room temperature for 8 h
Inhalation to 12 ml/m3 Rat, mouse, 10/species No effects Scala and Burtis (1973)
(saturation concentration at guinea pig
30 °C) for 6 h
Intraperitoneal Mouse n.f.i. LD50 600 mg/kg body weight RIFM (1963b)
2-Methylbutanol Intraperitoneal Rat n.f.i. 1000 mg/kg body weight: Haggard et al. (1945)
sedation, irritation of the
peritoneum and injury of the
lungs; 2000 mg/kg body weight:
respiratory arrest and death
Intraperitoneal Mouse 10 (5/sex) LD50 between 200 and RIFM (1979b)
700 mg/kg body weight
Inhalation, saturated Rat n.f.i. No mortality, escape behavior, RIFM (1979b)
atmosphere at 20 °C (calculated: intermittent respiration
10,050 mg/m3 bzw. 2744 ml/m3)
for 7 h
Inhalation, saturated vapor for Rat 6 No mortality Rowe and McCollister
8h (1982)
3-Methyl-1-pentanol Intraperitoneal Mouse 10 LD50 > 250 mg/kg body weight; RIFM (1982a)
P2000 mg/kg body weight:
10/10 animals died within
30 min (respiratory depression)
Subgroup: secondary
2,6-Dimethyl-4-heptanol Inhalation, exposure to Rat 12 No mortality Smyth et al. (1949)
substantially saturated vapor or
cooled mist (400 ml/m3) for 8 h
Inhalation, exposure to a Mouse 10 2.0 mg/l: no mortality McOmie and Anderson
saturated vapor–air mixture for (1949)
12 h
4-Methyl-2-pentanol Inhalation for 8 h at 2000 ppm Rat 6 5/6 animals died within 14 days Carpenter et al. (1949) and
Smyth et al. (1951)
Inhalation exposure to a Mouse 10 Somnolence and anesthesia McOmie and Anderson
saturated vapor–air at 20 °C for Mortality at 10 h (6/10) and 15 h (1949)
4–15 h (8/10)
3,4,5,6,6- Intraperitoneal injection at doses Mouse 2 One death at 1250 mg/kg RIFM (1985d)
Pentamethylheptan-2-ol of 50, 166, 500, 750, 1000, 1250, Clinical signs observed for all
1666, and 3000 mg/kg body mice above 1000 mg/kg
weight

S14
Table 3-1
Repeated dose toxicity studies – dermal.
Material Method Dose Species (No./dose) Results References

Subgroup: primary
2-Ethyl-1-hexanol Single application/day on 2 ml/kg body weight/ Rat (10) Absolute and relative thymus weights decreased, liver Schmidt et al. (1973)
the shaved back for 12 days day (1600 mg/kg body granulomas, bronchiectasis in the lung, renal tubular
weight/day) epithelial necroses, edematous heart and testes and
decreased spermatogenesis
5 days occlusive treatment, 0, 500, or 1000 mg/kg Fischer 344 rat (10/sex) P500 mg/kg body weight/day: exfoliation (minimal RIFM (1988); Weaver et al. (1989)
2 days untreated, 4 days body weight/day severity), spleen weight decreased; serum triglycerides
treated increased (females);
1000 mg/kg body weight: transient erythema (days 4–7)
(graded as barely perceptible), decreased absolute
spleen weight, lymphocytes decreased
Isooctanol (alcohols C7–C9 Occlusive, 18–24 h for 0 (isopropyl alcohol), Rabbit (Albino) (2/sex) Systemic NOAEL: 2000 mg/kg body weight/day 400 mg/ Esso Research and Engineering Company
branched CAS No. 12 days (10 treatments) 400, 2000 mg/kg body kg body weight/day: moderate to severe irritation, (1961) as cited in ExxonMobil Chemical
68526-83-0) weight/day fissure, coriaceous skin Company (2001a)
2000 mg/kg body weight/day:necrosis of the skin
Subgroup: secondary
3,4,5,6,6- Dermal (occlusive), 6 h/day 0 (water), 1000 mg/kg Rabbit (New Zealand Systemic NOAEL: 1000 mg/kg body weight/day RIFM (1985c)
Pentamethylheptan-2-ol for 28 days (OECD TG 410) body weight/day White) (5/sex) 1000 mg/kg body weight/day: (f), severe dermal
reactions: well defined severe erythema and edema,
histopathology of the skin: acanthotic and focal
ulcerative changes of epidermis, associated
inflammation, hyperkeratosis, scab formation
Dermal (occlusive), 6 h/day 30, 100, 300, and Rabbit (New Zealand Systemic NOAEL: 1000 mg/kg body weight/day Slight to RIFM (1986b)
for 28 days 1000 mg/kg/day White) (10/sex) moderate dermal irritation; severe irritation at high (300
and 1000 mg/kg/day) doses; reversible after 8 days
Abbreviations see Table 3-3.

Table 3-2
Repeated dose toxicity studies – oral.

Subgroup: primary
2-Ethyl-1-hexanol Gavage, 5 days/week, 0, 330, 660, 930 mg/kg body Rat (10) 930 mg/kg: body weight on day 17 decreased, mortality: Schmidt et al. (1973)
22 days weight in sunflower oil, 1/10
controls 10 ml oil/kg body
weight
Gavage, 9 treatments in 0, 100, 330, 1000, 1500 mg/ Fischer 344 rat Systemic NOAEL 100 mg/kg body weight/day RIFM (1988); Weaver et al.
11 days kg body weight/day, test (10/sex) 330 mg/kg body weight/day: hypoactivity, ataxia, (1989)
substance undiluted prostration, delayed righting reflex, muscle twitch,
lacrimation, and urine-stained fur. Food consumption and
body weights decreased (males), thymic atrophy and
lymphoid cell degeneration in the thymus;
1000 mg/kg body weight/day: food consumption and body
weights decreased (females), total peripheral blood
leukocytes and lymphocytes, spleen weight decreased
(females), absolute and relative liver weight increased
without histopathological findings, absolute and relative
stomach weight increased with hyperkeratosis, mucosal
hyperplasia, edema, exocytosis, and gastritis;
1500 mg/kg body weight/day: total peripheral blood
leukocytes and lymphocytes, spleen weight decreased
(males), absolute and relative testes weights decreased, no
histopathological findings in testes or kidneys at any dose
Drinking water, 9 days 0, 308 ppm (half-saturated) Fischer 344 rat No adverse effects RIFM (1988); Weaver et al.
and 636 ppm (saturated): (10/sex) (1989)
61.1 and 151.1 mg/kg body
weight/day for males and
73.4 and 173.5 mg/kg body
weight/day for females.
Gavage, 9 doses in 11 d 0, 100, 330, 1000, or B6C3F1 mice Systemic NOAEL 100 mg/kg body weight/day RIFM (1992a)
1500 mg/kg body weight/ (10/sex) 330 mg/kg body weight/day: relative liver and stomach
day, in propylene glycol weights (male) increased;
1000 mg/kg body weight/day: relative liver and stomach
weights (female) increased; 2/20 deaths;
1500 mg/kg body weight/day: ataxia, lethargy, piloerection,
dyspnea, hypothermy, abdominal or lateral position and loss
of consciousness, reduction in food consumption (males),
relative testes weight decreased; clinical chemistry and
hematology no substance-related changes. No

histopathological examinations; 10/20 deaths
Gavage, 9 doses in 11 d 0, 100, 330, 1000, or B6C3F1 mice Systemic NOAEL 100 mg/kg body weight/day RIFM (1992b)
1500 mg/kg body weight/ (10/sex) 300 mg/kg body weight/day: acanthosis with hyperkeratosis
day, in an aqueous emulsion in the forestomach;
in Cremophor EL P1000 mg/kg body weight/day: relative liver (males) and
stomach weights (female) increased, hypertrophy of
hepatocytes; 1/20 deaths;
abdominal or lateral position and loss of consciousness;
clinical chemistry and hematology, no substance-related
changes; 5/20 deaths.
Diet, 11 days 500, 980, 1430, or 2590 mg/ F344 rat (10/sex) NOAEL < 500 (m) or 540 (f) mg/kg bodyweight/day RIFM (1992c)
kg/day (males) 540, 1060, P500 (m) or 540 (f) mg /kg/d: relative stomach weights
1580, or 2820 mg/kg/day increased females (f); triglycerides and alanine
(females) aminotransferase decreased, males (m); feed consumption
significantly decreased (m)

S15
S16
Table 3-2 (continued)

P980 (m) or 1060 (f) mg/kg/d: absolute and relative liver
weights increased (m,f); feed consumption decreased (m, f);
water consumption significantly decreased (f); triglyceride
and alanine aminotransferase decreased (m);
P1430 (m) or 1580 (f) mg/kg/d: food consumption reduced
(m, f), hypertrophy of hepatocytes; body weight significantly
reduced (m); water consumption significantly reduced (m, f);
triglyceride and alanine aminotransferase decreased (males);
2590 (m) or 2820 (f) mg/kg/d: absolute and relative liver
weights increased (m, f);body weight decreased (m, f); feed
consumption decreased (m, f), water consumption
significantly decreased (m, f); triglyceride and alanine
aminotransferase decreased (m, f)
Gavage, 5 days/week, 0, 25, 125, 250 or 500 mg/kg F344 rat, B6C3F1 NOAEL: 125 mg/kg body weight/day, rats and mice Astill et al. (1996a)
13 weeks body weight/day mice (10/sex) P250 mg/kg body weight/day: relative liver, kidney (rats,
both sexes) and stomach weights (female rats) increase, fat
deposits in the liver cells (male rats) decrease, relative liver
and stomach weights (male mice) increased;
500 mg/kg body weight/day: acanthosis of the forestomach
(female mice); peroxisome proliferation (marker: cyanide-
insensitive palmitoyl CoA oxidase) (rats, both sexes) increase
Gavage, 24 months, 0 (water), 0 (vehicle), 50, F344 rats (50/sex) Systemic NOAEL: 50 mg/kg body weight/day Astill et al. (1996b)
5 days/week 150, 500 mg/kg/body P150 mg/kg body weight/day: body weight gain decreased,
weight/day in 0.005% poor clinical state, labored breathing, piloerection or urine-
Cremophor EL stained genital region
3 weeks, oral 833 mg/kg n.f.i. Rat (n = 5) Statistical increase (p < .05) in liver was observed Yamada (1974)
administration
Gavage, 18 months, 0 (water), 0 (vehicle), 50, B6C3F1 mice Systemic NOAEL: 200 mg/kg body weight/day Astill et al. (1996b)
5 days/week 200, 750 mg/kg body (50/sex) 750 mg/kg body weight/day: increased mortality, body
weight/day in 0.005% weight gains decreased, food consumption decreased, fatty
Cremophor EL liver, hyperplasia of the forestomach epithelium
Isoamyl alcohol Drinking water 0, 1000, 4000, 16,000 mg/l Wistar rat (10/sex) NOAEL females = 1280 mg/kg body weight/day Schilling et al. (1997) RIFM
3 months drinking water NOAEL males = 320 mg/kg body weight/day (1991b)
(purity > 98.6%); estimated 1280 mg/kg body weight (males): erythrocyte value
to be: 0, 80, 320, 1280 mg/ increased; mean corpuscular volume (MCV) decreased; mean
kg body weight/day corpuscular hemoglobin (MCH) decreased
320 and 1280 mg/kg/day (females): increased prothrombin

time
Gavage, daily for 0 (vehicle), 150, 500, Ash/CSE rat NOAEL females = 1000 mg/kg body weight/day NOAEL Carpanini and Gaunt (1973)
17 weeks 1000 mg/kg body weight/ (15/sex) males = 500 mg/kg body weight/day
day, in corn oil additional 5 1000 mg/kg body weight/day: males: body weight gain
animals examined decrease
after 3 and
6 weeks,
respectively
Drinking water, 0, 2% (2000 mg/kg body Wistar rat (20/sex) No significant effects Johannsen and Purchase
56 weeks weight/day) (1969)
Neurotoxicity: Whole 3–4 exposures to the Male albino SPF The concentration that evoked a 30% depression in the Frantik et al. (1994)
body exposures with a various solvent rats 16 (4/group) recorded activity was determined to be 1700 ppm
30 min habituation and concentrations (between
4 h exposure 25% and 75%)
Neurotoxicity: Whole 3–4 exposures to various Female mice of the The concentration that evoked a 30% depression in the Frantik et al. (1994)
body exposure with a solvent concentrations H strain 32 recorded activity was determined to be 950 ppm
30 min habituation and (between 25% and 75%) (4/group)
2 h exposure
Isotridecanol (Alcohols, Gavage, 7 days/week, 0 (distilled water), 100, 500, Sprague–Dawley NOAEL: 100 mg/kg body weight/day Exxon Biomedical Sciences
C11–14 iso, C13 for 14 weeks, OECD TG 1000 mg/kg body weight/ rat (20/sex) P500 mg/kg body weight/day: food consumption decreased Inc. (1986) as cited in
rich, CAS No. 68526- 408 day (m), body weight decreased (m), mean platelet counts ExxonMobil Chemical
86-3) increased (f), glucose decreased (f), liver weight increased (m, Company (2001b)
f),
1000 mg/kg body weight/day: glucose decreased (m),
cholesterol decreased (f), rel. brain and testes weight
increased (m), rel. adrenal weight increased (f)
3,5,5-Trimethyl-1- Gavage, males: 14 days 144 mg/kg body weight/day Alderly-Park Increase in the relative liver weight Rhodes et al. (1984)
hexanol Wistar rat No difference from controls in body weight, clinical, or
histopathological signs. Peroxisome proliferation,
hypocholesterolemia, and hypoglyceridaemia were not
evident
Gavage, males: 0, 12, 60, 300 mg/kg body SD (Crj:CD) rat NOAEL systemic toxicity males and females: 12 mg/kg body MHW, Japan (1997b) as
46 days, females: from weight/day in olive oil (12/sex) weight/day cited in OECD/SIDS (2003)
14 days before mating P12 mg/kg body weight/day: renal hyaline droplets,
to day 3 of lactation, eosinophilic bodies (m)
OECD TG 422 P60 mg/kg body weight/day: relative liver and kidney
weight increase (m, f), renal epithelial fatty change (f);
implantation index decreased (f)
300 mg/kg body weight/day: 1 f died, 3 f killed (weakness);
body weights increase (m), food consumption increased (m),
body weights decreased (f), food consumption decrease (f);
total litter loss in 2 dams
Subgroup: secondary
2,6-Dimethyl-4- Diet, 13 weeks 0, 11 (f), 11 (m) mg/kg body Rat (16/sex) No NOAEL (females) based on reductions of body weight gain Posternak and Vodoz (1975)
heptanol weight/day mixed with systemic NOAEL (males): 11 mg/kg body weight;
microcrystalline cellulose 11.06 mg/kg body weight/day: (females) body weight gain
and food efficiency (weight gained (g)/food consumed
(g) 100, 10.8%) decrease (body weight gain 12.1%).
Hematological and histological examinations without any
significant differences between test and control rats
4-Hydroxy-4-methyl-2- Gavage, males: 0, 30, 100, 300, 1000 mg/kg Crj:CD(SD) rat NOAEL: 100 mg/kg body weight/day MHW, Japan (1997) as cited
pentanone 44 days, females: from body weight/day in water (10/sex) P100 mg/kg body weight/day: male alpha-2u-nephropathy in OECD/SIDS (2007)
14 d before mating to P300 mg/kg body weight/day: locomotor activity and
day 3 of lactation stimulation response decrease (m, f); dilatation of the distal
(approx. 45 days), tubules and fatty degeneration of the proximal tubular
OECD TG 422 epithelium in kidneys (f)
P1000 mg/kg body weight/day: hepatocellular hypertrophy
(m, f), altered blood parameters (increase: platelet counts,
GOT, total protein, total cholesterol, total bilirubin, blood

urea nitrogen, creatinine, calcium (m); decrease: glucose)
(m), dilatation of distal tubules of kidneys (m), vacuolization
of the zona fasciculata of the adrenals (m); body weight gain
decrease (f), rel. liver weight increase (f)
Abbreviations see Table 3-3.

S17
and isoamyl alcohol were tested for their potency to induce DNA xy-4-methyl-2-pentanone, tested for chromosomal aberrations in
damage in V79 Chinese hamster fibroblasts, human lung carci- Chinese hamster lung cells, revealed significantly increased poly-
noma epithelial A549 cells and human peripheral blood cells with ploidy in the two highest doses (600 and 1200 lg/ml). Information
the alkaline comet assay. In V79 and A549 cells 2-methylbutanol as to whether this was done with or without S9 was not available.
and isoamyl alcohol showed DNA damage only at cytotoxic con- This test was considered negative because a trend test showed no
centrations. The COMET assay could not be performed in human dose-dependency (MHW, Japan, 1997 as cited in OECD/SIDS, 2007).
peripheral blood cells due to extreme cytotoxicity (cells with com-
pletely fragmented DNA) (Kreja and Seidel, 2001, 2002). 5.3.1.4. Micronucleus studies. The primary alcohols 2-methylbuta-
2-Methylbutanol and isoamyl alcohol gave negative results in a nol and isoamyl alcohol did not induce micronuclei in V79 Chinese
light absorption umu test and positive results in a luminescent hamster fibroblasts, with or without addition of hepatic S9 mix
umu test (Nakajima et al., 2006). These tests are based on the abil- from Aroclor induced rats (Kreja and Seidel, 2002).
ity of DNA damaging agents to induce expression of the umu oper-
on, which is responsible for chemical and radiation mutagenesis, in 5.3.2. In vivo studies
Escherichia coli. The positive result is not plausible in view of the The available studies are summarized in Table 4-2. No indica-
other negative tests for genotoxicity (see below) and the overall tion for a covalent binding of 2-ethyl-1-hexanol to liver DNA of rats
negative results for branched chain saturated alcohols. 2-Ethyl-1- and mice was noted (Albro et al., 1982; Däniken et al., 1984). 2-
hexanol gave a negative and a positive result in two rec-assays Ethyl-1-hexanol was not mutagenic in the dominant lethal test
(Saido et al., 2003; Tomita et al., 1982). The results of this test sys- (Rushbrook et al., 1982; only as abstract) and not clastogenic in a
tem are not considered for the evaluation of the genotoxicity of the bone marrow chromosome aberration test (Putman et al., 1983),
alcohols under study because positive results were often assessed although this result is not reliable because the doses used failed
with substances, which were negative in other genotoxicity test to induce toxicity. 2-Ethyl-1-hexanol (Astill et al., 1986; Barber
systems. A test for induction of unscheduled DNA synthesis with et al., 1985; only as abstract, no information on the method, and
2-ethyl-1-hexanol was negative in primary rat hepatocytes (Hodg- validity cannot be assessed) and 3,4,5,6,6-pentamethylheptan-2-
son et al., 1982). ol were not clastogenic in the mouse bone marrow micronucleus
4-Methyl-2-pentanone was negative in a vitro UDS test (no fur- test (RIFM, 1985d). Isoamyl alcohol showed an increase in chromo-
ther information; IPCS, 1990 as cited in OECD/SIDS, 2004). somal aberrations in bone marrow cells of rats (Barilyak and Koza-
chuk, 1988). The study is invalid as no information is available if a
5.3.1.2. Mutation studies. The primary alcohols 3,5,5-trimethyl-1- positive control group was used, the definite dose was not men-
hexanol, 2-ethyl-1-hexanol, isotridecan-1-ol (isomeric mixture), tioned (1/5 of LD50), only one dose was tested, the control animals
the secondary alcohols 4-methyl-2-pentanol, its metabolites 4- did not show any chromosomal aberrations, and the purity of the
methyl-2-pentanone and 4-hydroxy-4-methyl-2-pentanone, 2,6-di- substance was not given. The authors also found chromosomal
methyl-4-heptanol and its metabolite 2,6-dimethylheptan-4-one, aberrations with propanol, which was not genotoxic in a variety
as well as a mixture of the secondary alcohol 3,4,5,6,6-pentameth- of tests (Greim, 1996). An in vivo mouse micronucleus assay was
ylheptan-2-ol (55–80%) and 3,4,5,6,6-pentamethylheptan-2-on conducted on isoamyl alcohol (RIFM, 2008) at doses of 500, 1000,
(20-45%) were inactive in Ames tests. Urine from Sprague–Dawley and 2000 mg/kg there was no increase in the frequency of detected
rats dosed by oral gavage for 15 days with 1000 mg 2-ethyl-1-hex- micronuclei. Isoamyl alcohol was determined to be non-mutagenic
anol/kg body weight/day was found to be non-mutagenic in Salmo- in the micronucleus assay.
nella typhimurium with and without addition of rat liver Additionally, 4-methyl-2-pentanone was negative in an in vivo
microsomes or beta-glucuronidase/arylsulfatase (DiVincenzo micronucleus test (no further information; IPCS, 1990 as cited in
et al., 1983, 1985). 2-Ethyl-1-hexanol was mutagenic in S. typhimu- OECD/SIDS, 2004).
rium TA100 using the mutation to resistance to 8-azaguanine (Seed,
1982). As this test was performed only in one S. typhimurium strain 5.4. Carcinogenicity
and the other mutagenicity tests using reversion to histidine inde-
pendence were negative, this result seems to be of limited The available carcinogenicity studies are summarized in Tables
relevance. 5-1.
The primary alcohols 2-methylbutanol, isoamyl alcohol, and 2-
ethyl-1-hexanol were also inactive in mammalian cell systems 5.4.1. Cell transformation assays
(TK+/ mouse lymphoma mutagenicity assay in L5178Y cells or In a cell transformation study with mouse epidermis-derived
HPRT assay with Chinese hamster V79 fibroblast cells) (Kirby JB6 cells 2-ethyl-1-hexanol did not promote JB6 cells to anchorage
et al., 1983; Kreja and Seidel, 2002). For 4-methyl-2-pentanone, a independence (Ward et al., 1986). A cell transformation assay with
mouse lymphoma test was considered equivocal (no further infor- BALB 3T3 cells did not induce a significant number of transformed
mation; IPCS, 1990 as cited in OECD/SIDS, 2004). foci (Barber et al., 1985; RIFM, 1983b).
A Saccharomyces cerevisiae mitotic gene conversion assay was
negative for 2,6-dimethylheptan-4-one (OECD/SIDS, 2004). 5.4.2. Carcinogenicity studies
The secondary alcohol 4-methyl-2-pentanol tested for gene 2-Ethyl-1-hexanol was given to male and female rats and mice
mutation in Saccharomyces cerevisiae gave negative results (Clare, by gavage 5 times a week in 0.005% aqueous Cremophor EL (rats: 0
1983 as cited in OECD/SIDS, 2007). (water), 0 (vehicle), 50, 150, 500 mg/kg body weight/day,
24 months; mice: 0 (water), 0 (vehicle), 50, 200, 750 mg/kg body
5.3.1.3. Chromosome aberration studies. The primary alcohols 2- weight/day, 18 months). The incidences of carcinomas and baso-
ethyl-1-hexanol and 3,5,5-trimethyl-1-hexanol as well as the sec- philic foci in the liver increased in female mice with the dose
ondary alcohol 4-methyl-2-pentanol and 2,6-dimethylheptan-4- and attained statistical significance in the highest dose group com-
one, did not induce chromosome aberrations in vitro when incu- pared with the vehicle control group but not with the water con-
bated with Chinese hamster ovary, Chinese hamster lung or rat li- trol group. The time-adjusted incidence of hepatocellular
ver cells (Brooks et al., 1985 as cited in OECD/SIDS, 2004; Brooks carcinomas in female mice (13.1%) was outside the normal range
et al., 1988; Clare, 1983 as cited in OECD/SIDS, 2007; MHW, Japan, (0–2%), but in male mice (18.8%) was within the historical control
1997d as cited in OECD/SIDS, 2003; Phillips et al., 1982). 4-Hydro- range at the testing facility (0–22%). No adenomas were observed.
Table 3-3
Repeated dose toxicity studies – inhalation.
Material Method Concentration Species (No./dose) Results References

Subgroup: primary
2-Ethyl-1-hexanol OECD TG 413 90 days, 0, 15, 40, or 120 ml/m3 Wistar rat (10/sex) Local and systemic NOAEL: 120 ml/m3 Klimisch et al. (1998)
6 h/day, 5 days/week (highest vapour
concentration at room
temperature), purity: 99.9%
Isooctanol 13 days, 6 h/day 180 ml/m3 (highest vapour Alderly-Park rat (3 f) No mortality, clinical signs, autopsy findings and Gage (1970)
concentration at room histopathological changes
temperature)
Subgroup: secondary
2,6-Dimethylheptan-4-one 2 weeks, 5 h/day, 0, 98, 300, 905 ml/m3 Rats (10/sex) NOAEL: 98 ml/m3 Dodd et al. (1987)
5 days/week P 300 ml/m3: liver weight increased, alpha-2u-
globulin accumulation in the kidneys (m)
6 weeks, 7 h/day, 0, 125, 252, 534, 925, Rat (15/sex) NOAEL: 125 ml/m3 Carpenter et al. (1953)
5 days/week 1654 ml/m3 125 ml/m3: No adverse effects 252 ml/m3: Liver and
kidney weights increased (f)
534 ml/m3: Liver and kidney weights increased
(m + f)
925 ml/m3: Liver and kidney weights increased
(m + f)
1654 ml/m3: Mortality in all females and 3/15
males. Surviving males: body weight gain
decreased and liver and kidney weights increased
4-Methyl-2-pentanone 14 weeks, 6 h/day, 0, 50, 250, 1000 ml/m3 Fischer 344 rat (14/sex) NOAEL: 250 ml/m3 Phillips et al. (1987)
5 days/w (OECD TG (0, 204, 1020, 4090 mg/m3) P250 ml/m3: hyaline droplets in proximal tubular
413) cells (m)
1000 ml/m3: abs. and rel. liver weight (slight but
statistically significant) increase (m)
14 weeks, 6 h/day, 0, 50, 250, 1000 ml/m3 B6C3F1 mouse (14/sex) NOAEL: 50 ml/m3 1000 ml/m3: abs. and rel. liver Phillips et al. (1987)
5 days/w (OECD TG (0, 204, 1020, 4090 mg/m3) weight (slight but statistically significant) increase
413) (m)
4-Methyl-2-pentanol 12 4-h-exposures 0, 20,000 mg/m3 Mouse (9) Unclear description of effects, unclear extent of McOmie and Anderson (1949)
histopathology
6 weeks, 6 h/day, 0, 50.5, 198, 886 ml/m3 Wistar rat (12/sex) NOAEL: 198 ml/m3 Blair (1982) as cited in OECD/
5 days/w (OECD TG (0, 211, 825, 3700 mg/m3) P50.5 ml/m3: concentration of ketone bodies in SIDS (2007)
407) urine increased (f)
P198 ml/m3: concentration of ketone bodies in
urine increased (m)
886 ml/m3: abs. kidney weight increased (m),
serum alkaline phosphatase increased (f)
ADH: alcohol dehydrogenase, BUN: blood urea nitrogen, GOT: glutamate oxalacetate transaminase (now renamed: AST aspartate aminotransferase), GPT: gutamate pyruvate transaminase (now renamed: ALT alanine amino-
transferase), f: female, m: male, n.f.i.: no further information, n.s.: not statistically significant, s.a.: see above, s.c.: subcutaneous.
S19
The number of basophilic liver foci was increased in male mice in information) at the highest dose of 1000 mg/kg body weight/day.
the mid dose group only. The authors considered the liver tumors Therefore the NOAEL for fertility was 300 mg/kg body weight/day
in the mouse to be inconclusive because the incidence of hepato- (MHW, Japan, 1997 as cited in OECD/SIDS, 2007).
carcinoma precursors did not significantly increase with the dose. 2,6-Dimethyl-4-heptanol showed no effects on the reproductive
Nevertheless, they concluded that 2-ethylhexanol is weakly or organs of rats in a 13-week feeding study with the only tested dose
questionably carcinogenic for the female mouse. Under the condi- of 11 mg/kg body weight/day (Posternak and Vodoz, 1975). Its
tions of this study 2-ethyl-1-hexanol was not oncogenic to rats. metabolite 2,6-dimethylheptane-4-one given by gavage has been
Doses of 150 and 500 mg/kg body weight/day led to reduced body assessed in a reproduction/developmental toxicity screen (OECD
weight gains and in some animals to lethargy and unkemptness TG 421) and did not lead to reproductive effects up to the highest
which proves that the maximum tolerated dose was reached. At tested dose of 1000 mg/kg body weight/day (Shell HSE, 1996 as ci-
the end of the study the mortality was about 52% in the high-dose ted in OECD/SIDS, 2004).
group females and about 28% in the other groups (Table 5-1; Astill 5.5.1.4.3. Tertiary alcohols. No studies were available.
et al., 1996b).
5.5.1.5. Inhalation.
5.5. Reproductive and developmental toxicity
5.5.1.5.1. Primary alcohols. In a 90-day inhalation study in rats,
no effects on the reproductive organs were seen at concentrations
5.5.1. Fertility
up to 120 ml/m3 2-ethyl-1-hexanol (Klimisch et al., 1998).
5.5.1.1. In vitro. 2-Ethyl-1-hexanol (200 lM for 24 h) had no effect
5.5.1.5.2. Secondary alcohols. With 4-methyl-2-pentanone, the
on lactate and pyruvate production by Sertoli-cell-enriched cul-
metabolite of 4-methyl-2-pentanol, a two-generation study per-
tures derived from 28-day old Sprague–Dawley rats, whereas
formed in Sprague–Dawley rats (30/sex/group) exposed to 0, 500,
phthalate monoesters known to cause testicular atrophy in vivo in-
1000, or 2000 ml/m3 (0, 2050, 4090, or 8180 mg/m3), for 6 h per
creased Sertoli cell lactate production and lactate/pyruvate ratio
day, 7 days per week. Treatment started 70 days prior to mating
(Moss et al., 1988).
for the F0 and F1 generations, continued to the end of the mating
In an in vitro model of rat seminiferous tubules 200 lM 2-ethyl-
period for males and to day 20 of gestation for females. Treatment
1-hexanol did not induce dissociation of germinal cells from Sertoli
of females resumed at day 5 of lactation. Because of CNS depres-
cells (Gangolli, 1982).
sion in F1 pups upon initiation of exposures on post-natal day 22
Ethyl-1-hexanol (200 lM for 24 or 48 h) did not result in an in-
and the death of one F1 male pup from the 2000 ml/m3 group,
crease of germ-cell detachment in rat testicular-cell cultures (Gray,
treatment was interrupted and continued on day 28. In males of
1986; Gray and Beamand, 1984; Sjoberg et al., 1986).
all exposure groups alpha-2u-globulin nephropathy was observed.
F0 and F1 adults of the mid and high exposure groups showed a
5.5.1.2. In vivo. In vivo studies of reproductive and developmental
sedative effect, which was reversible 1 h after exposure. Decreased
toxicity of the branched chain saturated alcohols are summarized
body weight gain and slightly decreased food consumption during
in Tables 6-1 (dermal), 6-2 (oral), and 6-3 (inhalation).
the first 2 weeks of exposure occurred only at the high concentra-
tion in both generations. There were no effects on reproductive and
5.5.1.3. Dermal. Effects on the reproductive organs of rats treated
developmental parameters, or on estrous cycle and sperm param-
dermally with 1000 mg 3,4,5,6,6-pentamethylheptan-2-ol/kg body
eters. The NOAEL for systemic toxicity was established at 1000 ml/
weight/day for 28 days did not occur (see also Section 5.2.1; RIFM,
m3 (4090 mg/m3) due to slightly reduced body weight and feed
1985c).
consumption at 2000 ml/m3. The NOAEL for reproductive toxicity
was 2000 ml/m3 (8180 mg/m3) (Nemec et al., 2004). In view of
5.5.1.4. Oral.
the clinical signs of CNS depression of adults during the exposures
5.5.1.4.1. Primary alcohols. 2-Ethyl-1-hexanol administered by
at 1000 and 2000 ml/m3 the systemic parental NOAEL is 500 ml/
gavage, 167 mg/kg body weight/day, had no effects on Sertoli cells
m3.
and gonocytes of 3-day old CD Sprague–Dawley rats (4/group) (Li
Histopathological examinations in the 6-week inhalation study
et al., 2000). Daily gavage doses of 2.7 mmol 2-ethyl-1-hexanol/
with 4-methyl-2-pentanol (Blair, 1982 as cited in OECD/SIDS,
kg (350 mg/kg body weight) of for 5 days did not induce testicular
2007) showed no adverse effects on the reproductive organs of
damage in 35-day old male Sprague–Dawley rats (Sjoberg et al.,
male and female rats up to the highest concentration tested
1986).
(886 ml/m3). For further details see Section 5.2.1.2.
In a 90-day gavage systemic toxicity study no effects on repro-
ductive organs of rats and mice were noted up to doses of 500 mg 5.5.1.5.3. Tertiary alcohols. No studies were available.
2-ethyl-1-hexanol/kg body weight/day (see Section 5.2.1.1, Astill
et al., 1996a). 5.5.2. Developmental toxicity
In combined repeated dose and reproductive/developmental 5.5.2.1. Dermal. 2-Ethyl-1-hexanol (99.72% pure) was administered
toxicity screening test (OECD TG 422) with gavage application on the clipped dorsal skin by occlusive cover to F344 rats 6 h per
of3,5,5-trimethyl-1-hexanol (see Section 5.2.1.1) no effects on fer- day from gestation days 6–15 at doses of 0, 0.5, 1.0, 2.0, or
tility were observed in males. In females a dose dependent de- 3.0 ml/kg body weight/day (0, 420, 840, 1680, or 2520 mg/kg body
crease in implantation index was noted in the 60 and 300 mg/kg weight/day) in a range-finding study (8/group). In the main study
group (MHW, Japan, 1997b as cited in OECD/SIDS, 2003). Based (25/group) doses of 0, 0.3, 1.0, and 3.0 ml/kg body weight/day (0,
on these findings, the NOAELs for fertility were 12 mg/kg body 252, 840, or 2520 mg/kg body weight/day) were applied. Persistent
weight/day for females and 300 mg/kg body weight/day for males. exfoliation, crusting, and erythema on the application site were
5.5.1.4.2. Secondary alcohols. In the combined repeated dose seen in both studies from 840 mg/kg body weight/day. Maternal
and reproductive/developmental toxicity screening test (OECD TG weight gain was reduced at 1680 and 2520 mg/kg body weight/
422) with gavage application of 4-hydroxy-4-methyl-2-pentanone day. The NOAELs for maternal toxicity were 252 mg/kg body
(see Section 5.2.1.1), a metabolite of 4-methyl-2-pentanol, no sta- weight/day based on skin irritation and 840 mg/kg body weight/
tistically significant changes in any reproductive parameter at any day based on systemic toxicity. The developmental NOAEL was
dose were noted. According to the authors there was a tendency for the highest tested dose of 2520 mg/kg body weight/day (Fisher
lower reproductive indices (fertility and implantations, no further et al., 1989; Tyl et al., 1992).
Table 4-1
Mutagenicity and genotoxicity: in vitro studies.
Material Test system Concentration Results References

Subgroup: primary
2-Ethyl-1-hexanol Rec-assay Bacillus subtilis H17, M45 500 lg/disk in DMSO Negative Tomita et al. (1982)
Rec-assay Bacillus subtilis HA101, Rec-4 Diluted in DMSO to make the Positive Saido et al. (2003)
inhibition circle between I.D. 9 and
40 mm
Ames assay with and without S9 S. typhimurium TA98, TA100, TA1537, 1–1000 lg/plate in DMSO, growth Not mutagenic Shimizu et al. (1985)
activation (preincubation method) TA1538, TA 1535, E. coli WP2uvrA inhibition P500 lg/plate
Ames assay with and without S9 S. typhimurium TA98, TA100, TA1535, 3.3–333 lg/plate in DMSO Not mutagenic Zeiger et al. (1982)
activation (preincubation method) TA1537
Ames assay with and without S9 S. typhimurium TA98, TA100, TA1535, 3.3–220 lg/plate in DMSO Not mutagenic Zeiger et al. (1985)
activation (preincubation method) TA1537
Ames assay with and without S9 S. typhimurium TA98, TA100, TA1535, 100–2000 lg/plate in DMSO, tested Not mutagenic Agarwal et al. (1985)
activation (preincubation method) TA1537, 1538, 2637 up to cytotoxic concentrations
Ames assay with and without S9 S. typhimurium (unspecified) n.f.i. Not mutagenic Barber et al. (1985)
activation (method unspecified)
Ames assay with and without S9 S. typhimurium TA98, TA100, TA1535, 0.01–1.0 ll/plate in DMSO, cytotoxic Not mutagenic Kirby et al. (1983)
activation (preincubation method) TA1537, 1538 concentration P1.0 ll/plate
Ames assay with and without S9 S. typhimurium TA98, TA100 0.1–10.0 lM, n.f.i. Not mutagenic Warren et al. (1982)
activation (preincubation method)
L5178Y TK+/ mouse lymphoma L5178Y mouse lymphoma cells 0.013–1.0 ll/ml in DMSO, cytotoxic Not mutagenic Kirby et al. (1983)
mutagenicity assay concentration P1.0 ll/ml
8-Azaguanine resistance assay S. typhimurium TA100 0.5–1.5 lM, n.f.i. Mutagenic Seed (1982)
UDS assay Primary rat hepatocytes cultures Cells were treated simultaneously Did not induce detectable levels of Hodgson et al. (1982)
prepared from Fischer 344 rats with test compound and tritiated UDS
thymidine for 1 h, n.f.i.
Chromosomal aberration assay Chinese hamster ovary cells 1.5–2.8 mM Did not induce an increased Phillips et al. (1982)
frequency of chromosomal
aberrations compared to the control;
50% kill at 2.5 mM
Urine of 2-ethyl-1-hexanol Ames assay with and without S9 S. typhimurium TA98, TA100, TA1535, Up to 2 ml undiluted urine, negative Not mutagenic DiVincenzo et al. (1985)
treated rats (1000 mg/kg activation (standard plate assay) TA1537, TA 1538 and positive controls: urine of
body weight for 15 days) untreated rats and
8-hydroxyquinoline
Isoamyl alcohol Comet assay Chinese hamster V79 fibroblast cells, 0, 23, 46, 91 mM DNA damage at at cytotoxic Kreja and Seidel (2001, 2002)
human lung carcinoma epithelial cell concentrations (91 mM in V79 and
line A549, and human peripheral A549 cells), extremely cytotoxic in pB
blood cells (pB) (analyses not possible)
umu test: Light absorption S. typhimurium TA1535/pSK1002 Concentrations in which growth Negative Nakajima et al. (2006)
inhibition 650% (n.f.i.)
umu test: Luminiscent S. typhimurium TA1535/pTL210 concentrations in which growth Positive
inhibition 650% (n.f.i.)
Micronucleus test with and without Chinese hamster V79 fibroblast cells 0, 5, 9, 23 mM Not genotoxic Kreja and Seidel (2002)
S9 activation
HPRT test with and without S9 Chinese hamster V79 fibroblast cells Up to 51.5 mM (highest non-toxic Not mutagenic Kreja and Seidel (2002)
activation concentration)
Isotridecan-1-ol (isomeric Ames assay with and without S9 S. typhimurium TA98, TA100, TA1535, 20-5000 lg/plate no cytotoxicity Not mutagenic RIFM (1989)
mixture) activation TA1537
2-Methylbutanol umu test: Light absorption S. typhimurium TA1535/pSK1002 Concentrations in which growth Negative Nakajima et al. (2006)
umu test: Luminiscent S. typhimurium TA1535/pTL210 inhibition 650% (n.f.i.) Positive
Comet assay Chinese hamster V79 fibroblast cells, 0, 45, 90 mM DNA damage at cytotoxic Kreja and Seidel (2001, 2002)
human lung carcinoma epithelial cell concentrations (45 mM in A549,
line A549, and human peripheral 90 mM in V79 cells), extremely
blood cells (pB) cytotoxic in pB (analyses not
possible)

S21
S22
Material Test system Concentration Results References

Micronucleus test with and without Chinese hamster V79 fibroblast cells 0, 23, 45 mM Not genotoxic Kreja and Seidel (2002)
S9 activation
HPRT test with and without S9 Chinese hamster V79 fibroblast cells Up to 46 mM (highest non-toxic Not mutagenic Kreja and Seidel (2002)
activation concentration)
3,5,5-Trimethyl-1-hexanol Ames assay (preincubation assay) S. typhimurium TA98, TA100, TA1535, up to 500 lg/plate cytotoxicity: Not mutagenic MHW, Japan (1997c) as cited
with and without metabolic TA1537, E. coli WP2uvrA P150 lg/plate (±S9) in OECD/SIDS (2003)
activation OECD TG 471, 472
Chromosomal aberration and Chinese hamster lung cells (CHL/IU) up to 100 lg/ml cytotoxicity: Not genotoxic MHW, Japan (1997d) as cited
polyploidy OECD TG 473 200 lg/ml in OECD/SIDS (2003)
Subgroup: secondary
2,6-Dimethyl-4-heptanol Ames assay with and without S9 S. typhimurium TA98, TA100, TA1537, 3.33–1000 lg/plate with S9 mix in Not mutagenic Mecchi (2002) as cited in
activation (standard plate assay) TA1538, TA 1535, E.coli WP2uvrA DMSO, DOW (2003)
1.00–500 lg/plate iwith S9 mix in
DMSO, cytotoxic concentration:
P333 lg/plate
2,6-Dimethylheptan-4-one Mitotic gene conversion assay with Saccharomyces cerevisiae 0.01–5.0 mg/ml, cytotoxicity at Negative Mortelmans et al. (1986)
and without S9 0.5 mg/ml with S9, at 5.0 without S9
Ames assay with and without S9 S. typhimurium TA98, TA100, TA1535, 31.25-4000 lg/plate in DMSO, Not mutagenic Brooks et al. (1985) as cited
activation (standard plate assay) TA1537, TA 1538, E.coli WP2uvrA cytotoxic concentration: P500 lg/ in OECD/SIDS (2004) Brooks
plate et al. (1988)
Ames assay with and without S9 S. typhimurium n.f.i. 1–333 lg/plate, no cytotoxicity Not mutagenic Mortelmans et al. (1986)
activation (standard plate assay) observed
Cytogenetic assay Rat liver cell (RL4) 62.5–500 lg/ml, cytotoxicity at the No increased incidence of Brooks et al. (1985) as cited
highest dose level tested chromosome aberrations in OECD/SIDS (2004) Brooks
et al. (1988)
4-Hydroxy-4-methyl-2- Ames assay with and without S. typhimurium TA98, TA100, TA1535, 313–5000 lg/plate no cytotoxicity Not mutagenic MHW, Japan (1997) as cited
pentanone metabolic activation TA1537, E. coli WP2uvr A was observed in OECD/SIDS (2007)
Chromosomal aberrations and Chinese hamster lung cells (CHL/IU) 300–1200 lg/ml no cytotoxicity polyploidy increase at 600 and MHW, Japan, 1997, as cited
polyploidy OECD TG 473 observed at the highest concentration 1200 lg/ml, without dose- in OECD/SIDS (2007)
dependence not genotoxic
4-Methyl-2-pentanone UDS n.f.i. n.f.i. Negative IPCS, 1990 as cited in
OECD/SIDS (2004)
Ames assay n.f.i. n.f.i. Negative IPCS (1990) as cited in
OECD/SIDS (2004)
Mouse lymphoma test n.f.i. n.f.i. Equivocal IPCS (1990) as cited in

OECD/SIDS (2004)
4-Methyl-2-pentanol Ames assay with and without S9 S. typhimurium TA98, TA100, TA1535, up to 5000 lg/plate cytotoxicity: Not mutagenic Shimizu et al. (1985)
activation TA1537, TA1538, E. coli WP2uvr A 5000 lg/plate (±S9)
Ames assay with and without S. typhimurium TA98, TA100, TA1535, 31.25–4000 lg/plate no cytotoxicity Not mutagenic Clare (1983) as cited in
metabolic activation TA1537, TA1538, E. coli WP2 uvr A was observed OECD/SIDS (2007)
pkm 101
Gene mutation with and without Saccharomyces cerevisiae JD1 10–5000 lg/plate cytotoxicity: Not mutagenic Clare (1983) as cited in
metabolic activation 5000 lg/plate OECD/SIDS (2007)
Cytogenetic assay Rat liver cell (RL4) 0, 0.5, 1, 2 mg/ml no cytotoxicity was Negative Clare (1983) as cited in
observed OECD/SIDS (2007)
3,4,5,6,6- Ames assay with and without S. typhimurium TA98, TA100, TA1535, 1. test: up to 1000 lg/plate Not mutagenic RIFM (1985b)
Pentamethylheptan-2-ol metabolic activation (plate TA1537, TA1538, E. coli WP2 uvrA 2. test: up to 100 lg/plate
(55–80%) and 3,4,5,6,6- incorporation test) cytotoxicity: P500 lg/plate
pentamethylheptan-2-
on (20–45%)
DMSO: dimethylsulfoxide, n.f.i.: no further information, n.s.: not statistically significant.

Table 4-2
Mutagenicity and genotoxicity: in vivo studies.
Material Test system Species (No./dose) Dose/Concentration Results References

Subgroup: primary
2-Ethyl-1-hexanol DNA binding in vivo by [14C] labeled 2 Female Fischer 344 rats Diet containing 1% di(2-ethylhexyl) No indication for a covalent binding Däniken et al. (1984)
2-ethyl-1-hexanol; 16 h after the and 2 female NMRI mice phthalate (rat) or di(2-ethylhexyl) adipate of 2-ethyl-1-hexanol to liver DNA of
administration of the radiolabeled (mouse) for 4 weeks; radiolabeled [14C] 2- rats or mice; most if not all
test substance: isolation of liver DNA ethyl-1-hexanol was administered by radioactivity in liver DNA was due to
and analyzing for radioactivity gavage (rat: 51.1 or 53.4 mg/kg body biosynthetic incorporation
weight; mouse: 120.2 or 109.5 mg/kg
body weight)
DNA binding in vivo by [14C] labeled Male Fischer rat, n.f.i. Animals were fed a diet containing 1% No binding of the labeled test Albro et al. (1982)
2-ethyl-1-hexanol, 24 h after the di(2-ethylhexyl) phthalate for 11 days ad substance to liver DNA
administration of the radiolabeled libitum. On day 10 they were given a
test substance: isolation of liver DNA single oral dose of 100 lCi [1-14C] 2-ethyl-
and analyzing for radioactivity 1-hexanol and on day 11 they were
sacrificed
Bone marrow micronucleus assay, B6C3F1 mouse, n.f.i. Test protocol according to standard tests Not genotoxic, n.f.i. Astill et al. (1986); Barber et al.
n.f.i. performed by Litton Bionetics Inc., n.f.i. (1985)
Cytogenetic assay with bone marrow 5 Fischer 344 rat/group Oral gavage for 5 consecutive days with No increase in chromatid and Putman et al. (1983)
cells 0.02, 0.07, and 0.21 ml/kg body weight/ chromosome breaks compared to the
day (17, 58, 174 mg/kg body weight/ controls; mitotic index was not
day) = up to 1/10 of the 5-day-LD50 affected, no toxicity observed, no
reliable negative result
Dominant lethal test Male ICR/SIM mouse n.f.i. 250, 500, and 1000 mg/kg body weight/ No dominant lethal mutations; Rushbrook et al. (1982)
day (based on 5-day-LD50) for 5 fertility indices and average numbers
consecutive days, after treatment each of dead and total implants per
male was housed with 2 virgin femals per pregnancy were within the normal
week for 8 consecutive days, sacrifice of range
the females on days 14–17 of caging with
the males; positive control:
trimehtylenemelamine
Isoamyl alcohol Micronucleus Test with bone marrow NMRI mice (5/sex/dose) 500, 1000, or 2000 mg/kg body weight/ Non-mutagenic RIFM (2008)
cells day
Subgroup: secondary
4-Methyl-2-pentanone Micronucleus test n.f.i. n.f.i. Negative IPCS (1990) as cited in OECD/
SIDS (2004)
3,4,5,6,6- Bone marrow micronucleus assay Mouse (5/sex/dose) 0, 900 mg/kg body weight in corn oil Not genotoxic PCE/NCE reduced 48 RIFM (1985d)
Pentamethylheptan-2-ol (i.p.), sacrified: 30, 48, 72 h after and 72 h after dosing
application
n.f.i.: no further information, PCE: polychromatic erythrocytes, NCE: normochromatic erythrocytes.

S23
5.5.2.2. Oral. weight/day. No maternal toxicity was observed and the birth rate
5.5.2.2.1. Primary alcohols. Wistar rats were given a single dose was 93–96% in all groups. All of the litters survived and all gesta-
of 6.25 or 12.5 mmol 2-ethyl-1-hexanol/kg body weight (833 or tional parameters were normal. There were no external, visceral,
1666 mg/kg body weight) by gavage on day 12 of pregnancy, and or skeletal malformations and no increase in variations occurred.
underwent caesarean section on day 20 of pregnancy. At the higher The authors concluded that 2-ethyl-1-hexanol plays essentially
dose, 22.2% of the surviving fetuses had malformations (lower dose no role in the expression of DEHP-induced maternal and develop-
group 2% and controls 0%). These included hydronephrosis (7.8%), mental toxicity (NTP, 1991; Price et al., 1991). As no toxic doses
tail anomalies (4.9%), malformed limbs (9.7%), and ‘‘others” (1%). were reached, no conclusion on the potential of developmental
In the higher dose group the average fetal weight was reduced. toxicity of 2-ethyl-1-hexanol in mice can be drawn from this study.
Implantation index, numbers of dead and resorbed fetuses were In a screening test, mice (Charles River CD-1) were given
unaffected. Although the dose of 1666 mg/kg body weight is 1525 mg 2-ethyl-1-hexanol/kg body weight/day by gavage from
around half of the oral LD50, no maternal toxicity was reported days 7 to 14 of pregnancy (50 animals treated and 50 controls).
(Ritter et al., 1987). The dams and pups were observed until day 3 of lactation. Signs
Pregnant Sprague–Dawley rats (6/group) were gavaged with a of toxicity in the dams included significantly reduced body weight
single dose of 0, 6.25, 9.38, or 12.5 mmol 2-ethyl-1-hexanol/kg and movement, ataxia, hypothermia, unkempt coats, and blood in
body weight (equivalent to 0, 813, 1219, and 1625 mg/kg body the urine. Seventeen animals died of exposure-related causes. The
weight) in corn oil on gestation day 11.5, followed 8 h later by number of live pups and their weight were significantly reduced
32 lCi 65Zn and killed on gestation day 12.5. From 1219 mg/kg (Hardin et al., 1987). A NOAEL cannot be deduced from this study.
body weight the maternal food intake was reduced, maternal liver Twenty-five pregnant Wistar rats were gavaged with 0 (corn
metallothionein and 65Zn concentrations were higher, whereas in oil), 100, 500, or 1000 mg/kg body weight/day on gestation days
the embryos the 65Zn content was lower than in animals which 6–15. The test material was a mixture of C7–9 branched alcohols,
did not receive 2-ethyl-1-hexanol. The percentage of resorptions with isooctyl alcohol as the main component (CAS No. 68526-83-
was not affected by the test substance (Bui et al., 1998). 0). In the mid- and high-dose groups statistically significant in-
2-Ethyl-1-hexanol was administered daily by gavage to Wistar creases in the number of lumbar ribs were observed. The authors
rats (10/group) from gestation days 6 to 19 at doses of 0, 1, 5, or state that, due to the lack of embryotoxicity these findings were
10 mmol/kg body weight/day (equivalent to 0, 130, 650, and attributed to maternal toxicity observed during treatment. How-
1300 mg/kg body weight/day). At the lowest dose no maternal ever, in the 500 mg/kg body weight/day group no maternal toxicity
and fetal effects occurred. At 650 mg/kg body weight/day, fetus was reported. In high-dosed dams emaciation, rales, hypoactivity,
weights were significantly lower and the incidence of skeletal vari- decreased food consumption, and body weight gain were observed.
ations and retardations was increased. At 1300 mg/kg body The total number of fetuses with skeletal variations and with hypo-
weight/day maternal body weight measured on days 15 and 20 plastic skull bones was noted. These findings exceeded the histor-
was significantly reduced; clinical signs (salivation, CNS depres- ical control range of the laboratory but were not observed with
sion, nasal discharge) were observed, and 6 dams died. Post- litter-based analysis. The maternal NOAEL was set at 500 mg/kg
implantation losses, resorptions, number, and percent of fetuses body weight/day and the fetal NOAEL at 1000 mg/kg body
and litters with malformations and variations, and number and weight/day (EBSI, 1994a, as cited in Nishimura et al., 1994). As in-
percent of fetuses with retardations were increased. The fetal creased incidences of lumbar ribs were seen from 500 mg/kg body
weight was decreased. The maternal and developmental NOAEL weight/day at which dose no maternal toxicity was reported, the
were 130 mg/kg body weight/day each (Hellwig and Jäckh, 1997). NOAEL for developmental toxicity should better be evaluated as
Groups of 28 CD-1 Swiss mice were given >99% pure 2-ethyl-1- 100 mg/kg body weight/day.
hexanol microencapsulated in their diet at concentrations of 0%, Two different isomeric mixes of isononyl alcohol (isononanol
0.009%, 0.03%, and 0.09% from days 0 to 17 of pregnancy. This cor- type 1 and isononanol type 2, CAS No. 68515-81-1 for both) and
responded to calculated doses of 0.13, 43, and 129 mg/kg body isodecyl alcohol were administered by gavage to Wistar rats
Table 5-1
Carcinogenicity studies.

Subgroup: primary
2-Ethyl-1-hexanol Cell transformation 96–180 nl/ml; survival: BALB 3T3 cells Negative Barber et al. (1985) and
assay with and 31.7–72% in the RIFM (1983b)
without metabolic concomitant cytotoxicity
activation test, positive control:
cyclophosphamide
Cell transformation, 4–77 107 mM, no JB6 cell line of Negative Ward et al. (1986)
anchorage information on cytotoxicity mouse epidermis
independence, cells
without metabolic
activation
Oral (gavage), 0, 50, 200, 750 mg/kg body B6C3F1 mouse, 750 mg/kg body weight/day: Astill et al. (1996b)
5 days/week, weight/day 50/sex/group weak hepatocellular carcinoma
18 months increase (f), body weight gain
decrease, mortality increase
Oral (gavage), 0, 50, 150, 500 mg/kg body F344 rat, 50/sex/ P150 mg/kg body weight/day: Astill et al. (1996b)
5 days/w, 24 months weight/day group body weight gain decrease,
lethargy, unkemptness 500 mg/
kg body weight/day: mortality:
52% f
Table 6-1
Reproductive and developmental toxicity studies - dermal.
Material Method Concentration/dose Species (No./dose) Results References

2-Ethyl-1-hexanol Occlusive, 6 h/day, Range-finding study: 0, 0.5, 1.0, F344 rats (range-finder: NOAEL maternal toxicity: 252 mg/kg Deisinger et al. (1994);
on gestation days 2.0, and 3.0 ml/kg body weight/ 8 f/group; main study: body weight/day based on skin Tyl et al. (1992)
6–15, caesarean day (0, 420, 840, 1680, or 25 f/group) irritation and 840 mg/kg body
section at day 21 2520 mg/kg body weight/day) weight/day based on systemic
toxicity NOAEL developmental
toxicity: 2520 mg/kg body weight/
day
Main study: 25/group 99.72% Maternal: P840 mg/kg body weight/
pure 0, 0.3, 1.0, and 3.0 ml/kg day: Persistent exfoliation and
body weight/day (0, 252, 840, or crusting and erythema at application
2520 mg/kg body weight/day) site; maternal liver, kidney, thymus,
spleen, adrenal, and uterine weights
and gestational and fetal parameters
were unaffected by treatment;
P1680 mg/kg body weight/day:
weight gain decrease
Fetal: no treatment-related increases
in incidence of individual or pooled
external, visceral, or skeletal
malformations or variations
(10/group) daily on gestation days 6–15. The doses for the isononyl mental toxicity were considered 12 mg/kg body weight/day. Skel-
alcohols were 0, 1, 5, 7.5, and 10 mmol/kg body weight/day (0, 144, etal and visceral effects were not investigated in the pups.
720, 1080, and 1440 mg/kg body weight/day), for isodecyl alcohol 5.5.2.2.2. Secondary alcohols. In the combined repeated dose
0, 1, 5, and 10 mmol/kg body weight/day (0, 158, 790, and and reproductive/developmental toxicity screening test with ga-
1580 mg/kg body weight/day). Isononyl alcohol 1 mainly consists vage application of 4-hydroxy-4-methyl-2-pentanone [OECD TG
of dimethyl heptanols. Isononyl alcohol 2 mainly consists of di- 422] (see Sections 5.2.1.1 and 5.5.2), a tendency for a decrease of
methyl heptanols and methyl octanols. The test procedure was developmental parameters was observed at the highest dose of
according to OECD TG 414 with the exception that 10 instead of 1000 mg/kg body weight/day. These effects included the total
20 animals per dose level were used. At the lowest dose of isononyl number of pups born, delivery index, live birth index, number of
alcohol 1 there was an equivocal increase in the incidence of fe- pups alive and viability index on day 4 of lactation The NOAEL
tuses with hydroureter (11%, which was only slightly above the for developmental toxicity was 300 mg/kg body weight/day. The
highest incidence of 4 control groups used in the study, 9.2%). NOAEL for maternal toxicity was 100 mg/kg body weight/day
The highest historical control incidence was reported to be 7.7% (MHW, Japan 1997, as cited in OECD/SIDS, 2007). OECD TG 422
for studies conducted in the same time interval as the study under does not provide for an evaluation of skeletal and visceral effects
question. A clear dose–response was not seen. Therefore, a sub- in pups.
stance-related effect is questionable. At the lowest dose of isononyl 2,6-Dimethylheptan-4-one has been assessed in a reproduction/
alcohol 2 no maternal and fetal toxicity was seen. At a dose of developmental toxicity screening test 20 rats (10/sex) were given
720 mg/kg body weight/day and more of isononyl alcohols 1 and 0, 100, 300, or 1000 mg 2,6-dimethylheptan-4-one/kg body
2, signs of maternal and developmental toxicity, including de- weight/day in corn oil by gavage from 2 weeks prior to mating
creased body weight, increased resorption rates, and increased throughout pregnancy until weaning day 5 post partum when
skeletal variations and retardations were observed. At doses of the dams and offspring were sacrificed. Two dams at the top dose
1080 mg/kg body weight/day and more the incidences of malfor- level died during lactation due to the test substance. There was no
mations were elevated. For isodecyl alcohol, maternal toxicity (re- evidence of an effect on any of the reproductive parameters inves-
duced body weight gain and clinical signs) was evident at 790 mg/ tigated or on any of the surviving litters. The NOAEL for develop-
kg body weight/day and more. Developmental toxicity including mental effects is the highest tested dose of 1000 mg 2,6-
reduced mean fetal body weight and skeletal retardations were ob- dimethylheptan-4-one/kg body weight/day, with a parental NOAEL
served only in the highest dose group. The maternal NOAEL for of 300 mg/kg body weight/day (Shell HSE, 1996 as cited in OECD/
isononyl alcohol 1 and isononyl alcohol 2 is 144 mg/kg body SIDS, 2004). OECD TG 421 does not provide for an evaluation of
weight/day and for isodecyl alcohol 158 mg/kg body weight/day. skeletal and visceral effects in pups.
The NOAEL for developmental toxicity for isononyl alcohol 1 and 5.5.2.2.3. Tertiary alcohols. No studies were available.
2 is 144 mg/kg body weight/day and for isodecyl alcohol 790 mg/
kg body weight/day. Isononyl and isodecyl alcohol are develop- 5.5.2.3. Inhalation.
mental toxins only at doses that produce maternal toxicity (Hell- 5.5.2.3.1. Primary alcohols. Pregnant Wistar rats (20–25) were
wig and Jäckh, 1997; RIFM, 1991a). whole body exposed 6 h per day on gestation days 6–15 to 0,
In a combined repeated dose and reproductive/developmental 510, 2500, or 9800 mg isoamyl alcohol/m3 (0, 138, 675, and
toxicity screening test with gavage application of 3,5,5-trimethyl- 2646 ml/m3). Body weight gain was decreased at the highest con-
1-hexanol (OECD TG 422) (see Section 5.2.1.1) the following results centration between days 6 and 9 but there were no compound-re-
concerning developmental toxicity were observed: the number of lated effects on conception rate, mean number of corpora lutea,
pups born alive diminished in the 60 and 300 mg/kg body implantation sites, pre- and post-implantation losses, and number
weight/day groups. In the high-dose group total litter loss was ob- of resorptions, viable fetuses, sex ratio, mean fetal, and placental
served in two dams, the viability of neonates on day 4 of lactation weight. No external, visceral, or skeletal malformations were ob-
was lower, and male and female pups showed lower body weights served. The NOAEL for maternal toxicity was 2500 mg/m3
on day 0 of lactation (MHW, Japan, 1997b as cited in OECD/SIDS, (675 ml/m3) and the NOAEL for developmental toxicity 9800 mg/
2003). Therefore, the NOAEL for systemic toxicity and develop- m3 (2646 ml/m3) (Klimisch and Hellwig, 1995).
Table 6-2 S26
Reproductive and developmental toxicity studies – oral.

Subgroup: primary
2-Ethyl-1-hexanol Gavage, 3 days/week, 0, 167 mg/kg body CD Sprague–Dawley rats (4 m/group) No effect on Sertoli cells and gonocytes Li et al. (2000)
3-day old males weight/day
Gavage, 5 days, 35-day 2.7 mmol/kg body Sprague–Dawley rats No testicular damage Sjoberg et al. (1986)
old male rats weight/day (350 mg/kg
body weight/day)
Gavage on day 12 0 (untreated), 6.25 or Wistar rats (7 f/group) Maternal: no maternal toxicity was Ritter et al. (1987)
12.5 mmol (833, reported
1666 mg/kg body Fetal: 1666 mg/kg body weight/day: 22.2%
weight/day), undiluted of the surviving fetuses had
malformations (lower dose group 2%,
controls 0%). These included
hydronephrosis (7.8%), tail anomalies
(4.9%), malformed limbs (9.7%) and
‘‘others” (1%); average fetal weight
decreased
Implantation index, average fetal weight,
numbers of dead and resorbed fetuses
were not affected
Gavage, on gestation 0, 6.25, 9.38 or Sprague–Dawley rats (6 f/group) Maternal: P1219 mg/kg body weight: Bui et al. (1998); Taubeneck et al.
day 11.5; after 8 h 12.5 mmol 2-ethy-1- maternal food intake decreased; 1625 mg/ (1996)
intubated with 32 lCi hexanol/kg body kg body weight: percentage of 65Zn
65
Zn, killed on weight in corn oil retained in maternal liver increase
gestation day 12.5 (equivalent to 0, 813, Fetal: the percentage of resorptions was
1219, 1625 mg/kg body not affected
weight) 1625 mg/kg body weight: percentage of
65
Zn retained in the embryos decreased
Gavage from days 6 to 0, 1, 5, and 10 mmol/kg Wistar rats (10 f/group) NOAEL maternal and developmental Hellwig and Jäckh (1997)
19 of pregnancy body weight/day (0, toxicity: 130 mg/kg body weight/day
130, 650, and 1300 mg/
kg body weight/day)
Maternal: P650 mg/kg body weight/day:
1300 mg/kg body weight/day: body
weight decreased; mortality increased
Fetal: P650 mg/kg body weight/day:
weight decreased, skeletal variations and

retardation increased
1300 mg/kg body weight/day: post-
implantation loss, resorptions, number
and percent fetuses and litters with
malformations and variations, and
number and percentage of fetuses with
retardations increased; fetal weight
decreased
Days 0–17 of Diet: 0%, 0.009%, 0.03%, CD-1 Swiss mice (28 f/group) NOAEL maternal and developmental NTP (1991) and Price et al. (1991)
pregnancy and 0.09% toxicity: 129 mg/kg body weight/day but
(microencapsulated) no toxic dose tested
(0.13, 43 and 129 mg/
kg body weight/day)
>99% pure test No maternal toxicity; all of the litters
substance survived and all gestational parameters
were normal
Gavage from days 7 to 0, 1525 mg/kg body Charles River CD-1 mice (50 f/group) NOAEL for maternal/developmental Hardin et al. (1987)
14 of pregnancy; the weight/day in corn oil toxicity cannot be derived
dams and pups were Maternal: 1525 mg/kg/d: 17/49 died
observed until day 3 of (controls 0), reduced movement, ataxia,
lactation hypothermia, unkempt coats and blood in
the urine, body weight and fertility and
pregnancy index decrease
Fetal: 1525 mg/kg/day: number of live
pups and in their weight decrease. No
further parameters were considered in
this study
Isooctyl alcohol (C7–9 Gavage, days 6–15 p.c., 0, 100, 500, 1000 mg/ Sprague–Dawley rat NOAEL maternal toxicity: 500 mg/kg body EBSI (1994a) as cited in Exxon
alcohols, branched according to OECD TG kg body weight/day in (25 f/group) weight/day (2001a)
(CAS No. 68526-83- 414 corn oil NOAEL developmental toxicity: 100 mg/kg
0)) body weight/day
Maternal: 1000 mg/kg: food consumption
decreased, body weight gain from GD6–9
and GD6–15 decreased, clinical signs
(emaciation, rales, hypoactivity,
abdominal/anogenital staining, little or no
stool)
Fetal: P500 mg/kg: number of lumbar ribs
increased
1000 mg/kg body weight/day: number of
fetuses with skeletal variations increased,
hypoplastic skull bones increased only on
a per-fetus basis
Isotridecan-1-ol Gavage, days 6–19 p.c. 0 (olive oil), 60, 250, or Wistar rats (25/f/group) NOAEL for maternal toxicity: 250 mg/kg RIFM (2003b)
(isomeric mixture) 750 NOAEL for developmental toxicity:
750 mg/kg
Maternal: 750 mg/kg: transient
salivation;11% reduction of food
consumption (6–10 p..c); increased
alanine aminotransferase values;
increased triglycerides (14%) and relative
liver weights (18%); decreased total
protein and globulin concentrations
250 mg/kg: transient salivation
Fetal: 750 mg/kg body weight/day: no
effects
Isononyl alcohol Gavage, days 6–15 p.c. 0 (control 1: water, Wistar rats (10 f/group) NOAEL for maternal toxicity: 144 mg/kg Hellwig and Jäckh (1997) and EPA,
(Isononanol type 1 according to OECD TG control 2: water with body weight/day NOAEL for 1991
(CAS No. 68515-81- 414 0.005% Cremophor EL), developmental toxicity: 144 mg/kg body
1)) 1, 5, and 10 mmol/kg weight/day
body weight/day (0,
144, 720, and 1440 mg/
kg body weight/day) in
aqueous Cremophor EL
Supplementary study:
0 (control 1: water, Maternal: P720 mg/kg: food consumption
control 2: water with (days 6–10 p.c.) decreased, clinical signs
0.005% Cremophor EL) (apathy, nasal discharge)
and 7.5 mmol/kg body 1080 mg/kg: severe maternal signs (n.f.i.),
weight/day (0, mortality (1/10)
1080 mg/kg body 1440 mg/kg: mortality (10/10)
weight/day) because of Fetal: 144 mg/kg body weight/day: fetuses
mortality of all dams at with hydroureter (8/73; 11.0%, control 1:
10 mmol/kg (1440 mg/ 0/68, control 2: 3/69, 4.3%), no further
kg) body weight/day effects

S27
Material Method Concentration/dose Species (No./dose) Results References S28

720 mg/kg body weight/day: fetuses with
hydroureter (8/67, 12.0%), fetal number
decreased and % fetuses with skeletal
variations and retardations increased
1080 mg/kg: fetuses with hydroureter (3/
37, 8.1%, control 1: 6/65, 9.2%, control 2: 2/
58, 3.4%); mean uterine and fetal weights
decreased, resorptions increased, post-
implantation loss increased, number and
% fetuses and litters with malformations
increased (mainly related to the heart),
number and % fetuses with retardations
increase, skeletal variation increase
(rudimentary-cervical rib(s) increased
(11/0 control 1, 11/1 control 2))
1440 mg/kg body weight/day:
examination of fetuses not possible
because of maternal death
Isodecyl alcohol Gavage, days 6–15 p.c., 0, 1, 5, and 10 mmol/kg Wistar rats (10 f/group) NOAEL maternal toxicity: 158 mg/kg body Hellwig and Jäckh (1997)
according to OECD TG body weight/day (0, weight/day
414 (10 instead of 20 158, 790, and 1580 mg/ NOAEL developmental toxicity: 790 mg/
recommended kg body weight/day) in kg body weight/day
animals/group) aqueous Cremophor EL Maternal: P790 mg/kg: food consumption
decreased, body weight on days 15 and 20
decreased, clinical symptoms (nasal
discharge, salivation, and CNS depression)
1580 mg/kg: mortality increased
Fetal: 1580 mg/kg: mean uterine and fetal
weights decreased, resorptions increased,
postimplantation loss increased, number
and % fetuses with malformations and
retardations increased
3,5,5-Trimethyl-1- Gavage, males: 0, 12, 60, 300 mg/kg SD (Crj:CD) rat (12/sex/dose) NOAEL systemic toxicity males and MHW, Japan (1997b) as cited in
hexanol 46 days, females: from body weight/day in females: 12 mg/kg body weight/day OECD/SIDS (2003)
14 days before mating olive oil NOAEL fertility: 12 mg/kg body weight/
to day 3 of lactation, day (females)
OECD TG 422 300 mg/kg body weight/day (males)
NOAEL developmental toxicity: 12 mg/kg
body weight
Parental: P12 mg/kg body weight/day:
renal hyaline droplets, eosinophilic bodies
(m)
P60 mg/kg body weight/day: rel. liver
weight increase (m, f), abs. and rel. kidney
weight increase (m), pale discoloration of
kidneys (m), renal tubular epithelial
regeneration (m), formation of granular
casts in kidney (m), renal epithelial fatty
change (f); implantation index decrease (f)
300 mg/kg body weight/day: 1 f died, 3 f
killed (weakness); body weights increase
(m), food consumption increase (m), body
weights decrease (f), food consumption
decrease (f); urine volume increase (m),
water consumption increase (m); red
blood cell counts decrease (m), hematocrit
decrease (m), hemoglobin decrease (m),
BUN decrease (m), chloride decrease (m)
abs. liver weight increase (m, f), rel. kidney
weight increase (f), swelling of kidney (m),
yellowish white discoloration of liver (f),
irregularity in shape of follicles (m),
columnar change of follicular epithelium
(m), thyroid colloid decrease (m), thymus
atrophy (f); total litter loss in 2 dams
Fetal: P60 mg/kg body weight/day:
decreased pups born alive
300 mg/kg body weight/day: viability of
neonates on day 4 of lactation decreased,
body weights of male and female pups ?
decreased
Subgroup: secondary
2,6-Dimethylheptan-4- Gavage, from 2 weeks 0 (vehicle), 100, 300, Alpk:ApfsSD rats (10/sex/group) NOAEL parental systemic toxicity: Shell HSE (1996) as cited in OECD/
one prior to mating 1000 mg/kg body 300 mg/kg body weight/day SIDS (2003)
throughout pregnancy weight/day in corn oil NOAEL developmental/reproductive
until weaning day 5 effects: 1000 mg/kg body weight/day
post partum (OECD TG Maternal: 1000 mg/kg body weight/day:
421) two dams died during lactation,
attributable to the test substance. There
was no effect on the number of
pregnancies, positive smears, litters born,
number of implantations or proportion of
pups born live in any dose group
Paternal: 1000 mg/kg body weight/day:
male body weight gains decrease
No changes in organ weight and no
significant histopathological changes in
the male or female reproductive organs;
no evidence of an effect on any of the
reproductive parameters investigated or
on any of the surviving litters
4-Hydroxy-4-methyl-2- OECD TG 422 0, 30, 100, 300, Crj:CD(SD) rat (10/sex/dose) NOAEL parental systemic toxicity: MHW, Japan (1997) as cited in OECD/
pentanone (screening test): males: 1000 mg/kg body 100 mg/kg body weight/day SIDS (2007)
44 days, females: from weight/day in water NOAEL for fertility and developmental
14 days before mating toxicity: 300 mg/kg body weight/day
to day 3 of lactation Parental: tendency for lower reproductive
indices (fertility and implants) (n.f.i.)

Fetal:1000 mg/kg body weight/day:
tendency for decrease of the following
parameters: total number of pups born,
delivery index, live birth index, number of
pups alive, viability index on day 4 of
lactation (n.f.i.)
f: female, m: male, n.f.i.: no further information, n.s.: not statistically significant, p.c.: post coitum
S29
S30
Table 6-3
Reproductive and developmental toxicity studies – inhalation.

Subgroup: primary
2-Ethyl-1-hexanol Whole body exposure from day 0 0, 850 mg/m3 (160 ml/m3) Sprague–Dawley rats NOAEL 160 ml/m3 Nelson et al. (1989)
to 19 of pregnancy the maximum vapor (15 f/group) Maternal: 160 ml/m3: no maternal toxicity
concentration that could Fetal: 160 ml/m3: no significant differences in
be achieved without corpora lutea per litter, resorptions per litter,
increasing exposure numbers of females or males per litter, or fetal
chamber temperature weight of females or males, and no external,
above 80°F visceral, or skeletal malformations
Isoamyl alcohol Inhalation, days 6 through GD15, 0, 510, 2500, 9800 mg/m3 Wistar female rat NOAEL maternal toxicity: 675 ml/m3 Klimisch and Hellwig (1995)
6 h/day, caesarean section on (0, 138, 675, 2646 ml/m3) (20–25 f/group) NOAEL developmental toxicity: 2646 ml/m3 RIFM (1990a)
day 20 GD, OECD TG 414 Maternal: 2646 ml/m3: body weight gain (days 6–
9)decreased; no test substance-related clinical signs
Fetal: no litter parameters affected; no gross
external, soft tissue, or skeletal fetal alterations
Inhalation, days 7 through 19 pi, 0, 510, 2510, 9800 mg/m3 Himalayan female NOAEL maternal toxicity: 678 ml/m3 Klimisch and Hellwig (1995)
6 h/day, caesarean section on (0, 138, 678, 2646 ml/m3) rabbit (15 f/group) NOAEL developmental toxicity: 2646 ml/m3 RIFM (1990b)
day 29 pi OECD TG 414 Maternal: 2646 ml/m3: body weight gain (days 7–
10) decreased; eye irritation (redness, lid closure,
slight discharge)
Fetal: no litter parameters affected; no gross

external, soft tissue, or skeletal fetal alterations
Subgroup: secondary
4-Methyl-2-pentanone Inhalation 0, 500, 1000, or Sprague–Dawley rat NOAEL systemic toxicity: 1000 ml/m3 (excluding Nemec et al. (2004)
6 h/day, 7 days/w 2000 ml/m3 (0, 2050, (30/sex/group) male nephropathy)
Two-generation study, exposure 4090, or 8180 mg/m3) NOAEL reproductive toxicity: 2000 ml/m3
duration (F0, F1): F0 adults: P500 ml/m3: centrilobular hepatocellular
hypertrophy only in males, abs./rel. kidney weights
Males: 70 d prior to end through
increase (m)
mating period
1000 ml/m3: nephropathy (basophilic tubules with
Females: 70 d prior to mating to inflammation and thickening of the tubular
day 20 of gestation, resumed at basement membrane) (m), sedative effect (absent
5 days of lactation or reduced reaction to auditory startle stimulus
(normalized 1 h after end of exposure))
US EPA OPPTS Guideline 870- 2000 ml/m3: body weight gain decrease (f); abs.
3800 and rel. liver weights increase (m, f)
F1 adults: P500 ml/m3: kidney changes (alpha-2u-
globulin nephropathy) (m)
P1000 ml/m3: sedative effect (s.a.) (m),
centrilobular hepatocellular hypertrophy (m)
2000 ml/m3: absent or reduced reaction to auditory
startle stimulus (ameliorated 1 h after end of
exposure) (f); 1 m died on PND 22, clinical signs of
neurotoxicity (i.e., rocking, prostration, half-closed
eyelids) approx. 1 h post-exposure (PND
22) ) exposures for all groups of F1 weanlings
suspended through PND 27; body weight gain
(transient) decrease (m, f); abs. and rel. liver
weights increase (m, f), centrilobular hepatocellular
hypertrophy (m)
F1/F2 Offspring: reproductive parameters unaffected
Inhalation, days 6–15 p.c., 0 (air), 300, 1000, Fischer 344 rat NOAEL maternal toxicity: 1000 ml/m3 Tyl et al. (1987)
6 h/day, duration of study: 3000 ml/m3 (0, 1230, (35 f/group) NOAEL developmental toxicity: 1000 ml/m3
21 days, according to OECD TG 4090, 123,000 mg/m3) Maternal: 3000 ml/m3: neuromuscular effects (e.g.
414 loss of coordination, paresis); body weight and body
weight gain decreased, food consumption
decreased, rel. kidney weights increased
Fetal: 3000 ml/m3: body weight per litter decreased,
skeletal ossification retarded, unilateral
rudimentary rib at the first lumbar arch increased
Inhalation, days 6–15 p.c., 0 (air), 300, 1000, CD-1 mice (30 f/group) NOAEL maternal toxicity: 1000 ml/m3 Tyl et al., (1987)
6 h/day, duration of study: 3000 ml/m3 (0, 1230, NOAEL developmental toxicity: 1000 ml/m3
18 days, according to OECD TG 4090, 123,000 mg/m3) Maternal: 3000 ml/m3: 3 dams died on GD 6;
414 neuromuscular effects, abs. and rel. liver weights
increased
Fetal: 3000 ml/m3: body weight per litter decreased,
number of dead fetuses increased, visceral
variations (dilated lateral ventricles of the
cerebrum and dilated renal blood vessels)
increased, skeletal variations (vertebrae, sternbrae,
and distal limbs) increased, skeletal ossification
retarded
DEHP: di(2-ethylhexyl) phthalate, f: female, GD: gestation day, m: male, s.a.: see above, n.f.i.: no further information, MEHP: mono(2-ethylhexyl) phthalate, n.s.: not statistically significant, p.c.: post-coitum, pi: post-insemination.
4-Methyl-2-pentanone is not a fragrance material, but is structurally related.
S31
The same test procedure was performed with 14–15 pregnant A patch test (5 min under occlusion) was conducted on 12
Himalayan rabbits. The animals were exposed to 0, 510, 2510, or healthy volunteers and with 3 or 12 subjects of oriental ancestry
9800 mg isoamyl alcohol/m3 (0, 138, 678, and 2646 ml/m3) from with a 75% aqueous solution of isoamyl alcohol. Irritation reactions
day 7 to day 19 post-insemination. In dams exposed to the highest were observed in all volunteers (Wilkin and Fortner, 1985a,b; Wil-
concentration body weight gain was decreased between days 7 and kin and Stewart, 1987).
10 post insemination and irritant eye effects (reddish, lid closure, Further details on studies of dermal irritation in humans are
and slight discharge) were noted. Histopathological examination provided in Table 7-1.
of the dams revealed no substance-related effects. The reproduc-
tion parameters (e.g. mean number of corpora lutea, implantation 5.6.2. Animal studies
sites, values calculated for the pre- and post-implantation losses, Twelve of the alcohols under review with a worldwide use of
and number of resorptions) and malformations (external, visceral, greater than 0.01 tons per year have been tested in animal models
or skeletal) were within the levels of the concurrent control group of skin irritation using rabbits, rats, or guinea pigs. Studies with
or of historical control groups. The maternal NOAEL was 2500 mg/ single application are summarized in Table 7-2-1 and studies with
m3 (678 ml/m3) and the NOAEL for developmental toxicity was repeated application are shown in Table 7-2-2.
9800 mg/m3 (2646 ml/m3) (Klimisch and Hellwig, 1995). A single application of neat 3,4,5,6,6-pentamethylheptan-2-ol
Fifteen pregnant Sprague–Dawley rats were exposed (whole did not produce dermal irritation in rabbits (RIFM, 1984b) and rats
body) 7 h per day on gestation days 0–19 to 850 mg 2-ethyl-1-hex- (RIFM, 1985a). If applied undiluted as a single application, 2-ethyl-
anol/m3 (160 ml/m3), the maximum vapor concentration that 1-butanol, 2-ethyl-1-hexanol, isoamyl alcohol, 2-methylbutanol,
could be achieved without increasing exposure chamber tempera- 3,5,5-trimethyl-1-hexanol, 2,6-dimethyl-4-heptanol, 4-methyl-2-
ture above 80 ° F. After caesarean section on day 20, one-half of the pentanol, 2,6-dimethyl-2-heptanol, and 3,6-dimethyl-3-octanol
fetuses were examined for skeletal malformations, the other half (McOmie and Anderson, 1949; RIFM, 1973a, 1976a, 1977a; Scala
for visceral malformations. Aside from a decrease in feed consump- and Burtis, 1973; Cornu et al., 1992, 1984, 1978) led to slight or
tion in dams compared to control, there were no significant differ- moderate irritation in all studies with rabbits irrespectively of
ences in maternal, reproductive, or developmental parameters the method used. As an exception undiluted 2,6-dimethyl-2-hept-
(Nelson et al., 1989). The NOAEL for maternal and developmental anol was strongly irritating after 24 h occlusive application (RIFM,
toxicity was 850 mg/m3 (160 ml/m3). 1979a). The diluted substances led to no or only slight effects in
5.5.2.3.2. Secondary alcohols. Thirty-five pregnant Fischer 344 rabbits or guinea pigs: 3,6-dimethyl-3-octanol 15% no to slight
rats or 30 pregnant CD-1 mice were exposed 6 h per day on gesta- reactions (RIFM, 1970), 2,6-dimethyl-2-heptanol 10% no reaction
tion days 6–15 to 0, 300, 1000, and 3000 ml 4-methyl-2-pentanone/ (RIFM, 1981a), 3,7-dimethyl-7-methoxyoctan-2-ol 1% slight reac-
m3 (0, 1230, 4090, and 12,300 mg/m3). Maternal toxicity (neuro- tion (RIFM, 1973e).
muscular effects, e.g. loss of coordination or paresis) was observed Five percent 3,7-dimethyl-7-methoxyoctan-2-ol did not pro-
in both species after exposure to the highest concentration. Rat duce dermal irritation in guinea pigs after repeated application
dams showed reductions in body weights, body weight gain, and (RIFM, 1973d). Repeated application of neat 2-ethyl-1-hexanol
food consumption. The relative kidney weights were elevated. In led to slight dermal irritation in rats (Schmidt et al., 1973). Moder-
mice, three dams died at the first exposure and the relative and ate or strong irritation was observed after repeated applications of
absolute liver weights were increased. Reduced fetal body weight undiluted 2,6-dimethyl-4-heptanol, 4-methyl-2-pentanol, and
per litter and delayed skeletal ossification was observed in both 3,4,5,6,6-pentamethylheptan-2-ol (also diluted) in rabbits (McO-
species at the highest concentration. Rat fetuses showed an in- mie and Anderson, 1949; RIFM, 1985c, 1986a). Toxicity studies
creased incidence of unilateral rudimentary rib at the first lumbar with repeated dermal application (see Section 5.2.1) also showed
arch. In mice, the number of dead fetuses as well as visceral and dermal irritation especially with 3,4,5,6,6-pentamethylheptan-2-
skeletal variations was increased. The NOAELs for maternal and fe- ol. These studies were performed with high doses under occlusion
tal toxicity were 1000 ml/m3 for both species (Tyl et al., 1987 as ci- and are therefore not representative of human exposure.
ted in OECD/SIDS, 2007).
5.5.2.3.3. Tertiary alcohols. No studies were available. 5.7. Mucous membrane irritation
5.6. Skin irritation 5.7.1. Sensory irritation

5.7.1.1. Human data. The results of the human irritation studies are
5.6.1. Human studies summarized in Table 8.
Seven alcohols with saturated branched chain under review Human male volunteers (with and without self-reported multi-
with a worldwide use of greater than 0.01 tons per year have been ple chemical sensitivity) were exposed to 2-ethyl-1-hexanol by
well studied for their potential to produce dermal irritation in hu- inhalation for 4 h (exposure chamber). Fluctuating concentrations
mans (see Table 7-1). (time weighted average concentrations: 1.5 (control), 10, and
The following substances did not induce skin irritation in pre- 20 ml/m3) were used in the first experiment, and similar but con-
tests for a maximization study with single occlusive application stant vapor concentrations in a second experiment. Olfactory- and
for 48 h with the highest concentrations tested, i.e., 20% 3,6-di- trigeminal-mediated symptoms and intensities of odor, eye, and
methyl-3-octanol (RIFM, 1972a, 1973c), 10% 3,7-dimethyl-7-meth- nasal irritation were recorded. Self-reported nasal and eye irrita-
oxyoctan-2-ol (RIFM, 1982b), 10% 2,6-dimethyl-2-heptanol (RIFM, tion and perceived odor intensity were increased and concentra-
1976b, 1983a), 8% isoamyl alcohol (RIFM, 1976b), 8% 3,5,5-tri- tion-related at concentrations of 10 ml/m3 or more. Self-reported
methyl-1-hexanol (RIFM, 1977b), and 4% 2-ethyl-1-hexanol (RIFM, chemical sensitivity had only minor effects on chemosensory
1976c). symptoms in the second experiment (constant concentrations)
No irritation was observed with 2% 2,6-dimethyl-2-heptanol and no effect on intensity ratings in either experiment (van Thriel
during the induction phase of a human repeat insult patch test et al., 2005).
(HRIPT) in 10 healthy male and female volunteers (RIFM, 1969). An average of 12 subjects were exposed by inhalation to 2,6-di-
The repeated application of 15% 3,4,5,6,6-pentamethylheptan-2- methyl-4-heptanol for 15 min. At 5 ml/m3 or more, eye irritation
ol during the induction phase of a HRIPT led to erythema (6 grade was observed, and at 10 ml/m3 nose and throat irritation. The sen-
1 of 4, 4 grade 2 of 4) in 5 of 51 volunteers (RIFM, 1983c). sory response limit was reported to be less than 5 ml/m3 (Silver-
man et al., 1946). In the same study 4-methyl-2-pentanol led to In both subgroups of primary and secondary alcohols no evi-
eye irritation at 50 ml/m3 and higher concentrations resulted in dence of a sensitizing effect in a maximization test or in a human
nose and throat irritation. The NOEL was 25 ml/m3 (Silverman repeated insult patch test (HRIPT) with volunteers was observed
et al., 1946). with 4% 2-ethyl-1-hexanol (RIFM, 1976c), 8% isoamyl alcohol
(RIFM, 1976b), 8% 3,5,5-trimethyl-1-hexanol (RIFM, 1977b), 10%
5.7.1.2. Animal data. Sensory irritation was evaluated in 4 Swiss 3,7-dimethyl-7-methoxyoctan-2-ol (RIFM, 1982b), and 15%
male mice via measurement of changes in respiratory rate during 3,4,5,6,6-pentamethylheptan-2-ol (RIFM, 1983c). In the subgroup
a 10-min exposure to isoamyl alcohol. The concentration of iso- of tertiary alcohols 2,6-dimethyl-2-heptanol did not induce posi-
amyl alcohol that caused a 50% decrease in the respiratory rate tive reactions in a maximization test (10%, RIFM, 1976b) or a HRIPT
(RD50) of mice was 4452 ml/m3 with 95% confidence limits of (2%, RIFM, 1969). In a maximization test with 20% 3,6-dimethyl-3-
2885–12,459 ml/m3 (Kane et al., 1980). Another study reported a octanol in petrolatum (RIFM, 1972a), 4 of 25 volunteers exhibited
RD50 value of 2624 mg/m3 (729 ml/m3) (Korpi et al., 1999). positive reactions 24 and 48 h after challenge. However, since
After a 5-min exposure to 4-methyl-2-pentanol the RD50 for these four subjects also reacted strongly to a control material it
mice was 420 ml/m3 (6 animals/group) (Muller and Greff, 1984 was concluded that the reactions observed were due to a ‘‘spill
as cited in Greim, 2002). over” effect from the other material. In a second test with 10% in
petrolatum, the positive reactions could not be confirmed (RIFM,
5.7.2. Eye irritation 1973c).
No human studies on eye irritation are available. An overview of With a sub-irritating concentration (no further information) of
in vivo studies on eye irritation in rabbits can be found in Table 9. 3,7-dimethyl-7-methoxyoctan-2-ol in petrolatum, 0.9% positive
Several in vitro tests to investigate the eye irritation potential reactions (2 patients) were found in patch tests with 218 patients
did show an irritating effect of 2-ethyl-1-hexanol (Adriaens and with proven sensitization to fragrance materials (Table 10-2; Lar-
Remon, 2002; Adriaens et al., 2005; Casterton et al., 1996; Gauth- sen et al., 2002).
eron et al., 1994; Gilleron et al., 1997; Goethem et al., 2006; Ken-
nah et al., 1989a). 5.8.2. Animal studies
For 3,7-dimethyl-7-methoxyoctan-2-ol only one study with a Results of available animal studies are shown in Table 10-3. In
1% solution in propylene glycol was available, in which the sub- comparison to humans, limited data on sensitization in animals
stance did not cause irritating effects (RIFM, 1973e). are available. Only one secondary and one tertiary alcohol were
In 4 of 5 studies, isotridecan-1-ol (isomeric mixture) elicited no tested.
eye irritation in rabbits (Greim, 2000). Further information about 2,6-Dimethyl-2-heptanol was negative in guinea pigs at a con-
the test method and the concentration were not given. The undi- centration of 10% (Watanabe et al., 1988). No delayed-type hyper-
luted substance was moderately irritating to the rabbit eye in sensitivity was observed for 3,7-dimethyl-7-methoxyoctan-2-ol in
one study (Greim, 2000; Scala and Burtis, 1973). the same species (RIFM, 1973d).
Undiluted 3,6-dimethyl-3-octanol was evaluated as an eye irri-
tant. The substance led to redness and chemosis of the conjunctiva, 5.9. Phototoxicity and photoallergenicity
slight corneal opacity, and swelling of the iris. The effects were not
reversible within 3 days (RIFM, 1970). Limited data were available with regard to the phototoxicity
In three studies undiluted 2-ethyl-1-hexanol was moderately and photoallergenicity of the alcohols with saturated branched
irritating to the rabbit eye (Carpenter and Smyth, 1946; Schmidt chain (see Table 11). From human or animal studies reliable data
et al., 1973; Smyth et al., 1969). Observed effects were conjunctival were available only on the phototoxicity and photoallergenicity
redness and swelling, lacrimation, and discharge. The effects did of the tertiary alcohol 2,6-dimethyl-2-heptanol.
not clear within 96 h. Corneal effects were not found (Schmidt No phototoxic reactions were observed in 6 healthy female vol-
et al., 1973). In three other studies, the undiluted substance was unteers exposed to 10% 2,6-dimethyl-2-heptanol in 1:1 ethanol/
classified as a severe eye irritant (Kennah et al., 1989b; RIFM, acetone, followed by irradiation by UVA (RIFM, 1983a).
1978b; Scala and Burtis, 1973). These studies resulted in dullness In the only animal phototoxicity study, 10% 2,6-dimethyl-2-
and vascularization of the cornea (Scala and Burtis, 1973). The cor- heptanol in ethanol produced no phototoxic reactions after UVA
neal effects were persistent (RIFM, 1978b). In addition, iritis, con- or UVB irradiation in guinea pigs (RIFM, 1981a).
junctival erythema, chemosis, and discharge appeared (Scala and No studies have been performed which investigate the photoal-
Burtis, 1973). lergic potential in humans.
Undiluted 2,6-dimethyl-2-heptanol, 2,6-dimethyl-4-heptanol, 2,6-Dimethyl-2-heptanol was tested for its photoallergenicity
4-methyl-2-pentanol, and 3,4,5,6,6-pentamethylheptan-2-ol were in a reliable test with guinea pigs (RIFM, 1981b). No photoallerge-
moderate eye irritants (McOmie and Anderson, 1949; RIFM, nicity was seen in the animals induced with 10% in rectified alco-
1979a, 1984c; Smyth et al., 1951). The substances caused conjunc- hol, followed by irradiation with UVB and UVA (9 times in 18 days),
tivitis with edema and corneal injury. The effects disappeared and challenged after a 10-day rest with 10% of the test substance in
within 7 days (McOmie and Anderson, 1949; RIFM, 1984c) except rectified alcohol and irradiation.
for those caused by 2,6-dimethyl-2-heptanol (RIFM, 1979a). As the alcohols under review do not contain double bonds, they
Undiluted 2-ethyl-1-butanol, isoamyl alcohol, and 2-methylbu- cannot absorb UVA or UVB light. Indeed, UV spectra have been
tanol were highly irritating to the rabbit eye (Smyth et al., 1954, obtained for 12 materials (2-ethyl-1-hexanol, isoamyl alcohol,
1962, 1969). isotridecan-1-ol (isomeric mixture), 2-methylbutanol, 3-methyl-
1-pentanol, 2-methylundecanol, 3,5,5-trimethyl-1-hexanol, 2,6-di-
5.8. Skin sensitization methyl-4-heptanol, 3,7-dimethyl-7-methoxyoctan-2-ol, 6,8-dim-
ethylnonan-2-ol, 3,4,5,6,6-pentamethylheptan-2-ol, and 2,6-
5.8.1. Human studies dimethyl-2-heptanol). Five materials did not absorb UV light, the
Seven of the alcohols under review with a worldwide use of remaining 5 peaked in the UVC range (<290 nm) and returned to
greater than 0.01 tons per year have been evaluated for their po- baseline around 300 nm (see Table 12). 2-Ethyl-1-hexanol and
tential to induce sensitization in humans (see Tables 10-1 and 3,7-dimethyl-7-methoxyoctan-2-ol peaked between 200 and 215
10-2). with minor absorption returning to baseline at 400 nm. Based on
Table 7-1
S34
Skin irritation studies in humans.
Material Method Concentration Subjects Results References

Subgroup: primary
2-Ethyl-1-hexanol 48 h, occlusive (pre- 4% in petrolatum 29 healthy male volunteers No irritation RIFM (1976c)
test for a maximization
study)
Isoamyl alcohol 48 h, occlusive (pre- 8% in petrolatum 25 healthy volunteers No irritation RIFM (1976b)
study)
5 min, occlusive 75% in water 12 volunteers Irritation in all 12 Wilkin and Stewart (1987)
volunteers
5 min, occlusive 75% in water 12 volunteers (oriental) Irritation in all 12 Wilkin and Fortner (1985a)
volunteers
5 min, occlusive 75% in water 3 volunteers (oriental) Irritation in all 3 Wilkin and Fortner (1985b)
volunteers
3-Methyl-1-pentanol 24 h, occlusive (pre- 0.5% in alcohol SDA 39 C 41 healthy volunteers Little or no irritation RIFM (1973f)
test for a HRIPT)
3,5,5-Trimethyl-1-hexanol 48 h, occlusive (pre- 8%, in petrolatum 25 healthy volunteers No irritation RIFM (1977b)
study)
Subgroup: secondary
3,7-Dimethyl-7-methoxyoctan-2-ol 48 h, occlusive (pre- 10%, petrolatum 27 healthy male and female volunteers No irritation RIFM (1982b)
study)
3,4,5,6,6-Pentamethylheptan-2-ol During the induction 15% v/v solution in ethanol SDA 39C (99%) 51 healthy male and female volunteers 10/48 positive RIFM (1983c)
phase of a repeated reactions: 5 grade 1
insult patch test reactions (erythema
(HRIPT): 9 applications confined to the contact
with a duration of 24 h site and exceeding that
within a 3-week of the untreated skin)
period, occlusive, and 5 grade 2 reactions
0.2 ml, observations on (erythema confined to
the application days the contact site and
definitely exceeding
that of the untreated
skin; papules may or
may not be present)
Subgroup: tertiary
2,6-Dimethyl-2-heptanol 48 h, occlusive (pre- 10% in petrolatum 25 healthy volunteers No irritation RIFM (1976b)
study)
0.025 ml/2 cm2, 10% in 1:1 ethanol/acetone 6 healthy female volunteers No irritation RIFM (1983a)
occlusive, up to 72 h
Induction phase of 2% in dimethyl phthalate 10 healthy male and female volunteers No irritation RIFM (1969)
HRIPT
3,6-Dimethyl-3-octanola 48 h, occlusive (pre- 10% in petrolatum 5 healthy male volunteers No irritation RIFM (1973c)
study)
48 h, occlusive (pre- 20% in petrolatum 5 healthy male volunteers No irritation RIFM (1972a)
study)
3-Methyloctan-3-ola 48 h, occlusive (pre- 10% in petrolatum 29 healthy volunteers No irritation RIFM (1978a)
study)
a
Table 7-2-1
Skin irritation studies in animals, single application.
Material Method Concentration Species Results References

Subgroup: primary
2-Ethyl-1-butanol 24 h, uncovered, 0.01 ml sample on Undiluted Rabbit (n = 5) An average reaction to a trace of capillary injection Smyth et al. (1954)
the clipped skin
2-Ethyl-1-hexanol 5000 mg/kg, n.f.i. Undiluted Rabbit (n = 10) Moderate redness and edema in 10/10 RIFM (1977a)
24 h, uncovered, 0.01 ml sample on Undiluted or as a solution in water, Rabbit (n = 5) Moderate irritation observed Smyth et al. (1969)
the clipped skin propylene glycol or acetone
24 h, occlusive, 0.1, 0.316, 1.0, Undiluted Rabbit (n = 4) Moderate irritation: moderate erythema, moderate Scala and Burtis (1973)
3.16 mg/kg body weight, on the edema, atonia, blanching, desquamation,
clipped intact skin, observations daily coriaceousness, necrosis, and eschar
up to 7 days
Isoamyl alcohol Single application of 5.0 g/kg Undiluted Rabbit (n = 10) Marked erythema and moderate edema RIFM (1976a)
Single application Undiluted Rabbit (n = 6) Very irritating RIFM (1979c)
24 h, uncovered, 0.01 ml sample on Undiluted or as a solution in water, Rabbit (n = 5) Irritation was observed Smyth et al. (1969)
the clipped skin propylene glycol or acetone
isotridecan-1-ol (mixed Single occlusive patch for 24 h to Undiluted Rabbits Moderately irritating Scala and Burtis (1973)
isomers) intact skin of 4 rabbits
Single uncovered application of Undiluted Rabbits Moderately irritating Smyth et al. (1962)
0.01 ml for 24 h
Percutaneously to the intact dorsal Undiluted Rabbits Severe erythema and distinct edema at 24 h distinct RIFM (1963d,e)
skin for 20 h scarring and severe scaling at 8 days
4-h semi-occlusive irritation Undiluted Rabbits Slight to marked erythema, slight or moderate RIFM (2003a)
edema and scaling
2-Methylbutanol 24 h, uncovered, 0.01 ml sample on Undiluted Rabbit (n = 5) Irritation defined as the least visible capillary Smyth et al. (1962)
the clipped skin injection from the undiluted material
n.f.i. Undiluted Rabbit (n = 2) Moderately irritating RIFM (1979b)
3-Methyl-1-pentanol 0.5 ml application, 24 h contact, 0.5% in alcohol SDA 39C Rabbit (n = 3) No erythema and edema observed RIFM (1972c)
observed again at 48 h
3,5,5-Trimethyl-1-hexanol 5000 mg/kg body weight, n.f.i. Undiluted Rabbit (n = 10) Redness: mild: 2/10, moderate: 4/10, severe: 4/10; RIFM (1977a)
edema: mild: 1/10, moderate: 9/10, severe: 0/10
Subgroup: secondary
2,6-Dimethyl-4-heptanol Neat application as part ofl LD50 Undiluted Rabbit (n = 5) No irritation Smyth et al. (1949)
4 h, semi-occlusive, 3.9-9.4 ml/kg Undiluted Rabbit (n = 5) 2/5 some erythema and slight edema McOmie and Anderson
body weight on the shaved skin (1949)
3,7-Dimethyl-7- 24 h, occlusive, 0.5 ml, abraded and 1% in propylene glycol Rabbit (n = 6) Mildly irritating, PII 0.5, 5/6 very slight erythema in RIFM (1973e)
methoxyoctan-2-ol intact skin, observations after 24, the intact and abraded sites after 24 h, 1/6 very
72 h slight erythema in the intact and abraded sites after
72 h
4-Methyl-2-pentanol Details of the method not reported Concentration and vehicle not reported Rabbit, n.f.i. 2/10 defined as an average reaction equivalent to a Smyth et al. (1951)
trace of capillary injection
0.25 h, observation period of 10 days, Undiluted Rabbit (n = 3) Immediate slight erythema and delayed moderate McOmie and Anderson
n.f.i. erythema with drying of surface (1949)
7 applications (5 h) to the intact skin Undiluted Rabbits (n = 2) Erythema, flaking, and cracking of the skin with McOmie and Anderson
for 21 days bleeding fissures by the 7th exposure (1949)
3,4,5,6,6- 4 h, occlusive, 0.5 ml, clipped skin, Undiluted Rabbit (n = 6) No irritation RIFM (1984b)
Pentamethylheptan-2-ol observations at 24, 48, 72 h
24 h, occlusive, 2000 mg/kg body Undiluted Rats (n = 5/sex) No irritation RIFM (1985a)
weight, observations at 24 h, and
daily for 14 days
Subgroup: tertiary
2,6-Dimethyl-2-heptanol 5000 mg/kg body weight, n.f.i. Undiluted Rabbit (n = 10) 2/10 slight redness, 8/10 moderate redness, 1/10 RIFM (1976a)
slight edema, 9/10 moderate edema

S35
the UV spectra and review of phototoxic/photoallergy data, the

materials in this group would not be expected to elicit phototoxic-
ity or photoallergy under the current conditions of use as a fra-
grance ingredient.
RIFM (1979a)
RIFM (1981a)
RIFM (1973a)
RIFM (1978c)
RIFM (1970)
5.10. Miscellaneous studies
References
To address hepatotoxicity, several miscellaneous studies were

conducted. Ex vivo studies on the mechanism of hepatotoxicity
4/10: slight redness, 4/10: moderate redness, 2/10:

edema, slight redness already after 5 min reversible
PII 5.1, strongly irritating, after 24 h on intact skin:
observations were made after 3 days; 15% PII: 2.0, were conducted with 2-ethyl-1-hexanol, 2-methylbutanol, and
very slight to well-defined erythema no edema to
Undiluted PII: 3.4, very slight to moderate/severe
very slight edema, 3/6 animals were not entirely

within 8 days, redness after 24 h application not
6/6 strong redness, 5/6 slight edema, 1/6 strong
isoamyl alcohol, in vitro enzyme induction and peroxisome prolif-

recovered within 7 days a score of 5 or more is
regarded as signifying a primary skin irritant
eration studies were conducted with 2-ethyl-1-hexanol and iso-
8/8: slight redness, 3/8: slight edema, 4/8:
erythema, very slight to slight edema, no
amyl alcohol and in vivo repeated dose toxicity studies with 2-

ethyl-1-hexanol, isoamyl alcohol, isodecyl alcohol, isononyl alco-
slight edema, 8/10: moderate edema hol, isooctane-1-ol (isomeric mixture) and 3,5,5-trimethyl-1-hexa-
nol were performed. These studies are not summarized here but
may be found in detail in individual Fragrance Material Reviews
reversible within 8 days
(McGinty et al., 2010a,b,c,d,e,f,g,h,i,j,k,l,m,n,o,p,q). The data show

that 2-ethyl-1-hexanol is a peroxisome proliferator and that 2-
moderate edema
ethyl-1-hexanol, 2-methylbutanol, and isoamyl alcohol induce li-

ver enzymes.
No irritation
Results
6. Conclusion
The compounds assessed in this group have a close structural

Albino guinea-pig
relationship, similar metabolism, and toxicity profiles.

Rabbit (n = 10)
Rabbit (n = 6)
Rabbit (n = 8)
Rabbit (n = 6)
Data on metabolism for the compounds under review are avail-

able only for the primary alcohols 2-ethyl-1-butanol, 2-ethyl-1-
Species
(n = 8)
hexanol, isoamyl alcohol, 2-methylbutanol, and for the secondary

alcohol 4-methyl-2-pentanol.
The major pathways of metabolism and fate which are common
to the primary, secondary and tertiary alcohols in this group are:
– conjugation of the alcohol group with glucuronic acid;

Undiluted, 15% in distilled water
– oxidation of the alcohol group;

– side-chain oxidation yielding polar metabolites, which may be
conjugated and excreted – or further oxidation to an aldehyde,
a carboxylic acid, and to CO2;
– excretion of the unchanged parent compound.
10% in ethanol
Concentration
Undiluted
Undiluted
Undiluted
In most cases metabolism yields innocuous substances, which

are excreted in the urine and feces.
Because there is insufficient information for many of the 20
alcohols with saturated branched chain under review, the database
abraded skin, observations after 24 h,
4 h, patch test, observations after 4 h,

48 h, 8 days; (Federal Register 38, No.
24 h, 48 h (control of a phototoxicity
abraded skin, observations at 24, 48,
is supplemented with studies of 3 metabolites of these alcohols.

187, § 1500.41, S. 27019, 27. Sept.
24 h, occlusive, 0.5 ml, intact and
The Panel is of the opinion that there are no safety concerns

1, 5, 15 min, 2, 20 h, intact and
5000 mg/kg body weight, n.f.i.
regarding alcohols branched chain saturated under the present de-

clared levels of use and exposure. These materials have not been
5000 mg/kg body weight
n.f.i.: no further information, PII: primary irritation index.
evaluated at levels other than reported in this group summary.

Use of these materials at higher maximum dermal levels or higher
systemic exposure levels requires re-evaluation by the Panel. This
conclusion was based on the following reasons:
Method
study)
1973)
No, or only minimal, evidence of skin irritation in humans was

72 h
caused by 6 compounds tested at concentrations of 2–10%. Due

to the structural similarities, compounds not tested for skin irrita-

tion in humans are expected to show similar properties with
3,6-Dimethyl-3-octanola
respect to this endpoint. Therefore, the alcohols under review pose

3-Methyloctan-3-ola
Table 7-2-1 (continued)
no concern provided concentrations in end products are in the

range of 2–10%, which is above the current concentrations of use.
The 11 materials evaluated for eye irritation showed that the
undiluted materials cause moderate to severe eye irritation.
Material
However, since these materials are not used undiluted they

pose no concern for eye irritation at the concentrations cur-
a
rently in use in end products (0.001–1.7%).

Table 7-2-2
Skin irritation studies in animals, repeated application.

Subgroup: primary
2-Ethyl-1-hexanol 12 applications, over a period of 12 days, uncovered, Undiluted Rat (n = 10) After 10 days slight redness and scabbing Schmidt et al.
2 ml/kg body weight/day on the shaved skin, (1973)
observations daily
Subgroup: secondary
2,6-Dimethyl-4-heptanol 7 applications, 5–12 h duration over a period of 15– Undiluted Rabbit (n = 2) definite erythema after 2nd exposure; areas of flaking McOmie and
21 days, uncovered, 3.0 ml/kg on 100 cm2, after 4th exposure; cracking of skin, fissures with some Anderson (1949)
nonabraded skin, observations daily bleeding after 7th exposure
3,7-Dimethyl-7-methoxyoctan-2-ol 10 applications, 24 h duration on alternate days 2.5, 5% in water, Guinea pig (n = 10) No irritation, isolated occurences of slight erythema RIFM (1973d)
during a 3-week period, occlusive, 0.2 ml, shaved applications 1–7: during the treatment period
skin, observations 5%, applications
8–10: 2.5%
4-Methyl-2-pentanol 5 applications, 5–12 h duration over a period of 15– Undiluted Rabbit (n = 3) Severe drying of the skin with some sloughing and McOmie and
21 days, uncovered, 3.0 ml/kg on 100 cm2, cracking Anderson (1949)
nonabraded skin, observations daily
3,4,5,6,6-Pentamethylheptan-2-ol 9–28 applications, 6 h duration over a period of Undiluted, 1.5%, Rabbit (n = 10/sex) P30 mg/kg body weight/dayay: erythema and edema RIFM (1986a)
28 days, occlusive, nonabraded and clipped skin, 5%, 15%, 50% increased dose-dependently; P300 mg/kg body weight/
observations daily dissolved in 1% dayay: after 9 treatments the treatment was terminated
w/v aqueous as a result of irritation
methylcellulose
(ca. 30, 100, 300,
1000 mg/kg body
weight/dayay)
Daily applications for 6 h, duration over 28 days, Undiluted Rabbit (n = 13/sex) Severe and persistent irritation: dermal irritation RIFM (1985c)
occlusive, 1000 mg/kg body weight/dayay, progressed rapidly in all animals to well defined to
nonabraded skin, observations daily moderate erythema and edema within one week;
irritation progressed further in several rabbits becoming
severe within 2 weeks of treatment, scab formation
S37
These materials have no or low sensitizing potential. Available
van Thriel et al. (2005)
Silverman et al. (1946)
Silverman et al. (1946)

data for five of the substances show that they do not possess a
sensitization potential. However, for 3,6-dimethyl-3-octanol, a
low sensitization potential in humans cannot be excluded. Satu-
References rated alcohols do not form hydroperoxides. They oxidize and
become aldehydes or ketones. The use of these materials under
the declared levels of use and exposure will not induce sensitiza-
tion. For those individuals who are already sensitized, there is a
possibility that an elicitation reaction may occur. The relation-
ship between the no effect level for induction and the no effect
level for elicitation is not known for this group of materials.
and perceived odor intensity increase; no difference
Based on the lack of structures, which could absorb UVA or UVB

P10 ml/m3: self-reported nasal and eye irritation
Eye irritation at 5 and 10 ml/m3, nose and throat light, and review of phototoxic/photoallergy data, the alcohols
with saturated branch chains would not be expected to elicit
Eye irritation at 50 ml/m3, nose and throat
between subjects with and without sMCS
phototoxicity or photoallergy under the current conditions of

use as a fragrance ingredient.
The 15 compounds tested have a low order of acute toxicity.
The seven branched chain saturated alcohols and three of their
metabolites (see Tables in Section 5.2) tested were of low sys-
temic toxicity after repeated application. Changes indicative of
irritation at 10 ml/m3
irritation >50 ml/m3
enzyme induction in the liver (liver enlargement), peroxisome

proliferation and alpha-2u-nephropathy in male rats have been
observed at doses of 60 mg/kg body weight/day and more. The
Clinical signs
lowest NOAEL of all the subacute and sub-chronic oral studies

available, which were performed with five of the substances
under review and the metabolite 4-hydroxy-4-methyl-2-penta-
none, is 10 mg/kg body weight/day for 3,5,5-trimethyl-1-hexa-
nol. This value is taken as representative for all members of
the group as a worst-case. The database does not allow a defi-
nite conclusion that the toxicity after dermal application is
Constant concentrations:
lower than after oral application by gavage (oral bolus dose

7 males without and
12 males with sMCS
vs. slow uptake via the skin). However, at least 3,4,5,6,6-pen-

tamethylheptan-2-ol had a much higher systemic NOAEL of
concentration
No. subjects/
1000 mg/kg body weight/day in a subacute dermal study com-

pared to the lowest oral NOAEL of 10 mg/kg body weight/day
group
mentioned above. Several subacute and subchronic inhalation

12
12
studies showed a lowest NOAEL of 120 ml/m3 for 2-ethyl-1-

hexanol corresponding to a dose of 175 mg/kg body weight/
day, assuming a body weight of 261 g, a minute volume of
0.2 l for a rat (Bide et al., 2000) and 100% retention. Comparing
Inhalation, exposure, 4 h: constant concentrations:
the oral worst-case NOAEL of 10 mg/kg body weight/day to the

(1.5, 10, 20 ml/m3) or fluctuating concentrations
worst-case daily uptake of 0.14 mg/kg body weight/day which

(time-weighted average 1.5, 10, 20 ml/m3)
was estimated for 3,4,5,6,6-pentamethylheptan-2-ol (100% der-

mal absorption assumed as worst-case) the margin of safety is
70 (100% oral absorption is assumed as shown with 2-ethyl-1-
hexanol). For the other compounds for which systemic uptake
Inhalation, exposure for 15 min
Inhalation exposure for 15 min
in consumers (Table 1) has been estimated by RIFM, the margin

of safety is between 90 and 50,000. There is an adequate margin
of safety for the alcohols under review when applied in con-
sumer products at the current concentrations.
With 3,5,5-trimethyl-1-hexanol adverse effects on reproduction
sMCS: self-reported multiple chemical sensitivity.
were noted at a rather low oral dose (60 mg/kg body weight/
Dose route
day) with a NOAEL of about 10 mg/kg body weight/day. For this

compound the estimated systemic dose is 0.0036 mg/kg body
weight for consumers (Table 1), leading to a margin of safety
of 2700. 2-Ethyl-1-hexanol induced fetotoxic and teratogenic
Sensory irritation studies in humans
effects at high doses of 1300 mg/kg body weight/day in rats,

however, none of the group members tested induced adverse
effects on fertility and development at doses or concentrations

4-Methyl-2-pentanol
Subgroup: secondary
that were not toxic to the parental animals. It should be noted

2-Ethyl-1-hexanol
Subgroup: primary
that in a dermal study with 2-ethyl-1-hexanol no adverse

effects on development in rats were seen with the highest dose
of 2520 mg/kg body weight indicating, that dermal exposure is
Material
less effective in producing adverse effects than oral exposure

Table 8
most probably due to the different pharmacokinetic behavior

for both application routes.
Table 9
Eye irritation studies in rabbits.
Material Method Results References

Subgroup: primary
2-Ethyl-1-butanol Single application, undiluted or diluted in water of Produced an injury of necrosis to 63–87% of the eye Smyth et al. (1954)
propylene glycol, grading after 18–24 h, n.f.i.
2-Ethyl-1-hexanol Single application of 0.005 ml, undiluted, grading after Severe burn Carpenter and Smyth (1946)
18–24 h, n.f.i.
Smyth et al. (1969)
Single application, one drop, undiluted, 50%, 25%, 12.5% Conjunctival redness and swelling, lacrimation, Schmidt et al. (1973)
solutions in oil, observations up to 96 h, one rabbit per discharge, no effects on the cornea
concentration
Undiluted test substance: effects not reversible within
96 h
12.5% no effect
Single application of 0.1 ml, undiluted, observations Severe eye irritant Scala and Burtis (1973)
after 1, 4, and 24 h, 2, 3, 4, and 7 days, 6 rabbits
Median scores after 24, 72 h, and 7 days: 19, 20, 0
(Draize scores)
Corneal dullness, opacity (widespread corneal opacity),
and vascularization, irititis, conjunctival erythema,
chemosis, and discharge
Single application of 0.1 ml, undiluted, observations Persistent corneal effects RIFM (1978b)
after 24, 48, and 72 h, 6 rabbits
Draize scores
24 h: cornea: 17.5, iris: 2.5, conjunctivae: 7.0
Single application of 0.1 ml, undiluted and solution in Draize scores Kennah et al. (1989b)
propylene glycol or water: 110, 14, and 21 days, 6
rabbits
100% solution: 51 (severe), 30%: 35 (severe/moderate),
10%: 39 (moderate), 3%: 30 (moderate), 1%: 9 (mild)
Corneal swelling in % of control:
100% solution: 192%; 30%: 190%; 10%: 162%; 3%: 151%;
1%: 94%
Isoamyl alcohol Single application, undiluted or solution in water or Severe burn Smyth et al. (1969)
propylene glycol, n.f.i. RIFM (1979c)
Isotridecan-1-ol (isomeric mixture) Single application, undiluted and observations 1, 24, 48, Irritation was observed. In one animal slight corneal RIFM (2002b)
72 h and 7 days after application opacity and loss of corneal tissue
Single application, undiluted, 0.5 ml Small area of necrosis on the eye Smyth et al. (1962)
Single application, undiluted and observations 1 ant 24 h Slight irritation RIFM (1963d)
after application
RIFM (1963f)
Single application of 0.1 ml, undiluted, observations Moderately irritating Scala and Burtis (1973)
after 1, 4, and 24 h, 2, 3, 4, and 7 days, 6 rabbits
2-Methylbutanol Single application, undiluted or solution in water or Resulted in injury where corneal necrosis was observed Smyth et al. (1962)
propylene glycol, observations and grading after 24 h, 6
animals
Single application, undiluted and observations after 24, Turbidity at the cornea, inflammation on the iris, and RIFM (1979b)
48, and 72 h, 6 animals redness, swelling, or secretion of the conjunctivae
Subgroup: secondary
2,6-Dimethyl-4-heptanol Undiluted, 0.5 ml application, n.f.i. An average reaction, at most a very small area of Smyth et al. (1949)
necrosis resulting from 0.5 ml of undiluted chemical in
the eye
Single application, undiluted, observations after 24 h, Moderate; some conjunctivitis with some edema and McOmie and Anderson (1949)
and 72 h, 1 animal corneal injury; score 10 after 24 h, returned to score 0

S39
S40
Table 9 (continued)
Material Method Results References

within 72 h
3,7-Dimethyl-7-methoxyoctan-2-ol 0.1 ml of a solution of 1% in propylene glycol, single No irritation RIFM (1973b)
application, observations after 24, 48, and 72 h, 6 5/6 animals: erythema of the conjunctiva, 1/6 animals:
animals chemosis of the conjunctiva
No corneal or iris involvement
Effects cleared within 3 days
4-Methyl-2-pentanol Single application, undiluted or diluted in water or Severe burn from 0.005 ml Smyth et al. (1951)
propylene glycol, grading after 18–24 h, n.f.i.
Single application, undiluted, observations after 1 h, 24, Moderate; some conjunctivitis with some edema and McOmie and Anderson (1949)
and 72 h, 3 animals corneal injury; score 11 after 1 h, 25 after 24 h, 17 after
72 h
Returned to normal within 7 days
3,4,5,6,6-Pentamethylheptan-2-ol Single application, undiluted, 0.1 ml, irrigation for 5 min moderately irritating RIFM (1984c)
after 4 s or 30 s, respectively, or without irrigation, Without irrigation
observations after 1 h, 1, 2, 3, 7 days, 3 animals/group 3/3 animals: hyperaemia of the conjunctiva after 1 h
1/3 animals: chemosis of the conjunctiva after 1 h
2/3 animals: corneal opacity after 1 h
Returned to normal after 7 days
1/3 animals was sacrificed in a moribund state after
2 days (bacterial infection)
Irrigation after 30 s
3/3 animals: hyperaemia and chemosis of the
conjunctiva after 1 h
Returned to normal within 2 days
Irrigation after 4 s
2/3 animals: hyperaemia of the conjunctiva after 1 h
Returned to normal within 1 day
Subgroup: tertiary
2,6-Dimethyl-2-heptanol Single application, undiluted, observations after 24, 48, Primary irritation index (PII): 29.8, moderate irritant RIFM (1979a)
72 h, 8 days, 6 animals After 24 h: 6/6 slight corneal opacity, 2/6 slight iris
effects, 5/6 moderate conjunctival redness, 6/6 moderate

conjunctival swellings, 3/6 conjunctival scars, which
were not reversible within 8 days
3,6-Dimethyl-3-octanola 10% (5 animals), 15% (6 animals), 50% (1 animal), primary irritation index (PII): irritant RIFM (1970)
undiluted (6 animals), solutions in 1.25% Tween 20, 10%: 2.8
observations at 24, 48, 72 h 15%: 3.6
50%: 4.0
Undiluted: 3.6, ranges of grading: corneal opacity 0–1,
iris swelling 0–1, redness and chemosis of conjunctiva
1–2, not reversible within 3 days

a
Table 10-1
Skin sensitization studies in humans.
Material Method Concentration Subjects Results References

Subgroup: primary
2-Ethyl-1-hexanol Maximization test 4% in petrolatum 29 healthy volunteers No sensitization reactions RIFM (1976c)
Isoamyl alcohol Maximization test 8% in petrolatum 25 healthy volunteers No sensitization reactions RIFM (1976b)
3-Methyl-1-pentanol HRIPT 0.5% in alcohol SDA 39C 41 healthy volunteers No sensitization reactions RIFM (1973f)
3,5,5-Trimethyl-1-hexanol Maximization test 8% in petrolatum 25 healthy volunteers No sensitization reactions RIFM (1977b)
Subgroup: secondary
3,7-Dimethyl-7- Maximization test 10% in petrolatum 27 healthy volunteers No sensitization reactions RIFM (1982b)
methoxyoctan-2-ol
3,4,5,6,6-Pentamethylheptan- HRIPT 15% v/v solution in ethanol 51 healthy male and No sensitization reactions RIFM (1983c)
2-ol SDA 39C (99%) female volunteers
Subgroup: tertiary
2,6-Dimethyl-2-heptanol Maximization test 10% in petrolatum 25 healthy volunteers No sensitization reactions RIFM (1976b)
HRIPT 2% in dimethyl phthalate 53 healthy volunteers No sensitization reactions RIFM (1969)
(18 males and 35 females)
HRIPT 5% in alcohol SDA 39C 45 healthy volunteers No sensitization reactions RIFM (1971, 1972b)
(33 females, and 12 males)
3,6-Dimethyl-3-octanola Maximization test 20% in petrolatum 25 healthy male volunteers Inconclusive because subjects RIFM (1972a)
reacted to other test material
on the same Panel
Maximization test 10% in petrolatum 25 healthy male volunteers No sensitization reactions RIFM (1973c)
(this was a retest)
a
3-Methyloctan-3-ol Maximization test 10% in petrolatum 29 healthy male volunteers No sensitization reactions RIFM (1978a)
HRIPT: human repeated insult patch test.

a
Table 10-2
Diagnostic patch tests.
Material Method Concentration Subjects Results Reference

Subgroup: secondary
3,7-Dimethyl-7- Patch Concentration and vehicle not 218 patients with proven contact dermatitis 2 positive Larsen et al.
methoxyoctan-2-ol test reported were tested with 3,7-dimethyl-7- reactions (2002)
methoxyoctan-2-ol
Table 10-3
Skin sensitization studies in animals.

Subgroup: secondary
3,7-Dimethyl-7- According to Food and Drug Administration of the Applications 1–7: 5% Guinea pig (n = 10) No delayed-type RIFM
methoxyoctan- United States of America in ‘‘Appraisal of the Safety of (irritating), hypersensitivity (1973d)
2-ol Chemicals in Food, Drugs and Cosmetics” 1959, p. 51, applications 8–10: 2.5%
except that the test material was applied topically and
not injected: induction: 10 applications with 2.5 or 5%
topically, challenge: 2 weeks later with 2.5% in water
Subgroup: tertiary
2,6-Dimethyl-2- Maximization test Induction: 10% in FCA Guinea pig (10 in test No sensitization Watanabe
heptanol (intradermal), group, 10 in control reactions et al.
challenge: 20% in acetone group) (1988)
FCA: Freund’s complete adjuvant.
Available data on genotoxicity for eight alcohols and three mechanism cannot be completely discounted, it is reasonable
metabolites do not show such a potential in vitro or in vivo. to assume that humans are less sensitive than rodents. In view
Due to the structural similarities of the members of this group of the low use of 2-ethyl-1-hexanol in cosmetic products (0.1–
of alcohols, and because both terpene alcohols (Belsito et al., 1 tons/y) and the low systemic exposure estimated by RIFM
2008) and unsaturated branched chain alcohols (Belsito et al., (0.0005 mg/kg body weight/day), the margin of exposure is
2008) did not show a genotoxic potential, no genotoxicity is 100,000 compared to the NOAEL for liver carcinomas in mice
expected for the other materials of the group. of 50 mg/kg body weight, which is considered to be sufficient
A valid carcinogenicity study showed that 2-ethyl-1-hexanol is for a non-genotoxic compound.
a weak inducer of liver tumors in female mice. Mechanistic
studies showed that 2-ethyl-1-hexanol is an activator of Conflict of interest statement
PPAR-alpha. These substances can contribute to liver carcino-
genesis by increasing tumor promotion. The relevance of this This research was supported by the Research Institute for Fra-
mechanism for humans is still a matter of debate. While this grance Materials, an independent research institute that is funded
Table 11
Phototoxicity and photoallergenicity.

Subgroup: tertiary
2,6-Dimethyl-2-heptanol 0.025 ml/test site on the back (36 test sites, 2 cm2), 10% in 1:1 6 healthy Not phototoxic RIFM
covered, 30 min later the test sites were exposed to ethanol/acetone volunteers (1983a)
UVA irradiation (320–400 nm, 1, 2.5, 5, 10, 20 J/cm2), (females)
observations 4, 24, 48 and 72 h after irradiation
Patch applied 48 h, 4 h after the removal of the 10% in ethanol Albino guinea pig Not phototoxic, after RIFM
patches the animals did receive: (n = 8/group) 4 h 1/8 slight reaction (1981a)
Group A: UVA (320–400 nm), 30 min (in each group), which
Group B: UVB (280–370 nm), 15 min was cleared within
Group C: no irradiation, Group D: not pretreated and 24 h
Radiated from both light sources, observations 4, 24,
48 h after the irradiation
Photoallergy test: induction: 0.1 ml on 8 cm2 of the 10% in rectified Guinea pig No photoallergenicity RIFM
test area, 15 min UVB, 4 h UVA (Westinghouse black alcohol (n = 8/sex) (1981b)
light tubes, from a distance of 25 cm) every 2nd day,
total nine times in 18 days, challenge: after resting
time of 10 days 0.025 ml applied on both flanks, left
flank irradiated as for induction, skin reading 24 and
48 h after challenge
Table 12
Summary of UV spectra data.
Material UV spectra range of absorption (nm)

2-Ethyl-1-hexanol Peaked at 210–215
Returned to baseline at 400 (with minor absorption 290–400)
Isoamyl alcohol Does not absorb UV light
Isotridecan-1-ol (isomeric mixture) Does not absorb UV light
2-Methylbutanol Peaked at 200–215
Returned to baseline at 220–225
3-Methyl-1-pentanol Peaked at 200–210
2-Methylundecanol Peaked at 200–205
3,5,5-Trimethyl-1-hexanol Does not absorb UV light
2,6-Dimethyl-4-heptanol Does not absorb UV light
3,7-Dimethyl-7-methoxyoctan-2-ol Peaked at 200–210
Returned to baseline at 400 (with minor absorption 290–400)
6,8-Dimethylnonan-2-ol Peaked at 200–210
Returned to baseline 230–240 (with minor absorption 260–320)
3,4,5,6,6-Pentamethylheptan-2-ol Peaked at 200–205
Returned to baseline 264–271
2,6-Dimethyl-2-heptanol Does not absorb UV light
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Number 55416. RIFM, Woodcliff Lake, NJ, USA. Range-finding toxicity data, list VII. American Industrial Hygiene Association
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Acute Eye Irritation in Rabbits. Unpublished Report from BASF. Report Number Taubeneck, M.W., Uriu-Hare, J.Y., Commisso, J.F., Borschers, A.T., Bui, L.M., Faber, W.,
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Toxicolology 28, 262–266. development program. Environmental Health Perspectives 45, 99–101.

Review
Fragrance material review on 3,5,5-trimethyl-1-hexanol

D. McGinty *, J. Scognamiglio, C.S. Letizia, A.M. Api
Research Institute for Fragrance Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
Keywords: A toxicologic and dermatologic review of 3,5,5-trimethyl-1-hexanol when used as a fragrance ingredient
Review is presented. 3,5,5-Trimethyl-1-hexanol is a member of the fragrance structural group branched chain
Fragrance
saturated alcohols. The common characteristic structural elements of the alcohols with saturated
branched chain are one hydroxyl group per molecule, and a C4 to C12 carbon chain with one or several
methyl side chains. This review contains a detailed summary of all available toxicology and dermatology
papers that are related to this individual fragrance ingredient and is not intended as a stand-alone doc-
ument. A safety assessment of the entire branched chain saturated alcohol group will be published simul-
taneously with this document; please refer to Belsito et al. (2010) for an overall assessment of the safe
use of this material and all other branched chain saturated alcohols in fragrances.
Ó 2010 Published by Elsevier Ltd.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S48
1. Identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S48
2. Physical properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S48
3. Usage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S48
4. Toxicology data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49
4.1. Acute toxicity (see Table 2). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49
4.2. Skin irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49
4.2.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49
4.3. Mucous membrane (eye) irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49
4.4. Skin sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49
4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49
4.5. Phototoxicity and photoallergy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49
4.6. Absorption, distribution and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49
4.7. Repeated dose toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49
4.7.1. Two to fourteen days studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49
4.7.2. Subchronic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49
4.7.3. Chronic (90+ days) studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S50
4.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S50
4.9.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S50
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S50
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S50
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090.
E-mail address: dmcginty@RIFM.org (D. McGinty).
0278-6915/$ - see front matter Ó 2010 Published by Elsevier Ltd.

doi:10.1016/j.fct.2010.05.026
S48 D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S47–S50
Introduction granted B – information required – 28 days oral study

(COE No. 702).
This document provides a summary of the toxicologic review of 1.7. JECFA (1998): The Joint FAO/WHP Expert Committee on
3,5,5-trimethyl-1-hexanol when used as a fragrance ingredient Food Additives (JECFA No. 268) concluded that the substance
including all human health endpoints. 3,5,5-Trimethyl-1-hexanol does not present a safety concern at current levels of intake
(see Fig. 1; CAS Number 3452-97-9) is a fragrance ingredient used when used as a flavouring agent.
in cosmetics, fine fragrances, shampoos, toilet soaps and other 1.8. FEMA (1970): Flavor and Extract Manufacturers’ Association
toiletries as well as in non-cosmetic products such as household states: generally Recognized as safe as a flavor ingredient –
cleaners and detergents. It is a colorless oily liquid with an oily- GRAS 5.
herbaceous odor (Arctander, 1969). This material has been reported
to occur in nature, with quantities observed in black currants, crab, 2. Physical properties
and strawberry guava (VCF, 2009).
In 2006, a complete literature search was conducted on 3,5,5- 2.1. Physical form: a colorless oily liquid.
trimethyl-1-hexanol. On-line toxicological databases were 2.2. Boiling point (calculated; EPA, 2010): 188.53 °C.
searched including those from the Chemical Abstract Services, 2.3. Flash point: 174 °F; CC.
[e.g. ToxCenter (which in itself contains 18 databases including 2.4. Henry’s law (calculated; EPA, 2010): 0.0000412 atm m3/mol
chemical abstracts)], and the National Library of Medicine [e.g. 25 °C.
Medline, Toxnet (which contains 14 databases)] as well as 26 addi- 2.5. Log Kow (calculated; EPA, 2010): 3.11.
tional sources (e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, 2.6. Refractive index: 1.4318.
fragrance companies were asked to submit all test data. 2.7. Specific gravity: 0.832 (20 °C); 0.8252 (25 °C).
The safety data on this material was last reviewed by Letizia et 2.8. Vapor pressure (calculated; EPA, 2010): 0.2 mm Hg (20 °C);
al. (2000). All relevant references are included in this document. 0.106 mm Hg (25 °C); 14.1 Pa (25 °C)2.9 water solubility
More details have been provided for unpublished data. The number (calculated; EPA, 2010): 572 mg/l (25 °C).
of animals, sex and strain are always provided unless they are not 2.9. UV spectra available. Does not absorb UV light.
given in the original report or paper. Any papers in which the vehi-
cles and/or the doses are not given have not been included in this
3. Usage
review. In addition, diagnostic patch test data with fewer than 100
consecutive patients have been omitted.
3,5,5-Trimethyl-1-hexanol is a fragrance ingredient used in
many fragrance compounds. It may be found in fragrances used
1. Identification in decorative cosmetics, fine fragrances, shampoos, toilet soaps
and other toiletries as well as in non-cosmetic products such as
1.1. Synonyms: 1-hexanol, 3,5,5-trimethyl-; i-nonyl alcohol; household cleaners and detergents. Its use worldwide is in the re-
nonylol; trimethylhexanol; 3,5,5-trimethylhexanol; 3,5,5- gion of 1–10 metric tons per annum (IFRA, 2004). The reported vol-
trimethylhexan-1-ol; 3,5,5-trimethylhexyl alcohol. ume of use is for 3,5,5-trimethyl-1-hexanol as used in fragrance
1.2. CAS Registry Number: 3452-97-9. compounds (mixtures) in all finished consumer product categories.
1.3. EINECS Number: 222-376-7. The volume of use is surveyed by IFRA approximately every 4 years
1.4. Formula: C9H20O. through a comprehensive survey of IFRA and RIFM member com-
1.5. Molecular weight: 144.26. panies. As such the volume of use data from this survey provides
1.6. Council of Europe (2000): 3,5,5-trimethyl-1-hexanol was volume of use of fragrance ingredients for the majority of the
included by the Council of Europe in the list of substances fragrance industry.
The dermal systemic exposure in cosmetic products (see Table 1)
is calculated based on the concentrations of the same fragrance
ingredient in ten types of the most frequently used personal care
and cosmetic products (anti-perspirant, bath products, body lotion,
eau de toilette, face cream, fragrance cream, hair spray, shampoo,
shower gel, and toilet soap). The concentration of the fragrance
HO ingredient in fine fragrances is obtained from examination of sev-
eral thousand commercial formulations. The upper 97.5 percentile
Fig. 1. 3,5,5-Trimethyl-1-hexanol. concentration is calculated from the data obtained. This upper 97.5
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 3,5,5-trimethyl-1-hexanol.
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixturea Ingredient mg/kg/dayb
Anti-perspirant 0.5 1 1 0.01 0.14 0.000100
Bath products 17 0.29 0.001 0.02 0.14 0.000001
Body lotion 8 0.71 1 0.004 0.14 0.000500
Eau de toilette 0.75 1 1 0.08 0.14 0.001400
Face cream 0.8 2 1 0.003 0.14 0.000100
Fragrance cream 5 0.29 1 0.04 0.14 0.001400
Hair spray 5 2 0.01 0.005 0.14 0.000010
Shampoo 8 1 0.01 0.005 0.14 0.000010
Shower gel 5 1.07 0.01 0.012 0.14 0.000010
Toilet soap 0.8 6 0.01 0.015 0.14 0.000020
Total 0.0036
a
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products.
b
Based on a 60-kg adult.
D. McGinty et al. / Food and Chemical Toxicology 48 (2010) S47–S50 S49
percentile concentration is then used for all 10 consumer products. subjects for 48 h under occlusion. No subject had any irritation
These concentrations are multiplied by the amount of product ap- (RIFM, 1977b).
plied, the number of applications per day for each product type,
and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account 4.2.2. Animal studies
for the length of time a product may remain on the skin and/or Irritation was evaluated during the acute dermal study of 3,5,
likelihood of the fragrance ingredient being removed by washing. 5-trimethyl-1-hexanol in 10 rabbits. A single dose of 5.0 g/kg
The resultant calculation represents the total consumer exposure resulted in mild, moderate, or severe erythema and mild or
(mg/kg/day) (Cadby et al., 2002; Ford et al., 2000). moderate edema (RIFM, 1977a).
This is a conservative calculation of dermal systemic exposure
because it makes the unlikely assumption that a consumer will 4.3. Mucous membrane (eye) irritation
use these 10 products containing; which are all perfumed with
the upper 97.5 percentile level of the fragrance ingredient from a No information available.
fine fragrance type of product (Cadby et al., 2002; Ford et al.,
2000). The 97.5% percentile use level in formulae for use in cosmet- 4.4. Skin sensitization
ics in general has been reported to be 0.14 (IFRA, 2007), which
would result in a maximum daily exposure on the skin of 4.4.1. Human studies
0.0035 mg/kg for high end users. 4.4.1.1. Induction studies. In a study involving 25 subjects, a maxi-
A maximum skin level is then determined for consideration of mization test (Kligman, 1966; Kligman and Epstein, 1975) was
potential sensitization. The exposure is calculated as the percent carried out with 3,5,5-trimethyl-1-hexanol in petrolatum on vari-
concentration of the fragrance ingredient applied to the skin based ous panels of volunteers. Application was under occlusion to the
on the use of 20% of the fragrance mixture in the fine fragrance same site on the forearms or backs of all subjects for five alter-
consumer product (IFRA, 2007). The average maximum use level nate-day 48 h periods. Patch sites were pre-treated for 24 h with
in formulae that go into fine fragrances has been reported to be 2.5% aqueous sodium lauryl sulfate (SLS) under occlusion. Follow-
0.68% (IFRA, 2007), assuming use of the fragrance oil at levels up ing a 10–14 days rest period, challenge patches were applied under
to 20% the final product. occlusion to fresh sites for 48 h. Challenge applications were pre-
ceded by 60 min SLS treatment. Reactions were read at patch
4. Toxicology data removal and again at 24 h. There was no evidence of contact
sensitization to 8% 3,5,5-trimethyl-1-hexanol (RIFM, 1977b).
4.1. Acute toxicity (see Table 2)
4.4.1.2. Animal studies. No information available.
4.1.1. Oral studies
The acute oral LD50 of 3,5,5-trimethyl-1-hexanol in rats (10/ 4.5. Phototoxicity and photoallergy
dose) was reported to be 2.3 (95% C.I. 1.7–3.1) g/kg. Mortality was
0, 0, 7, and 10 of 10 rats at 0.67, 1.31, 2.56, and 5.0 g/kg, respec- No information available.
tively. Deaths occurred on days 1, 2, or 3. The observation period
was 14 days. Clinical signs included lethargy, coma, ataxia, diar- 4.6. Absorption, distribution and metabolism
rhea, piloerection, ptosis, and chromorhinorrhea. Necropsy obser-
vations included red/yellow oral/nasal exudates, yellow/brown No information available.
anogenital exudates, dark areas/orange lungs, dark/mottled liver,
dark/mottled kidneys, red/yellow areas of intestines, stomach 4.7. Repeated dose toxicity
bloated/red–yellow areas/fluid filled, spleen mottled (RIFM, 1977a).
4.7.1. Two to fourteen days studies
3,5,5-Trimethyl-1-hexanol was included in a repeat dose oral
4.1.2. Dermal studies
gavage study of a series of compounds related to diethylhexl
The acute dermal LD50 of 3,5,5-trimethyl-1-hexanol in rabbits
phthalate and diethylhexyl adipate in male Alderley Park Wistar-
(10/dose) was reported to be greater than 5.0 g/kg. Mortality was
derived rats. Animals were dosed for 14 days with 1 mM/kg/d
3 of 10 rabbits at 5.0 g/kg. Deaths occurred on days 9, 13, and 14.
(144 mg/kg/d) 3,5,5-trimethyl-1-hexanol dissolved in polyethyl-
Observation period was 14 days. Clinical signs included lethargy,
ene glycol 300. At termination of the study, there was no difference
diarrhea, and anorexia. Necropsy observations included mild, mod-
from controls in body weight, or any clinical or histopathological
erate, or severe erythema and mild or moderate edema, yellow/
signs of hepatotoxicity. At necropsy, relative liver weight was sig-
brown anogenital exudates, dark/mottled liver, dark/mottled/mal-
nificantly greater than that of controls, but peroxisome prolifera-
formed kidneys, red/yellow areas of intestines, stomach bloated
tion and hypocholesterolemia and hypotriglyceridaemia were not
(RIFM, 1977a).
evident (Rhodes et al., 1984).
4.2. Skin irritation

4.7.2. Subchronic studies
Male SD (CRJ:CD) rats were given 3,5,5-trimethyl-1-hexanol by
4.2.1. Human studies
gavage for 46 days at doses of 0, 12, 60, or 300 mg/kg body weight/
In a human maximization test pre-screen, 8% 3,5,5-trimethyl-1-
day in olive oil. Females were dosed 14 days before mating and
hexanol was applied to the volar forearms or backs of 25 healthy
through to day 3 of lactation. Renal hyaline droplets and eosino-
philic bodies were observed (slight to moderate) in all dosed male
Table 2 rats, but these findings were not observed in females. The 60 mg/
Summary of acute toxicity studies. kg body weight/day dose group experienced relative liver and kid-
ney weight increases (males and females), renal epithelial fatty
Route Species No. animals/dose group LD50 (g/kg) References
changes (females), and a decreased implantation index (females).
Oral Rat 10 2.3 RIFM (1977a)
At 300 mg/kg body weight/day one female died, and three were
Dermal Rabbit 10 >5.0 RIFM (1977a)
put down because of weakness. Body weights increased and food
consumption increased in males, but decreased in females. Fe- References

males showed a litter loss in two dams. On the basis of these find-
ings the NOAEL was considered to be 12 mg/kg/day for male and Arctander, S., 1969. Perfume and Flavor Chemicals (Aroma Chemicals), vol. II, No.
3006. S. Arctander, Montclair, New Jersey.
female rats (MHW, Japan, 1997b as cited in OECD/SIDS (2003)). Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,
Sipes, I.G., Smith, R.L., Tagami, H. 2010. A safety assessment of branched chain
4.7.3. Chronic (90+ days) studies saturated alcohols when used as fragrance ingredients, Food and Chemical
Toxicology 48 (S4), S1–S46.
No information available. Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:
providing estimates for safety evaluation. Regulatory Toxicology and
4.8. Reproductive and developmental toxicity Pharmacology 36, 246–252.
Council of Europe, 2000. Partial Agreement in the Social and Public Health Field.
Chemically-defined Flavouring Substances. Group 2.1.3 Aliphatic Alcohols,
No information available. Branched Chain. Number 702. Council of Europe Publishing, Strasbourg. p. 59.
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface
4.9. Genotoxicity Suite™ for MicrosoftÒ Windows, v 4.00 or insert version used. United States
Environmental Protection Agency, Washington, DC, USA.
FEMA (Flavor, Extract Manufacturers Association), 1970. Recent progress in the
4.9.1. In vitro studies consideration of flavoring ingredients under the food additives amendment 4.
4.9.1.1. Bacterial test systems. 3,5,5-Trimethyl-1-hexanol was not GRAS substances. Food Technology 24 (5), 25–34.
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria for
mutagenic in an Ames test (preincubation assay with and without development of a database for safety evaluation of fragrance ingredients.
metabolic activation) in Salmonella typhimurium TA98, TA100, Regulatory Toxicology and Pharmacology 31, 166–181.
TA1535, TA1537 and in E. coli WP2 uvrA assays (MHW, Japan IFRA (International Fragrance Association), 2004. Use Level Survey, August 2004.
IFRA (International Fragrance Association), 2007. Volume of Use Survey, February
1997c as cited in OECD/SIDS (2003) and Kusakabe et al. (2002)). 2007.
JECFA (Joint Expert Committee on Food Additives), 1998. Safety Evaluation of
4.9.1.2. Studies in mammalian cells. 3,5,5-Trimethyl-1-hexanol up to Certain Food Additives. WHO Food Additives Series: 40. Prepared by the Forty-
ninth Meeting of the Joint FAO/WHO Expert Committee on Food Additives
100 lg/plate (cytotoxicity occurred at 200 lg/plate) with or with- (JECFA). World Health Organization, Geneva, 1998.
out metabolic activation, did not induce chromosomal aberrations Kligman, A.M., 1966. The identification of contact allergens by human assay. III. The
or polyploidy in an in vitro Chinese hamster lung cell (OECD TG maximization test. A procedure for screening and rating contact sensitizers.
Journal of Investigative Dermatology 47, 393–409.
473) study (MHW, Japan 1997c as cited in OECD/SIDS (2003) and
Kligman, A.M., Epstein, W., 1975. Updating the maximization test for identifying
Kusakabe et al. (2002). contact allergens. Contact Dermatitis 1, 231–239.
Kusakabe, H., Yamakage, K., Wakuri, S., Sasaki, K., Nakagawa, Y., Watanabe, M.,
4.9.1.3. In vivo studies. No information available. Hayashi, M., Sofuni, T., Ono, H., Tanaka, N., 2002. Relevance of chemical
structure and cytotoxicity to the induction of chromosome aberrations based on
the testing results of 98 high production volume industrial chemicals. Mutation
4.10. Carcinogenicity Research 517 (1–2), 187–198.
Letizia, C.S., Cocchiara, J., Wellington, G.A., Funk, C., Api, A.M., 2000. Monographs on
fragrance raw materials, 3,5,5-trimethyl-1-hexanol. Food and Chemical
No information available. Toxicology 38 (Suppl. 3), S223–S235.
OECD and Screening Information Datasets (SIDS), (2003). High Production Volume
This individual fragrance material review is not intended as a Chemicals 3,5,50 -trimethyl-1-hexanol (CAS No.: 3452-97-9). Processed by
United Nations Environmental Program, (UNEP). Available online: <http://
stand-alone document. Please refer to A Safety Assessment of www.chem.unep.ch/irptc/sids/OECDSIDS/indexcasnumb.htm>.
Branched Chain Saturated Alcohols When Used as Fragrance Ingre- Rhodes, C., Soames, T., Stonard, M.D., Simpson, M.G., Vernall, A.J., Elcombe, C.R.,
dients (Belsito et al., 2010) for an overall assessment of this 1984. The absence of testicular atrophy and in vivo and in vitro effects on
hepatocyte morphology and peroxisomal enzyme activities in male rats
material. following the administration of several alkanols. Toxicology Letters 21, 103–
109.
Conflict of interest statement RIFM (Research Institute for Fragrance Materials, Inc.), 1977a. Acute Toxicity Study
in Rats, Rabbits and Guinea Pigs. RIFM Report Number 1695, July 25 (RIFM,
Woodcliff Lake, NJ, USA).
This research was supported by the Research Institute for Fra- RIFM (Research Institute for Fragrance Materials, Inc.), 1977b. Report on Human
grance Materials, an independent research institute that is funded Maximization Studies. RIFM Report Number 1702, May 09 (RIFM, Woodcliff
Lake, NJ, USA).
by the manufacturers of fragrances and consumer products con- VCF (Volatile Compounds in Food): database. In: Nijssen, L.M., Ingen-Visscher, C.A.
taining fragrances. The authors are all employees of the Research van, Donders, J.J.H. (Eds.), Version 11.1.1 – Zeist (The Netherlands): TNO Quality
Institute for Fragrance Materials. of Life, 1963–2009.

Review
Fragrance material review on 3,7-dimethyl-7-methoxyoctan-2-ol

Keywords: A toxicologic and dermatologic review of 3,7-dimethyl-7-methoxyoctan-2-ol when used as a fragrance

Review ingredient is presented. 3,7-Dimethyl-7-methoxyoctan-2-ol is a member of the fragrance structural
Fragrance
group branched chain saturated alcohols. The common characteristic structural elements of the alcohols
with saturated branched chain are one hydroxyl group per molecule, and a C4–C12 carbon chain with one
or several methyl side chains. This review contains a detailed summary of all available toxicology and
dermatology papers that are related to this individual fragrance ingredient and is not intended as a
stand-alone document. A safety assessment of the entire branched chain saturated alcohol group will
be published simultaneously with this document; please refer to Belsito et al. (2010) for an overall assess-
ment of the safe use of this material and all other branched chain saturated alcohols in fragrances.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S52
3. Usage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S52
4.1. Acute toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53
4.2. Skin irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53
4.2.2. Animal studies (see Table 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53
4.3. Mucous membrane (eye) irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53
4.4. Skin sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53
4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53
4.4.2. Diagnostic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53
4.4.3. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53
4.5. Phototoxicity and photoallergy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S54
4.6. Absorption, distribution and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S54
4.7. Repeated dose toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S54
4.8. Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S54
4.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S54
4.10. Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S54
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S54

doi:10.1016/j.fct.2010.05.027
Introduction 1.3. EINECS number: 255-574-7.

1.4. Formula: C11H24O2.
This document provides a summary of the toxicologic review, 1.5. Molecular weight: 188.31.
including all human health endpoints, of 3,7-dimethyl-7-meth-
oxyoctan-2-ol when used as a fragrance ingredient. 3,7-Dimethyl-
2. Physical properties
7-methoxyoctan-2-ol (see Fig. 1; CAS Number 41890-92-0) is a
fragrance ingredient used in cosmetics, fine fragrances, shampoos,
2.1. Physical form: An almost colorless liquid.
toilet soaps and other toiletries as well as in non-cosmetic products
2.2. Boiling point (calculated; EPA, 2010): 229.67 °C.
such as household cleaners and detergents. It is an almost colorless
2.3. Flash point:>110 °C (230°F).
liquid and has a sandalwood odor with a flowery, woodsy note.
2.4. Henry’s law (calculated; EPA, 2010): 0.000000404 atm m3/
In 2006, a complete literature search was conducted on 3,7-Di-
mol 25 °C.
methyl-7-methoxyoctan-2-ol. On-line toxicological databases 2.5. Log Kow (calculated; EPA, 2010): 2.76.
were searched including those from the Chemical Abstract Ser-
2.6. Refractive index: 1.446.
vices, [e.g. ToxCenter (which in itself contains 18 databases includ- 2.7. Specific gravity: 0.898.
ing Chemical Abstracts)], and the National Library of Medicine [e.g.
2.8. Vapor pressure (calculated; EPA, 2010): 0.0119 mm Hg;
Medline, Toxnet (which contains 14 databases)] as well as 26 addi- 1.58 Pa (25 °C).
tional sources (e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition,
2.9. Water solubility (calculated; EPA, 2010): 707.1 mg/l (25 °C).
fragrance companies were asked to submit all test data. 2.10. UV spectra available at RIFM, peaks at 200–210 nm and
The safety data on this material was last reviewed by Ford et al.,
returns to baseline at 400 nm. Minor absorption from 290–
1992. All relevant references are included in this document. More 400 nm.
details have been provided for unpublished data. The number of
animals, sex and strain are always provided unless they are not gi-
ven in the original report or paper. Any papers in which the vehi- 3. Usage
cles and/or the doses are not given have not been included in this
review. In addition, diagnostic patch test data with fewer than 100 3,7-Dimethyl-7-methoxyoctan-2-ol is a fragrance ingredient
consecutive patients have been omitted. used in many fragrance compounds. It may be found in fragrances
used in decorative cosmetics, fine fragrances, shampoos, toilet
1. Identification soaps and other toiletries as well as in non-cosmetic products such
as household cleaners and detergents. Its use worldwide is in the
1.1. Synonyms: 7-Methoxy-3,7-dimethyloctan-2-ol; 2-Octanol, region of 1–10 metric tons per annum (IFRA, 2004). The reported
7-methoxy-3,7-dimethyl; Osirol; Osyrol; 7-Methoxy-3,7- volume of use is for 3,7-dimethyl-7-methoxyoctan-2-ol as used
dimethyloctan-2-ol. in fragrance compounds (mixtures) in all finished consumer prod-
1.2. CAS Registry number: 41890-92-0. uct categories. The volume of use is surveyed by IFRA approxi-
mately every 4 years through a comprehensive survey of IFRA
and RIFM member companies. As such the volume of use data from
O this survey provides volume of use of fragrance ingredients for the
majority of the fragrance industry.
is calculated based on the concentrations of the same fragrance
ingredient in ten types of the most frequently used personal care
and cosmetic products (anti-perspirant, bath products, body lotion,
ingredient in fine fragrances is obtained from examination of several
thousand commercial formulations. The upper 97.5 percentile con-
centration is calculated from the data obtained. This upper 97.5 per-
centile concentration is then used for all 10 consumer products.
HO These concentrations are multiplied by the amount of product ap-
Fig. 1. 3,7-Dimethyl-7-methoxyoctan-2-ol. and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account for
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 3,7-dimethyl-7-methoxyoctan-2-ol.
Anti-perspirant 0.5 1 1 0.01 3.52 0.0029
Bath products 17 0.29 0.001 0.02 3.52 0.0001
Body lotion 8 0.71 1 0.004 3.52 0.0133
Eau de toilette 0.75 1 1 0.08 3.52 0.0352
Face cream 0.8 2 1 0.003 3.52 0.0028
Fragrance cream 5 0.29 1 0.04 3.52 0.0340
Hair spray 5 2 0.01 0.005 3.52 0.0003
Shampoo 8 1 0.01 0.005 3.52 0.0002
Shower gel 5 1.07 0.01 0.012 3.52 0.0004
Toilet soap 0.8 6 0.01 0.015 3.52 0.0004
Total 0.0897
a
b
Table 2
Summary of animal irritation studies.
Method Dose Species Results References

Dermal application 1% Rabbit Slight erythema RIFM (1973a)
Occluded dermal application Induction Guinea pig During the induction, three animals exhibited slight RIFM (1973b)
5% erythema and one was moderate
2.5% No response to challenge
Challenge
2.5%
the length of time a product may remain on the skin and/or likeli- was no observable response to treatment. At 72 h, the reactions
hood of the fragrance ingredient being removed by washing. The had ameliorated. One animal showed very slight erythema at the
resultant calculation represents the total consumer exposure (mg/ intact and abraded sites. There was no observable response to
kg/day) (Cadby et al., 2002; Ford et al., 2000). treatment in the remaining 5 animals. The Primary Irritation Index
This is a conservative calculation of dermal systemic exposure was calculated to be 0.5 (RIFM, 1973a).
because it makes the unlikely assumption that a consumer will In a guinea pig (n = 10) sensitization study conducted according
use these 10 products containing; which are all perfumed with to US FDA Guidelines, irritation was not induced by 0.2 ml of 2.5%
the upper 97.5 percentile level of the fragrance ingredient from a or 5% 3,7-Dimethyl-7-methoxyoctan-2-ol in water applied under
fine fragrance type of product (Cadby et al., 2002; Ford et al., occlusion to a 0.5 inch square to the shaved area of the shoulder
2000). The 97.5% percentile use level in formulae for use in cosmet- 24 h per day on alternate days during a 3 week period for a total
ics in general has been reported to be 3.52 (IFRA, 2007), which of 10 applications. Applications 1 – 7 were at 5% and applications
would result in a maximum daily exposure on the skin of 8 – 10 were at 2.5%. Challenge dose was applied in the same man-
0.0896 mg/kg for high end users. ner using 2.5% 14 days after the last induction dose. Three animals
A maximum skin level is then determined for consideration of exhibited 1 grade 1 response for erythema once each during the
potential sensitization. The exposure is calculated as the percent induction period and 1 animal exhibited 2 grade 1 erythema re-
concentration of the fragrance ingredient applied to the skin based sponses during induction. There were no positive responses fol-
on the use of 20% of the fragrance mixture in the fine fragrance lowing challenge (RIFM, 1973b).
consumer product (IFRA, 2007). The average maximum use level
in formulae that go into fine fragrances has been reported to be 4.3. Mucous membrane (eye) irritation
1.27% (IFRA, 2007), assuming use of the fragrance oil at levels up
to 20% the final product. In a rabbit (n = 6) eye irritation study conducted according to US
FDA Guidelines, 0.1 ml of 1% 3,7-Dimethyl-7-methoxyoctan-2-ol in
4. Toxicology data propylene glycol produced only temporary mild conjuctival reac-
tions in 5 animals. In one animal chemosis of the conjunctiva
4.1. Acute toxicity was observed. No corneal or iris involvement occurred and all ef-
fects cleared within 3 days (RIFM, 1973c).
4.1.1. Oral studies
The acute oral LD50 of 3,7-dimethyl-7-methoxyoctan-2-ol in 4.4. Skin sensitization
rats was reported to be approximately 5.0 g/kg. Mortality was 2/
5 males at less than 4 h after dosing and 3/5 females at less than 4.4.1. Human studies
23 h after dosing. Symptoms included lethargy, piloerection, diure- 4.4.1.1. Induction studies. In a human Maximization study involving
sis, salivation, and ataxia. Necropsy revealed darkening of the liver 27 subjects, there was no evidence of contact sensitization to 10%
and injection of blood vessels of the abdominal viscera. Recovery of 3,7-Dimethyl-7-methoxyoctan-2-ol (6900 lg/cm2). Test material
survivors was apparently complete within 8 days of dosing. was applied in petrolatum under occlusion to the forearms for a to-
Slightly depressed body weight gains were observed during the tal of five alternate day, 48 h periods. Each application was pre-
first week after dosing in male rats, but returned to normal during ceded by a 24 h occlusive treatment of the patch sites with 7.5%
the second week of observation. Terminal necropsy findings of sur- aqueous sodium lauryl sulfate. Following a 10–14 day rest period,
vivors were normal (RIFM, 1976). challenge patches were applied under occlusion to fresh sites for
48 h. Challenge applications were preceded by 30 min applications
4.1.2. Dermal studies of 7.5% sodium lauryl sulfate under occlusion on the left side and
No available information. no pretreatment on the right side. Challenge sites were evaluated
at removal of the patches and 24 h later (RIFM, 1982).
4.2. Skin irritation
4.4.1.2. Cross-sensitization. No available information.
4.2.1. Human studies
In a human maximization test pre-screen, 10% 3,7-Dimethyl-7- 4.4.2. Diagnostic studies
methoxyoctan-2-ol (6900 lg/cm2) was applied under occlusion to In a diagnostic patch test study, there were positive responses
the backs of 27 healthy subjects for 48 h. No significant evidence of to 3,7-dimethyl-7-methoxyoctan-2-ol (concentration not speci-
irritation was observed (RIFM, 1982). fied) in 2 of 218 dermatology patients with previous positive reac-
tion to at least one fragrance material (Larsen et al., 2002).
4.2.2. Animal studies (see Table 2)
In a rabbit (n = 6) dermal irritation study conducted according 4.4.3. Animal studies
to US FDA Guidelines, 0.5 ml of 1% 3,7-Dimethyl-7-methoxyoc- 4.4.3.1. Maximization Test. No available information.
tan-2-ol in propylene glycol on an occlusive 24 h patch was consid-
ered mildly irritating. Very slight erythema was observed in the 4.4.3.2. Other studies. In a guinea pig (n = 10) sensitization study
intact and abraded sites of 5 animals at 24 h. In one animal there conducted according to US FDA Guidelines, sensitization was not
induced by 0.2 ml of 2.5% or 5% 3,7-dimethyl-7-methoxyoctan-2-ol Conflict of interest statement

in water applied under occlusion to a 0.5 inch square to the shaved
area of the shoulder 24 h per day on alternate days during a 3 week This research was supported by the Research Institute for Fra-
period for a total of 10 applications. Applications 1–7 were at 5% grance Materials, an independent research institute that is funded
and applications 8–10 were at 2.5%. Challenge dose was applied by the manufacturers of fragrances and consumer products con-
in the same manner using 2.5% 14 days after the last induction taining fragrances. The authors are all employees of the Research
dose. Three animals exhibited 1 grade 1 response for erythema Institute for Fragrance Materials.
once each during the induction period and 1 animal exhibited
grade 1 erythema responses twice during induction. There were
References
no positive responses following challenge (RIFM, 1973b).
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,
4.4.3.3. Local Lymph Node Assay (LLNA). No available information. Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chain
saturated alcohols when used as fragrance ingredients. Food and Chemical
Toxicology 48 (S4), S1–S46.
4.5. Phototoxicity and photoallergy Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:
No available information. Pharmacology 36, 246–252.
Suite™ for MicrosoftÒ Windows, V 4.00 or Insert Version Used. United States
4.6. Absorption, distribution and metabolism Environmental Protection Agency, Washington, DC, USA.
Ford, R.A., Api, A.M., Letizia, C.S., 1992. Monograph on 3,7-dimethyl-7-
methoxyoctan-2-ol. Food and Chemical Toxicology 30 (Suppl.), 25S.
No available information.
development of a database for safety evaluation of fragrance ingredients.
4.7. Repeated dose toxicity Regulatory Toxicology and Pharmacology 31, 166–181.
IFRA (International Fragrance Association), 2004. Use Level Survey, August 2004.
No available information. 2007.
Larsen, W., Nakayama, H., Fischer, T., Elsner, P., Frosch, P., Burrows, D., Jordan, W.,
4.8. Reproductive and developmental toxicity Shaw, S., Wilkinson, J., Marks, J., Sugawara, M., Nethercott, M., Nethercott, J.,
2002. Fragrance contact dermatitis – a worldwide multicenter investigation
(Part III). Contact Dermatitis 46 (3), 141–144.
No available information. RIFM (Research Institute for Fragrance Materials, Inc.), 1973a. Irritant Effects of
3,7-Dimethyl-7-methoxyoctan-2-ol on Rabbit Skin. Unpublished Report from
Bush Boake Allen Ltd., 07 June. Report Number 1765. RIFM, Woodcliff Lake,
4.9. Genotoxicity NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1973b. Screening Test for
No available information. Delayed Dermal Sensitization with 3,7-Dimethyl-7-methoxyoctan-2-ol in the
Albino Guinea Pig. Unpublished Report from Bush Boake Allen Ltd., 03 May.
Report Number 1766. RIFM, Woodcliff Lake, NJ, USA.
4.10. Carcinogenicity RIFM (Research Institute for Fragrance Materials, Inc.), 1973c. Irritant effects of 3,7-
Dimethyl-7-methoxyoctan-2-ol on Rabbit Eye Mucosa. Unpublished Report
from Bush Boake Allen Ltd., 07 June. Report Number 1767. RIFM, Woodcliff
Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1976. Acute Oral Toxicity of
This individual Fragrance Material Review is not intended as a Valanone B, Cytenol, 3,7-Dimethyl-7-methoxyoctan-2-ol, 8-Methoxy-p-
stand-alone document. Please refer to A Safety Assessment of menthene and Pinocarvyl Acetate in Rats. Unpublished Report from Bush
Boake Allen Ltd., 23 March. Report Number 1764. RIFM, Woodcliff Lake, NJ, USA.
Branched Chain Saturated Alcohols When Used as Fragrance Ingre-
RIFM (Research Institute for Fragrance Materials, Inc.), 1982. Report on Human
dients (Belsito et al., 2010) for an overall assessment of this Maximization Studies. RIFM Report Number 1643, October 05. RIFM, Woodcliff
material. Lake, NJ, USA.

Review
Fragrance material review on 4-methyl-2-pentanol

Research Institute for Fragrance Materials Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
Keywords: A toxicologic and dermatologic review of 4-methyl-2-pentanol when used as a fragrance ingredient is
Review presented. 4-Methyl-2-pentanol is a member of the fragrance structural group branched chain saturated
Fragrance
alcohols. The common characteristic structural elements of the alcohols with saturated branched chain
are one hydroxyl group per molecule, and a C4–C12 carbon chain with one or several methyl side chains.
This review contains a detailed summary of all available toxicology and dermatology papers that are
related to this individual fragrance ingredient and is not intended as a stand-alone document. A safety
assessment of the entire branched chain saturated alcohol group will be published simultaneously with
this document; please refer to Belsito et al. (2010) for an overall assessment of the safe use of this mate-
rial and all other branched chain saturated alcohols in fragrances.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S56
3. Usage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S56
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57
4.1.3. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57
4.1.4. Miscellaneous studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57
4.3. Mucous membrane (eye) irritation (see Table 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57
4.6.1. Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57
4.6.2. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57
4.6.3. Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57
4.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S58
4.9.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S58
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S58

doi:10.1016/j.fct.2010.05.028
Introduction 2. Physical properties
This document provides a comprehensive summary of the 2.1. Physical form: no information available.
toxicologic review, including all human health endpoints, of 2.2. Boiling point (calculated; EPA, 2010): 124.88 °C.
4-Methyl-2-pentanol when used as a fragrance ingredient. 2.3. Flash point: no information available.
4-Methyl-2-pentanol (see Fig. 1; CAS Number 108-11-2) is a fra- 2.4. Henry’s law (calculated; EPA, 2010): 0.0000176 atm m3/mol
grance ingredient used in cosmetics, fine fragrances, shampoos, 25 °C.
toilet soaps and other toiletries as well as in non-cosmetic prod- 2.5. Log Kow (calculated; EPA, 2010): 1.68.
ucts such as household cleaners and detergents. This material 2.6. Refractive index: no information available.
has been reported to occur in nature, with highest quantities 2.7. Specific gravity: no information available.
observed in annatto extract (VCF, 2009). 2.8. Vapor pressure (calculated; EPA, 2010): 3.7 mm Hg 20 °C;
In 2006, a complete literature search was conducted on 4- 3.74 mm Hg (25 °C); 498 Pa (25 °C).
Methyl-2-pentanol. On-line toxicological databases were searched 2.9. Water solubility (calculated; EPA, 2010): 13,800 mg/l at
including those from the Chemical Abstract Services, [e.g., ToxCen- 25 °C.
ter (which in itself contains 18 databases including Chemical Ab- 2.10. UV spectra not available at RIFM.
stracts)], and the National Library of Medicine [e.g., Medline,
Toxnet (which contains 14 databases)] as well as 26 additional
sources (e.g., BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fra- 3. Usage
grance companies were asked to submit all test data.
The safety data on this material has never been reviewed before 4-Methyl-2-pentanol is a fragrance ingredient used in many fra-
by RIFM (Research Institute for Fragrance Materials, Inc.). All rele- grance compounds. It may be found in fragrances used in decora-
vant references are included in this document. More details have tive cosmetics, fine fragrances, shampoos, toilet soaps and other
been provided for unpublished data. The number of animals, sex toiletries as well as in non-cosmetic products such as household
and strain are always provided unless they are not given in the ori- cleaners and detergents. Its use worldwide is in the region of
ginal report or paper. Any papers in which the vehicles and/or the 0.01–0.1 metric tons per annum (IFRA, 2004). The reported volume
doses are not given have not been included in this review. In addi- is for the use of 4-methyl-2-pentanol used in fragrance compounds
tion, diagnostic patch test data with fewer than 100 consecutive (mixtures) used in all finished consumer product categories. The
patients have been omitted. volume of use is surveyed by IFRA approximately every four years
through a comprehensive survey of IFRA and RIFM member com-
panies. As such the volume of use data from this survey provides
1. Identification volume of use of fragrance ingredients for the majority of the fra-
grance industry.
1.1. Synonyms: Isobutyl methyl carbinol; 4-methylpentan-2-ol; The dermal systemic exposure in cosmetic products (see Table 1)
methyl isobutyl carbinol; MIC; 2-pentanol, 4-methyl- is calculated based on the concentrations of the same fragrance
1.2. CAS registry number: 108-11-2. ingredient in ten types of the most frequently used personal care
1.3. EINECS number: 203-551-7. and cosmetic products (anti-perspirant, bath products, body lotion,
1.4. Formula: C6H14O. eau de toilette, face cream, fragrance cream, hair spray, shampoo,
1.5. Molecular weight: 102.18. shower gel, and toilet soap). The concentration of the fragrance
These concentrations are multiplied by the amount of product ap-
HO and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account for
the length of time a product may remain on the skin and/or likeli-
hood of the fragrance ingredient being removed by washing. The
resultant calculation represents the total consumer exposure (mg/
Fig. 1. 4-Methyl-2-pentanol. kg/day) (Cadby et al., 2002; Ford et al., 2000).
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 4-methyl-2-pentanol.
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixturea Ingredient (mg/kg/day)b
Anti-perspirant 0.5 1 1 0.01 .02 0.000001
Bath products 17 0.29 0.001 0.02 .02 0.000001
Body lotion 8 0.71 1 0.004 .02 0.000100
Eau de toilette 0.75 1 1 0.08 .02 0.000200
Face cream 0.8 2 1 0.003 .02 0.000001
Fragrance cream 5 0.29 1 0.04 .02 0.000200
Hair spray 5 2 0.01 0.005 .02 0.000001
Shampoo 8 1 0.01 0.005 .02 0.000001
Shower gel 5 1.07 0.01 0.012 .02 0.000001
Toilet soap 0.8 6 0.01 0.015 .02 0.000001
Total 0.0005
a
b
Table 2 4.1.3. Inhalation studies

Summary of acute toxicity studies. The acute inhalation exposure of six rats to 4-methyl-2-penta-
Route Species No. animals/ LD50 References nol at 2000 ppm for 8 h was reported to result in mortality of
dose group (g/kg) 5/6. The maximum time for no death was 2 h. No additional details
Oral Rat 5 2.59 Smyth et al., 1951 were reported (Smyth et al., 1951; Carpenter et al., 1949).
Oral Rat N/A 2.95 Bar and Griepentrog, 1967 When mice were exposed to 4-methyl-2-pentanol vapor satu-
Oral Rat N/A 2.59 Nishimura et al., 1994 rated air at 20 °C, mortality was 0, 0, 6, and 8 of 10 animals follow-
Dermal Rabbit 5 3.56 Smyth et al., 1951
ing 4, 8.5, 10, and 15 h, respectively. The observation period was
7 days. Somnolence was induced in 1 h, anesthesia in 4 h, and
death in 10 h. No additional details were reported (McOmie and
Anderson, 1949).
Table 3
4.1.4. Miscellaneous studies
Method Dose Species Reactions References No available Information.
(%)
Dermal irritation 100 Rabbit Trace of capillary Smyth et al., 4.2. Skin irritation
injection 1951
Dermal irritation 100 Rabbit Dry skin with some McOmie and
sloughing and Anderson, 4.2.1. Human studies
cracking 1949 No available information.
4.2.2. Animal studies (see Table 3)

This is a conservative calculation of dermal systemic exposure In a rabbit skin irritation study, 4-methyl-2-pentanol induced
because it makes the unlikely assumption that a consumer will grade 2 irritation defined as an average reaction equivalent to a
use these 10 products containing; which are all perfumed with trace of capillary injection. No additional details were reported
the upper 97.5 percentile level of the fragrance ingredient from a (Smyth et al., 1951, 1949).
fine fragrance type of product (Cadby et al., 2002; Ford et al., In a three rabbit skin irritation study, exposure of rabbits to va-
2000). The 97.5 percentile use level in formulae for use in cosmet- pors of 4-methyl-2-pentanol for 0.25 h resulted in immediate
ics for 2-ethyl-1-hexanol has been reported to be 0.02% (IFRA, slight erythema and delayed moderate erythema with drying of
2007), which would result in a maximum daily exposure on the surface. Five direct applications of the 3.0 ml/kg over a 100 cm2
skin of 0.0005 mg/kg for high end users (see Table 1). area material to the skin of rabbits (n = 3) resulted in severe drying
A maximum skin level is then determined for consideration of of skin with some sloughing and cracking (McOmie and Anderson,
potential sensitization. The exposure is calculated as the percent 1949).
concentration of the fragrance ingredient applied to the skin based
on the use of 20% of the fragrance mixture in the fine fragrance 4.3. Mucous membrane (eye) irritation (see Table 4)
consumer product (IFRA, 2007). The maximum skin level that re-
sults from the use of 4-Methyl-2-pentanol in formulae that go into In a rabbit eye irritation study, 0.005 ml of undiluted 4-methyl-
fine fragrances has not been reported. A default value of 0.02% is 2-pentanol induced injury of up to 5.0 points. A score of five points
used assuming use of the fragrance oils at levels up to 20% in the is given for necrosis on 63–87% visible after fluorescein staining,
final product. without corneal opacity. No additional details were reported
(Smyth et al., 1951, 1949).
4. Toxicology data In a three rabbit eye irritation study conducted according to the
method of Draize, 4-methyl-2-pentanol produced moderate irrita-
4.1. Acute toxicity (see Table 2) tion; some conjunctivitis with some edema and corneal injury but
returned to normal after 7 days (McOmie and Anderson, 1949).
4.1.1. Oral studies
The acute oral LD50 of 4-methyl-2-pentanol in five rats was re- 4.4. Skin sensitization
ported to be 2.59 (2.26–2.97) g/kg. No additional details were re-
ported (Smyth et al., 1951). No available information.
The acute oral LD50 of 4-methyl-2-pentanol in rats was reported
to be 2.95 g/kg. No additional details were reported (Bar and Grie- 4.5. Phototoxicity and photoallergy
pentrog, 1967).
The acute oral LD50 of 4-methyl-2-pentanol in rats was reported No available information.
to be 2.59 g/kg. No additional details were reported (Nishimura
et al., 1994). 4.6. Absorption, distribution and metabolism
4.1.2. Dermal studies 4.6.1. Absorption

The acute dermal LD50 of 4-methyl-2-pentanol in rabbits was No available information.
reported to be 3.56 (2.72–4.76) ml/kg (3.56 g/kg). No additional
details were reported (Smyth et al., 1951). 4.6.2. Distribution
Table 4
Summary of eye irritation studies. 4.6.3. Metabolism
4.6.3.1. In vivo studies in animals. 4-Methyl-2-pentanol (methyl iso-
Dose (%) Reactions References
butyl carbinol, MIBC) is an oxygenated solvent that is metabolized
100 Irritation observed Smyth et al., 1951
to methylisobutyl ketone (MIBK) and then to 4-hydroxymethyl-2-
100 Irritation observed McOmie and Anderson, 1949
pentanone (HMP). Plasma levels of MIBC, MIBK, and HMP were
Table 5
Summary of bacterial studies.
Test system Concentration Results References

Ames assay with and without S9 activation Salmonella typhimurium Up to 5000 lg/plate Not mutagenic Shimizu et al., 1985
TA98, TA100, TA 1535, TA1537 and TA 1538
Escerichia coli WP 2 uvrA
Ames assay with and without S9 activation Salmonella typhimurium 31.25–4000 lg/plate Not mutagenic OECD/SIDS, 2007
TA98, TA100, TA 1535, TA1537 and TA 1538
Escerichia coli WP 2 uvrA pkm 101
Mutation assay Saccharomyces cerevisiae JD1 10–5000 lg/plate Not mutagenic OECD/SIDS, 2007
determined up to 12 h after oral gavage administration of 5 mmol/ 4-Methyl-2-pentanol is not mutagenic according to a gene
kg of MIBC or MIBK (510 and 500 mg/kg, respectively) in corn oil to mutation study with and without metabolic activation in saccharo-
male Sprague–Dawley rats (n = at least three blood samples per myces cerevisiae JD1 at 10–5000 lg/plate (OECD/SIDS, 2007).
sampling time). The major material in the plasma for both test
materials was HMP, with similar areas under the curve (AUCs) 4.9.1.2. Studies in mammalian cells. Rat liver cells (RL4) were tested
and C-max at 9 h after dosing for both MIBC and MIBK. MIBK plas- in a cytogenetic assay with 0, 0.5, 1, or 2 mg/ml of 4-methyl-2-
ma levels and AUC were also comparable after MIBK or MIBC pentanol. According to the conditions of this study the results were
administration. MIBC AUC was only about 6% of the total material negative (OECD/SIDS, 2007).
in the blood following MIBC administration, and insignificant after
MIBK administration. No other metabolites were detected in the 4.9.2. In vivo studies
plasma. The extent of metabolism of MIBC to MIBK was at least No available information.
73% (Gingell et al., 2003; Granvil et al., 1994).
In an occupational exposure study of workers exposed to mixed 4.10. Carcinogenicity
solvents including MIBK or MIBK alone, 4-methyl-2-pentanol was
identified by GCMS in the urine (Hirota, 1991a). No available information.
4-Methyl-2-pentanol was identified as a metabolite following
intraperitoneal administration of MIBK to rats (Hirota, 1991b).
This individual Fragrance Material Review is not intended as a
Excessive urinary glucuronide excretion, compared to that of
stand-alone document. Please refer to A Safety Assessment of
controls, by rabbits (n = 3) following oral gavage administration
of 3 ml/rabbit of 4-methyl-2-pentanol, represented 33.7% of the
dients (Belsito et al., 2010) for an overall assessment of this
administered dose (Kamil et al., 1953).
material.
4.6.3.2. In vitro studies in animals. No available information. Conflict of interest statement
4.7. Repeated dose toxicity This research was supported by the Research Institute for
Fragrance Materials, an independent research institute that is
4-Methyl-2-pentanol was exposed to nine mice 12 times for 4 h funded by the manufacturers of fragrances and consumer products
at 20 mg/l. No deaths were observed (McOmie and Anderson, containing fragrances. The authors are all employees of the
1949). Research Institute for Fragrance Materials.
4-Methyl-2-pentanol was given at doses of 0, 50.5, 198, or
886 ml/m3 to Wistar rats (12/sex) for 6 h per day, 5 days a week, References
over the course of 6 weeks according to OECD guideline TG 407.
At the two lowest doses the concentration of ketone bodies in Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chain
the urine increased for males and females. At 886 ml/m3 the abso- saturated alcohols when used as fragrance ingredients. Food and Chemical
lute kidney weight increased (males) and the serum alkaline phos- Toxicology 48 (S4), S1–S46.
phatase increased (females). The authors concluded a NOAEC at Bar, V.F., Griepentrog, F., 1967. Die Situation in der gesundheitlichen Beurteilung
der Aromatisierungsmittel fur Lebensmittel (where we stand concerning the
198 ml/m3 (OECD/SIDS 2007). evaluation of flavoring substances from the viewpoint of health). Medizin
Ernahr. 8, 244–251.
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:
4.8. Reproductive and developmental toxicity providing estimates for safety evaluation. Regulatory Toxicology and
Pharmacology 36, 246–252.
Carpenter, C.P., Smyth, H.F., Pozzani, U.C., 1949. The assay of acute vapor toxicity,
and the grading and interpretation of results on 96 chemical compounds. The
Journal of Industrial Hygiene and Toxicolology 31 (6), 343–346.
4.9. Genotoxicity Suite™ for MicrosoftÒ Windows, v 4.00 or insert version used. United States
4.9.1. In vitro studies Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria for
4.9.1.1. Bacterial test systems (see Table 5). 4-Methyl-2-pentanol up Regulatory Toxicology and Pharmacology 31, 166–181.
to 5000 lg/plate was not mutagenic in Salmonella typhimurium Gingell, R., Regnier, J.F., Wilson, D.M., Guillaumat, P.O., Appelqvist, T., 2003.
strains TA 98, TA 100, TA1535, TA 1537, and TA 1538 and Escerichia Comparative metabolism of methyl isobutyl carbinol and methyl isobutyl
ketone in male rats. Toxicology Letters 136 (1–2), 199–204.
coli strain WP 2 uvrA, Ames with and without addition of S9 liver
Granvil, C.P., Sharkawi, M., Plaa, G.L., 1994. Metabolic fate of methyl n-butyl ketone,
fractions from KC500 induced rats (Shimizu et al., 1985). methyl isobutyl ketone and their metabolites in mice. Toxicology Letters 70 (3),
An Ames assay with and without metabolic activation found 4- 263–267.
methyl-2-pentanol as non-mutagenic using Salmonella typhimuri- Hirota, N., 1991a. The metabolism of methyl isobutyl ketone and biological
monitoring: part 2. Qualitative and quantitative study of 4-methyl-2-pentanol
um TA98, TA100, TA1535, TA1537, TA1538, E. coli WP2 uvr A excreted in the urine of workers exposed to methyl isobutyl ketone. Okayama
pkm 101 at 31.25–4000 lg/plate (OECD/SIDS, 2007). Igakkai Zasshi 103 (4), 327–336.
Hirota, N., 1991b. The metabolism of methyl isobutyl ketone and its biological 1. Acute oral toxicity to rats. Sangyo Igaku 36 (5), 314–323. Japanese Journal
monitoring: part 1. Qualitative and quantitative studies of methyl isobutyl Industrial Health.
ketone exhaled from the lungs and excreted in the urine, and the metabolites in OECD and Screening Information Datasets (SIDS), (2007). High production volume
the urine of rats inject. Okayama Igakkai Zasshi 103 (4), 315–326. chemicals 4-methylpentan-2-ol (Cas no: 108-11-2). Processed by United
IFRA (International Fragrance Association), 2004. Use level survey, August 2004. Nations Environmental Program, (UNEP) available online: <http://
IFRA (International Fragrance Association), 2007. Volume of use survey, February www.chem.unep.ch/irptc/sids/OECDSIDS/indexcasnumb.htm>.
2007. Shimizu, H., Suzuki, Y., Takemura, N., Goto, S., Matsushita, H., 1985. The results of
Kamil, I.A., Smith, J.N., Williams, R.T., 1953. Studies in detoxication. 46. The microbial mutation test for forty-three industrial chemicals. Japanese Journal of
metabolism of aliphatic alcohols. The glucuronic acid conjugation of acyclic Industrial Health 27 (6), 400–419.
aliphatic alcohols. Biochemical Journal 53, 129–136. Smyth, H.F., Carpenter, C.P., Weil, C.S., 1949. Range-finding toxicity data, list III. The
McOmie, W.A., Anderson, H.H., 1949. Comparative toxicologic effects of some Journal of Industrial Hygiene and Toxicolology 31 (1), 60–62.
isobutyl carbinols and ketones. University California Publications Pharmacology Smyth, H.F., Carpenter, C.P., Weil, C.S., 1951. Range finding toxicity data: List IV.
2 (17), 217–230. Archives of Industrial Hygiene and Occupational Medicine 4, 119–122.
Nishimura, H., Saito, S., Kishida, F., Matsuo, M., 1994. Analysis of acute toxicity VCF, 2009. (Volatile Compounds in Food): database/Nijssen, L.M., Ingen-Visscher,
(LD50-value) of organic chemicals to mammals by solubility parameter (delta). C.A. van, Donders, J.J.H. (Eds.). – Version 11.1.1 – TNO Quality of Life, Zeist, The
Netherlands, 1963–2009.

Review
Fragrance material review on 2-methylundecanol

Keywords: A toxicologic and dermatologic review of 2-methylundecanol when used as a fragrance ingredient is pre-
Review sented. 2-Methylundecanol is a member of the fragrance structural group branched chain saturated alco-
Fragrance
hols. The common characteristic structural elements of the alcohols with saturated branched chain are
one hydroxyl group per molecule, and a C4–C12 carbon chain with one or several methyl side chains. This
review contains the information available on this individual fragrance ingredient and is not intended as a
stand-alone document. A safety assessment of the entire branched chain saturated alcohol group will be
published simultaneously with this document; please refer to Belsito et al. (2010) for an overall assess-
ment of the safe use of this material and all other branched chain saturated alcohols in fragrances.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S60
3. Usage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S61
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S62
Introduction The safety data on this material has never been reviewed before
by RIFM (Research Institute for Fragrance Materials, Inc.). All rele-
This document provides a summary of the toxicologic review, vant references are included in this document. More details have
including all human health endpoints, of 2-methylundecanol when been provided for unpublished data. The number of animals, sex
used as a fragrance ingredient. 2-Methylundecanol (see Fig. 1; CAS and strain are always provided unless they are not given in the ori-
Number 10522-26-6) is a fragrance ingredient used in cosmetics, ginal report or paper. Any papers in which the vehicles and/or the
fine fragrances, shampoos, toilet soaps and other toiletries as well doses are not given have not been included in this review. In addi-
as in non-cosmetic products such as household cleaners and tion, diagnostic patch test data with fewer than 100 consecutive
detergents. patients have been omitted.
In 2006, a complete literature search was conducted on 2-Meth-
ylundecanol. On-line toxicological databases were searched 1. Identification
including those from the Chemical Abstract services, [e.g., ToxCen-
ter (which in itself contains 18 databases including Chemical Ab- 1.1 Synonyms: 1-undecanol, 2-methyl-; 2-methylundecan-1-ol
stracts)], and the National Library of Medicine [e.g., Medline, 1.2 CAS registry number: 10522-26-6
Toxnet (which contains 14 databases)] as well as 26 additional 1.3 EINECS number: 234-067-4
sources (e.g., BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fra- 1.4 Formula: C12H26O
grance companies were asked to submit all test data. 1.5 Molecular weight: 186.39
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090. 2.1 Physical form: no information available
E-mail address: dmcginty@RIFM.org (D. McGinty). 2.2 Boiling point (calculated; EPA, 2010): 262.99 °C

doi:10.1016/j.fct.2010.05.029
use of fragrance ingredients for the majority of the fragrance

industry.
The dermal systemic exposure in cosmetic products (see Ta-
ble 1) is calculated based on the concentrations of the same fra-
grance ingredient in ten types of the most frequently used
personal care and cosmetic products (anti-perspirant, bath prod-
ucts, body lotion, eau de toilette, face cream, fragrance cream, hair
spray, shampoo, shower gel, and toilet soap). The concentration of
the fragrance ingredient in fine fragrances is obtained from exam-
ination of several thousand commercial formulations. The upper
97.5 percentile concentration is calculated from the data obtained.
This upper 97.5 percentile concentration is then used for all 10
consumer products. These concentrations are multiplied by the
amount of product applied, the number of applications per day
for each product type, and a ‘‘retention factor” (ranging from
0.001 to 1.0) to account for the length of time a product may re-
main on the skin and/or likelihood of the fragrance ingredient
being removed by washing. The resultant calculation represents
the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford
Fig. 1. 2-Methylundecanol.
et al., 2000).
because it makes the unlikely assumption that a consumer will
2.3 Flash point: no information available use these 10 products containing; which are all perfumed with
2.4 Henry’s law (calculated; EPA, 2010): 0.0000963 atm m3/mol the upper 97.5 percentile level of the fragrance ingredient from a
25 °C fine fragrance type of product (Cadby et al., 2002; Ford et al.,
2.5 Log Kow (calculated; EPA, 2010): 4.7 2000). The 97.5% percentile use level in formulae for use in cosmet-
2.6 Refractive index: no information available ics in general has been reported to be 0.2 (IFRA, 2007), which
2.7 Specific gravity: no information available would result in a maximum daily exposure on the skin of
2.8 Vapor pressure (calculated; EPA, 2010): 0.0014 mm Hg; 0.0051 mg/kg for high end users.
0.186 Pa (25 °C) A maximum skin level is then determined for consideration of
2.9 Water solubility (calculated; EPA, 2010): 16.18 mg/l (25 °C) potential sensitization. The exposure is calculated as the percent
2.10 UV spectra available at RIFM, peaks at 200–205 nm and concentration of the fragrance ingredient applied to the skin based
returns to baseline at 270–280 nm on the use of 20% of the fragrance mixture in the fine fragrance
in formulae that go into fine fragrances has been reported to be
3. Usage
to 20% in the final product.
2-Methylundecanol is a fragrance ingredient used in many fra-
grance compounds. It may be found in fragrances used in decora-
tive cosmetics, fine fragrances, shampoos, toilet soaps and other 4. Toxicology data
toiletries as well as in non-cosmetic products such as household
cleaners and detergents. Its use worldwide is in the region of No data available on this material.
<0.01 metric tons per annum (IFRA, 2004). The reported volume
of use is for 2-methylundecanol as used in fragrance compounds This individual Fragrance Material Review is not intended as a
(mixtures) in all finished consumer product categories. The volume stand-alone document. Please refer to A Safety Assessment of
of use is surveyed by IFRA approximately every four years through Branched Chain Saturated Alcohols When Used as Fragrance Ingre-
a comprehensive survey of IFRA and RIFM member companies. As dients (Belsito et al., 2010) for an overall assessment of this
such the volume of use data from this survey provides volume of material.
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2-methylundecanol.
Anti-perspirant 0.5 1 1 0.01 0.2 0.000170
Bath products 17 0.29 0.001 0.02 0.2 0.000001
Body lotion 8 0.71 1 0.004 0.2 0.000760
Eau de toilette 0.75 1 1 0.08 0.2 0.002000
Face cream 0.8 2 1 0.003 0.2 0.000160
Fragrance cream 5 0.29 1 0.04 0.2 0.001930
Hair spray 5 2 0.01 0.005 0.2 0.000020
Shampoo 8 1 0.01 0.005 0.2 0.000010
Shower gel 5 1.07 0.01 0.012 0.2 0.000020
Toilet soap 0.8 6 0.01 0.015 0.2 0.000020
Total 0.0051
a
b
Conflict of interest statement assessment of alcohols branched chain saturated when used as fragrance
ingredients. Food and Chemical Toxicology, this issue 48 (S4), S1–S46.
This research was supported by the Research Institute for Fra- providing estimates for safety evaluation. Regulatory Toxicology and
grance Materials, an independent research institute that is funded Pharmacology 36, 246–252.
EPA (Environmental Protection Agency), 2010. Estimation programs interface
by the manufacturers of fragrances and consumer products con-
suite™ for MicrosoftÒ Windows, v 4.00 or insert version used]. United States
taining fragrances. The authors are all employees of the Research Environmental Protection Agency, Washington, DC, USA.
Institute for Fragrance Materials. Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria for
Regulatory Toxicology and Pharmacology 31, 166–181.
References IFRA (International Fragrance Association), 2004. Use level survey, August 2004.
IFRA (International Fragrance Association), 2007. Volume of use survey, February
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H., 2007.
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A toxicologic and dermatologic

Review
Fragrance material review on 3,4,5,6,6-pentamethylheptan-2-ol

Keywords: A toxicologic and dermatologic review of 3,4,5,6,6-pentamethylheptan-2-ol when used as a fragrance

Review ingredient is presented. 3,4,5,6,6-Pentamethylheptan-2-ol is a member of the fragrance structural group
Fragrance
branched chain saturated alcohols. The common characteristic structural elements of the alcohols with
saturated branched chain are one hydroxyl group per molecule, and a C4–C12 carbon chain with one or
several methyl side chains. This review contains a detailed summary of all available toxicology and der-
matology papers that are related to this individual fragrance ingredient and is not intended as a stand-
alone document. A safety assessment of the entire branched chain saturated alcohol group will be pub-
lished simultaneously with this document; please refer to Belsito et al. (2010) for an overall assessment
of the safe use of this material and all other branched chain saturated alcohols in fragrances.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S64
1. Identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S64
2. Physical properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S64
3. Usage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S64
4. Toxicology data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S65
4.1. Acute toxicity (see Table 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S65
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S65
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S65
4.1.3. Intraperitoneal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S65
4.2. Skin irritation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S65
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S65
4.2.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S65
4.3. Mucous membrane (eye) irritation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S65
4.4. Skin sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S65
4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S65
4.4.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S65
4.5. Phototoxicity and photoallergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S65
4.6. Absorption, distribution and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S66
4.7. Repeated dose toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S66
4.7.1. Two to fourteen day studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S66
4.7.2. Subchronic studies (see Table 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S66
4.7.3. Chronic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S66
4.8. Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S66
4.9. Genotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S66
4.9.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S66
4.9.2. In vivo studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S66
4.10. Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S66
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S66
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S66

doi:10.1016/j.fct.2010.05.030
Introduction 2.4. Henry’s law (calculated; EPA, 2010): 0.0000963 atm m3/mole.
2.5. Log Kow: 4.0587 at 19 °C.
This document provides a summary of the toxicologic review, 2.6. Refractive index: no information available.
including all human health endpoints, of 3,4,5,6,6-pentamethyl- 2.7. Specific gravity: no information available.
heptan-2-ol when used as a fragrance ingredient. 3,4,5,6,6-Pen- 2.8. Vapor pressure: 2.088 Pa at 298 K.
tamethylheptan-2-ol (see Fig. 1; CAS Number 87118-95-4) is a 2.9. Water solubility: 0.066 g/l at 19 °C.
fragrance ingredient used in cosmetics, fine fragrances, shampoos, 2.10. UV spectra available at RIFM, peaks at 200–205 nm and
toilet soaps and other toiletries as well as in non-cosmetic prod- returns to baseline 264–271 nm.
ucts such as household cleaners and detergents.
In 2006, a complete literature search was conducted on 3. Usage
3,4,5,6,6-pentamethylheptan-2-ol. On-line toxicological databases
were searched including those from the Chemical Abstract Services 3,4,5,6,6-Pentamethylheptan-2-ol is a fragrance ingredient used
[e.g. ToxCenter (which in itself contains 18 databases including in many fragrance compounds. It may be found in fragrances used
Chemical Abstracts)], and the National Library of Medicine [e.g. in decorative cosmetics, fine fragrances, shampoos, toilet soaps and
Medline, Toxnet (which contains 14 databases)] as well as 26 addi- other toiletries as well as in non-cosmetic products such as house-
tional sources (e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, hold cleaners and detergents. Its use worldwide is in the range of
fragrance companies were asked to submit all test data. 10–100 metric tons per annum (IFRA, 2004). The reported volume
The safety data on this material has never been reviewed before of use is for 3,4,5,6,6-pentamethylheptan-2-ol as used in fragrance
by RIFM (Research Institute for Fragrance Materials, Inc.). All rele- compounds (mixtures) in all finished consumer product categories.
vant references are included in this document. More details have The volume of use is surveyed by IFRA approximately every four
been provided for unpublished data. The number of animals, sex years through a comprehensive survey of IFRA and RIFM member
and strain are always provided unless they are not given in the ori- companies. As such the volume of use data from this survey pro-
ginal report or paper. Any papers in which the vehicles and/or the vides volume of use of fragrance ingredients for the majority of
doses are not given have not been included in this review. In addi- the fragrance industry.
tion, diagnostic patch test data with fewer than 100 consecutive The dermal systemic exposure in cosmetic products (see Table 1)
patients have been omitted. is calculated based on the concentrations of the same fragrance
ingredient in 10 types of the most frequently used personal care
1. Identification and cosmetic products (anti-perspirant, bath products, body lotion,
1.1. Synonyms: 2-heptanol, 3,4,5,6,6-pentamethyl-; Koavol DH. shower gel, and toilet soap). The concentration of the fragrance
1.2. CAS Registry Number: 87118-95-4. ingredient in fine fragrances is obtained from examination of sev-
1.3. EINECS Number: 401-030-0. eral thousand commercial formulations. The upper 97.5 percentile
1.4. Formula: C12H26O. concentration is calculated from the data obtained. This upper
1.5. Molecular weight: 186.39. 97.5 percentile concentration is then used for all 10 consumer prod-
ucts. These concentrations are multiplied by the amount of product
2. Physical properties applied, the number of applications per day for each product type,
and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account for
2.1. Physical form: no information available. the length of time a product may remain on the skin and/or likeli-
2.2. Boiling point: 220.2–231.7 °C. hood of the fragrance ingredient being removed by washing. The
2.3. Flash point: 365.5 K (92.5 °C). resultant calculation represents the total consumer exposure (mg/
kg/day) (Cadby et al., 2002; Ford et al., 2000).
the upper 97.5 percentile level of the fragrance ingredient from a
2000). The 97.5 percentile use level in formulae for use in cosmet-
ics in general has been reported to be 5.5% (IFRA, 2007), which
would result in a maximum daily exposure on the skin of
Fig. 1. 3,4,5,6,6-Pentamethylheptan-2-ol. 0.1403 mg/kg for high end users.
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 3,4,5,6,6-pentamethylheptan-2-ol.
Anti-perspirant 0.5 1 1 0.01 5.5 0.0046
Bath products 17 0.29 0.001 0.02 5.5 0.0001
Body lotion 8 0.71 1 0.004 5.5 0.0208
Eau de toilette 0.75 1 1 0.08 5.5 0.0550
Face cream 0.8 2 1 0.003 5.5 0.0044
Fragrance cream 5 0.29 1 0.04 5.5 0.0532
Hair spray 5 2 0.01 0.005 5.5 0.0005
Shampoo 8 1 0.01 0.005 5.5 0.0004
Shower gel 5 1.07 0.01 0.012 5.5 0.0006
Toilet soap 0.8 6 0.01 0.015 5.5 0.0007
Total 0.1401
a
b
A maximum skin level is then determined for consideration of placed on the subjects’ skin between the left scapula and spinal
potential sensitization. The exposure is calculated as the percent mid-line for 24 h under occlusion. After a 24–48 h rest period, sub-
concentration of the fragrance ingredient applied to the skin based jects were again patched at the same site. Nine applications were
on the use of 20% of the fragrance mixture in the fine fragrance made in a three week period. Slight irritation was observed in 5
consumer product (IFRA, 2007). The average maximum use level of the 51 male and female volunteers (RIFM, 1983).
1.73% (IFRA, 2007), assuming use of the fragrance oil at levels up 4.2.2. Animal studies
to 20% in the final product. A group of six male albino New Zealand rabbits were given
0.5 ml of the undiluted 3,4,5,6,6-pentamethylheptan-2-ol and ob-
4. Toxicology data served for up to 72 h. Erythema and edema were not observed in
any of the six rabbits tested (RIFM, 1984b).
4.3. Mucous membrane (eye) irritation
4.1.1. Oral studies
Sprague–Dawley albino rats were divided into three groups of 3,4,5,6,6-Pentamethylheptan-2-ol was evaluated for eye irrita-
10 animals, consisting of five males and five females per group. tion in nine healthy albino rabbits. Undiluted aliquots of 0.1 ml
The three dose levels of undiluted 3,4,5,6,6-pentamethylheptan- were instilled into one eye. The untreated eye of each animal
2-ol was orally administered (via gavage) at 7.81, 6.25, or 5.0 g/ served as a control. Observations were made at 1 h, and daily
kg bodyweight. Animals were observed immediately after dosing, thereafter for a week. Irritation was observed in the cornea and
at 1 and 4 h, and twice daily thereafter for 14 days. At 5.0 g/kg 1 conjunctiva, but cleared by the seventh day (RIFM, 1984c).
of 10 died, and clinical signs included moderate salivation, piloe-
rection, lethargy, lacrimation, hunched posture, and epistaxis. At 4.4. Skin sensitization
6.25 g/kg, 8 of 10 died with clinical signs including diarrhea, 4.4.1. Human studies
hunched posture, lethargy, piloerection, ataxia, moderate tremors, 4.4.1.1. Induction studies. A repeated insult patch tests was con-
lacrimation, and epistaxis. In the highest dosage group (7.81 g/kg) ducted to determine if 15% 3,4,5,6,6-pentamethylheptan-2-ol in
9 of 10 died, and clinical signs were the same as above. No controls alcohol SDA-39C would induce dermal sensitization in 51 human
were used and the LD50 was calculated to be 5.845 (5.36–6.375) g/ volunteers. During the induction phase 0.2 ml was applied onto
kg bodyweight (RIFM, 1984a). Parke–Davis Readi–Bandages and applied to the backs of each vol-
unteer for 24 h. Induction applications were made for a total of
4.1.2. Dermal studies nine applications during three week period. Following a one week
A group of 10 (5/sex) HC/CFY (remote Sprague–Dawley) rats rest period, a challenge patch was applied to a site previously un-
were treated with the 3,4,5,6,6-pentamethylheptan-2-ol at 2.0 g/ exposed on the upper back. Patches were applied as in the induc-
kg bodyweight. A dermal application was made to the dorso-lum- tion phase and kept in place for 24 h after which time they were
bar region (which had been previously clipped free of fur), covered removed. Reactions to the challenge were scored at 24, 48, and
with a gauze patch, and held in place with an impermeable dress- 72 h after application. There were no sensitization reactions during
ing. All animals were observed soon after dosing, frequently on day the challenge phase (RIFM, 1983).
1, and at least twice per day for 14 days after dosing. There were no
mortalities, clinical signs of toxicity, or skin reactions at the site of 4.4.2. Animal studies
application. The acute LD50 was determined to be greater than No information available.
2.0 g/kg bodyweight (RIFM, 1985c).
4.5. Phototoxicity and photoallergy
4.1.3. Intraperitoneal studies No information available.
In a preliminary dose range finding study, 3,4,5,6,6-pentameth-
4.6. Absorption, distribution and metabolism
ylheptan-2-ol was administered intraperitoneally to eight groups
(2/sex/group) of CD-1 mice at doses of 50, 166, 500, 750, 1000, No information available.
1250, 1666 and 3000 mg/kg bodyweight. Signs were observed at
4.7. Repeated dose toxicity
all levels of 1000 mg/kg and higher. One animal died at 1250 mg/
kg and all animals at the two highest dosage levels. Due to the
4.7.1. Two to fourteen day studies
severity of the signs and mortality, 900 mg/kg was selected as
No information available.
the maximum tolerated dose (RIFM, 1985a).
4.7.2. Subchronic studies (see Table 3)
4.2. Skin irritation 3,4,5,6,6-Pentamethylheptan-2-ol was assessed for its toxicity
to 10 New Zealand white rabbits (5/sex) when administered to
4.2.1. Human studies the occluded skin. Applications of 1000 mg/kg were made for 6 h
Irritation was evaluated during the induction phase in a human each day for 28 consecutive days. Irritation progressed rapidly in
repeated insult patch test (HRIPT). A 0.2 ml aliquot of a 15% solu- all rabbits and within two weeks severe erythema and edema were
tion in alcohol SDA-39C was applied to clear plastic patches, observed. Histopathological examination revealed the treated skin
1.5 1.5 in. (Parke–Davis Readi–Bandages). The patches were to have acanthotic and focal ulcerative changes in the epidermis,
Table 2
along with associated inflammation, hyperkeratosis, and scab for-
Summary of acute toxicity studies. mation. A systemic NOAEL of 1000 mg/kg bodyweight/day was
decided for 3,4,5,6,6-pentamethylheptan-2-ol although severe irri-
Route Species Number of LD50 (g/kg) References
animals/dose group
tation was observed (RIFM, 1985d).
At concentrations of 1.5%, 5.0%, 15%, and 50% 3,4,5,6,6-pentam-
Oral Rat 10 5.8 RIFM (1984a)
ethylheptan-2-ol in 1% aqueous methylcellulose (equivalent to 30,
Dermal Rat 10 >2.0 RIFM (1985a)
100, 300, and 1000 mg/kg/day) was applied to the intact skin of
Table 3
Summary of subchronic studies.

(mg/kg/day)
Dermal application under occlusion 1000 Rabbits NOAEL: 1000 mg/kg bodyweight/day RIFM (1985d)
Severe irritation; associated inflammation,
hyperkeratosis, and scabbing
Dermal application under occlusion Up to 1000 Rabbits NOAEL: 1000 mg/kg bodyweight/day RIFM (1986)
Slight to moderate dermal irritation; severe
irritation at high doses; reversible after 8 days
New Zealand white rabbits (10/sex). The two lowest dosages (30 dients (Belsito et al., 2010) for an overall assessment of this
and 100 mg/kg/day) were allowed to run for 6 h per day, and 28 material.
consecutive days under an occlusive patch. Slight to moderate der-
mal irritation developed for both dosages but ameliorated by day
16 for 30 mg/kg/day, and persisted to termination for 100 mg/kg/ Conflict of interest statement
day. Treatment of the two highest dosages (300 and 1000 mg/kg/
day) was terminated after nine applications because of the severity This research was supported by the Research Institute for Fra-
of the dermal reactions. However, after 8 days irritation subsided grance Materials, an independent research institute that is funded
and the data suggests the dermal reactions are reversible. A sys- by the manufacturers of fragrances and consumer products con-
temic NOAEL of 1000 mg/kg bodyweight/day was decided for taining fragrances. The authors are all employees of the Research
3,4,5,6,6-pentamethylheptan-2-ol although severe irritation was Institute for Fragrance Materials.
observed (RIFM, 1986).
4.7.3. Chronic studies

References
4.8. Reproductive and developmental toxicity saturated alcohols when used as fragrance ingredients. Food and Chemical
No information available. Toxicology 48 (S4), S1–S46.
4.9. Genotoxicity
4.9.1. In vitro studies Suite™ for MicrosoftÒ Windows, v 4.00 or Insert Version Used. United States
4.9.1.1. Bacterial test systems. An Ames test using 0.1 ml of
3,4,5,6,6-pentamethylheptan-2-ol was added to Escherichia coli development of a database for safety evaluation of fragrance ingredients.
WP2 uvrA, Salmonella typhimurium TA 98, 100, 1535, 1537, and Regulatory Toxicology and Pharmacology 31, 166–181.
1538 cultures at concentrations up to 1000 lg/plate with and IFRA (International Fragrance Association), 2004. Use Level Survey, August 2004.
without S9 activation. Toxicity was observed with tester strains 2007.
TA 98, 100, and 1535 at the higher dose levels. A second round RIFM (Research Institute for Fragrance Materials, Inc.), 1983. Evaluation of Potential
of tests, up to 100 lg/plate, did not show any substantial increases Irritation and Sensitization Hazards by Dermal Contact: Repeated Insult Patch
Test with 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished Report from
in revertant colony numbers. It was concluded that the test mate- International Flavors and Fragrances, 27 October. Report Number 48462,
rial showed no evidence of mutagenic activity in these bacterial RIFM, Woodcliff Lake, NJ, USA.
systems (RIFM, 1985b). RIFM (Research Institute for Fragrance Materials, Inc.), 1984a. Acute Oral LD50
Determination in the Rat on 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished
Report from International Flavors and Fragrances, Report Number 47552, RIFM,
4.9.1.2. Studies in mammalian cells. No information available.
Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1984b. Primary Dermal
4.9.2. In vivo studies Irritation Test of 3,4,5,6,6-Pentamethylheptan-2-ol on the Rabbit. Unpublished
Report from International Flavors and Fragrances, Report Number 47792, RIFM,
In a CD-1 mouse micronucleus test, three groups of 10 animals
(5 males and 5 females per group) were given single doses of RIFM (Research Institute for Fragrance Materials, Inc.), 1984c. Acute Eye Irritation/
3,4,5,6,6-pentamethylheptan-2-ol in corn oil by intraperitoneal Corrosion Test to the Rabbit of 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished
injection at 900 mg/kg and sacrificed at 30, 48, and 72 h. All groups Report from International Flavors and Fragrances, Report Number 47677, RIFM,
showed significantly lower ratios of polychromatic erythrocytes to RIFM (Research Institute for Fragrance Materials, Inc.), 1985a. Acute Dermal
normochromatic erythrocytes (PCE/NCE) suggesting the bioavail- Toxicity to the Rat of 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished Report
ability of the test article. Statistically significant increases in the from International Flavors and Fragrances, Report Number 47587, RIFM,
incidence of micronuclei of experimental animals were not ob- RIFM (Research Institute for Fragrance Materials, Inc.), 1985b. Microbial Metabolic
served. Based upon the inability of the test article to produce a sig- Activation Test to Assess the Potential Mutagenic Effect of 3,4,5,6,6-
nificant increase in the incidence of micronuclei per 1000 Pentamethylheptan-2-ol. Unpublished Report from International Flavors and
Fragrances, Report Number 48164, RIFM, Woodcliff Lake, NJ, USA.
polychromatic erythrocytes in the treated versus the negative con- RIFM (Research Institute for Fragrance Materials, Inc.), 1985c. Micronucleus Test
trol groups, 3,4,5,6,6-pentamethylheptan-2-ol was determined to (MNT) OECD on 3,4,5,6,6-Pentamethylheptan-2-ol. Unpublished Report from
be negative in the micronucleus test (RIFM, 1985c). International Flavors and Fragrances, Report Number 48252, RIFM, Woodcliff
Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1985d. Twenty-eight Day
4.10. Carcinogenicity
Dermal Irritation Study in Rabbits with 3,4,5,6,6-Pentamethylheptan-2-ol.
No available information. Unpublished Report from International Flavors and Fragrances, Report
Number 47793, RIFM, Woodcliff Lake, NJ, USA.
This individual Fragrance Material Review is not intended as a RIFM (Research Institute for Fragrance Materials, Inc.), 1986. Twenty-eight Day
Dermal Irritation Study in Rabbits with 3,4,5,6,6-Pentamethylheptan-2-ol.
stand-alone document. Please refer to A Safety Assessment of Unpublished Report from International Flavors and Fragrances, Report
Branched Chain Saturated Alcohols When Used as Fragrance Ingre- Number 48027, RIFM, Woodcliff Lake, NJ, USA.

Review
Fragrance material review on isodecyl alcohol

Keywords: A toxicologic and dermatologic review of isodecyl alcohol when used as a fragrance ingredient is pre-
Review sented. Isodecyl alcohol is a member of the fragrance structural group branched chain saturated alcohols.
Fragrance
The common characteristic structural elements of the alcohols with saturated branched chain are one
hydroxyl group per molecule, and a C4–C12 carbon chain with one or several methyl side chains. This
review contains a detailed summary of all available toxicology and dermatology papers that are related
to this individual fragrance ingredient and is not intended as a stand-alone document. A safety assess-
ment of the entire branched chain saturated alcohol group will be published simultaneously with this
document; please refer to Belsito et al. (2010) for an overall assessment of the safe use of this material
and all other branched chain saturated alcohols in fragrances.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S67
3. Usage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S68
4.1. Acute toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S69
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S69
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S69
4.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S69
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S69
Introduction Number 25339-17-7) is a fragrance ingredient used in cosmetics,

fine fragrances, shampoos, toilet soaps and other toiletries as well
This document provides a summary of the toxicologic review, as in non-cosmetic products such as household cleaners and
including all human health endpoints, of isodecyl alcohol when detergents.
used as a fragrance ingredient. Isodecyl alcohol (see Fig. 1; CAS In 2006, a complete literature search was conducted on isodecyl
alcohol. On-line toxicological databases were searched including
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090. those from the Chemical Abstract Services [e.g. ToxCenter (which
E-mail address: dmcginty@RIFM.org (D. McGinty). in itself contains 18 databases including Chemical Abstracts)],

doi:10.1016/j.fct.2010.05.031
2.1. Physical form: no information available.

2.3. Flash point: no information available.
2.4. Henry’s law (calculated; EPA, 2010): 0.0000547 atm m3/mol
(25 °C).
2.5. Log Kow (calculated; EPA, 2010): 3.71.
2.6. Refractive index: no information available.
2.7. Specific gravity: no information available.
2.72 Pa (25 °C).
2.9. Water solubility (calculated; EPA, 2010): 151.8 mg/l (25 °C).
2.10. UV spectra not available at RIFM.
3. Usage
Isodecyl alcohol is a fragrance ingredient used in many fra-

tive cosmetics, fine fragrances, shampoos, toilet soaps and other
cleaners and detergents. Its use worldwide is in the region of
0.1–1.0 metric tons per annum (IFRA, 2004). The reported volume
Fig. 1. Isodecyl alcohol. of use is for isodecyl alcohol as used in fragrance compounds (mix-
use is surveyed by IFRA approximately every four years through
a comprehensive survey of IFRA and RIFM member companies.
and the National Library of Medicine [e.g. Medline, Toxnet
As such the volume of use data from this survey provides volume
(which contains 14 databases)] as well as 26 additional sources
of use of fragrance ingredients for the majority of the fragrance
(e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance
industry.
companies were asked to submit all test data.
The dermal systemic exposure in cosmetic products (see
The safety data on this material has never been reviewed before
Table 1) is calculated based on the concentrations of the same fra-
grance ingredient in 10 types of the most frequently used personal
vant references are included in this document. More details have
care and cosmetic products (anti-perspirant, bath products, body
been provided for unpublished data. The number of animals, sex
lotion, eau de toilette, face cream, fragrance cream, hair spray,
and strain are always provided unless they are not given in the ori-
shampoo, shower gel, and toilet soap). The concentration of the
ginal report or paper. Any papers in which the vehicles and/or the
fragrance ingredient in fine fragrances is obtained from examina-
doses are not given have not been included in this review. In addi-
tion of several thousand commercial formulations. The upper
tion, diagnostic patch test data with fewer than 100 consecutive
patients have been omitted.
1. Identification amount of product applied, the number of applications per day
1.1. Synonyms: isodecanol; 8-methylnonan-1-ol. 0.001 to 1.0) to account for the length of time a product may re-
1.2. CAS Registry Number: 25339-17-7. main on the skin and/or likelihood of the fragrance ingredient
1.3. EINECS Number: 246-869-1. being removed by washing. The resultant calculation represents
1.4. Formula: C10H22O. the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford
1.5. Molecular weight: 158.85. et al., 2000).
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing isodecyl alcohol.
Anti-perspirant 0.5 1 1 0.01 0.0009 0.0000001
Bath products 17 0.29 0.001 0.02 0.0009 0.0000001
Body lotion 8 0.71 1 0.004 0.0009 0.0000001
Eau de toilette 0.75 1 1 0.08 0.0009 0.0000100
Face cream 0.8 2 1 0.003 0.0009 0.0000001
Fragrance cream 5 0.29 1 0.04 0.0009 0.0000100
Hair spray 5 2 0.01 0.005 0.0009 0.0000001
Shampoo 8 1 0.01 0.005 0.0009 0.0000001
Shower gel 5 1.07 0.01 0.012 0.0009 0.0000001
Toilet soap 0.8 6 0.01 0.015 0.0009 0.0000001
Total 0.00002
a
b
This is a conservative calculation of dermal systemic exposure and 10 mmol/kg (0, 158, 790, and 1580 mg/kg/day) on gestation
because it makes the unlikely assumption that a consumer will days 6–15. Maternal toxicity and incidences of fetal retardations
use these 10 products containing; which are all perfumed with and rare malformations were observed at 10 mmol/kg. Maternal
the upper 97.5 percentile level of the fragrance ingredient from a mortality was 4/10 in this dose group. Body weight on days 15
fine fragrance type of product (Cadby et al., 2002; Ford et al., and 20, uterus weight, and fetal weights were all significantly low-
2000). The 97.5 percentile use level in formulae for use in cosmet- er than controls in the 10 mmol/kg group. Post-implantation loss,
ics in general has been not been reported. As such the default value resorptions, and number of fetuses with malformations were all
of 0.02% is used to calculate the maximum daily exposure on the higher than controls at 10 mmol/kg. There was no maternal mor-
skin of 0.00002 mg/kg for high end users. tality in any of the other groups. Some maternal signs, but no fetal
A maximum skin level is then determined for consideration of signs were observed at 5 mmol/kg. The clinical signs included nasal
potential sensitization. The exposure is calculated as the percent discharge, salivation, and signs of CNS depression. None of the
concentration of the fragrance ingredient applied to the skin based measured maternal or fetal parameters were significantly different
on the use of 20% of the fragrance mixture in the fine fragrance than controls at this dose. The NOEL for maternal effects was
consumer product (IFRA, 2007). The average maximum use level 1 mmol/kg and for fetal effects 5 mmol/kg (Hellwig and Jackh,
in formulae that go into fine fragrances has not been reported. A 1997).
default value of 0.02% is used, assuming use of the fragrance oil
levels up to 20% in the final product. 4.9. Genotoxicity
4. Toxicology data No information available.
4.1. Acute toxicity 4.10. Carcinogenicity
4.1.1. Oral studies No information available.

The acute oral LD50 of isodecyl alcohol in rats was reported to be
6.5 g/kg. No additional details available (Article in Japanese) This individual Fragrance Material Review is not intended as a
(Nishimura et al., 1994). stand-alone document. Please refer to A Safety Assessment of
4.1.2. Dermal studies dients (Belsito et al., 2010) for an overall assessment of this
No information available. material.
4.2. Skin irritation Conflict of interest statement
No information available. This research was supported by the Research Institute for Fra-
grance Materials, an independent research institute that is funded
4.3. Mucous membrane (eye) irritation by the manufacturers of fragrances and consumer products con-
taining fragrances. The authors are all employees of the Research
No information available. Institute for Fragrance Materials.
4.4. Skin sensitization References
No information available. Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,
4.5. Phototoxicity and photoallergy Toxicology 48 (S4), S1–S46.
No information available. Pharmacology 36, 246–252.
4.6. Absorption, distribution and metabolism Suite™ for MicrosoftÒ Windows v 4.00 or Insert Version Used. United States
No information available. development of a database for safety evaluation of fragrance ingredients.
Hellwig, J., Jackh, R., 1997. Differential prenatal toxicity of one straight-chain and
five branched-chain primary alcohols in rats. Food and Chemical Toxicology 35
(5), 489–500.
No information available. IFRA (International Fragrance Association), 2004. Use Level Survey, August 2004.
2007.
4.8. Reproductive and developmental toxicity Nishimura, H., Saito, S., Kishida, F., Matsuo, M., 1994. Analysis of acute toxicity
(LD50-value) of organic chemicals to mammals by solubility parameter (delta).
In a comparative developmental toxicity study, isodecyl alcohol 1. Acute oral toxicity to rats. Sangyo Igaku 36 (5), 314–323 (Japanese Journal
Industrial Health).
was administered by gavage to Wistar rats (10/group) at 0, 1, 5,

Review
Fragrance material review on isooctan-1-ol

Keywords: A toxicologic and dermatologic review of isooctan-1-ol when used as a fragrance ingredient is presented.
Review Isooctan-1-ol is a member of the fragrance structural group branched chain saturated alcohols. The com-
Fragrance
mon characteristic structural elements of the alcohols with saturated branched chain are one hydroxyl
group per molecule, and a C4–C12 carbon chain with one or several methyl side chains. This review con-
tains a detailed summary of all available toxicology and dermatology papers that are related to this indi-
vidual fragrance ingredient and is not intended as a stand-alone document. A safety assessment of the
entire branched chain saturated alcohol group will be published simultaneously with this document;
please refer to Belsito et al. (2010) for an overall assessment of the safe use of this material and all other
branched chain saturated alcohols in fragrances.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S70
1. Identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S71
2. Physical properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S71
3. Usage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S71
4. Toxicology data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S72
4.1. Acute toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S72
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S72
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S72
4.1.3. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S72
4.2. Skin irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S72
4.3. Mucous membrane (eye) irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S72
4.4. Skin sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S72
4.5. Phototoxicity and photoallergy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S72
4.6. Absorption, distribution and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S72
4.7. Repeated dose toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S72
4.8. Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S72
4.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S72
4.10. Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S72
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S72
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S72
Introduction grances, shampoos, toilet soaps and other toiletries as well as in

non-cosmetic products such as household cleaners and detergents.
This document provides a summary of the toxicologic review, In 2006, a complete literature search was conducted on isooc-
including all human health endpoints, of isooctan-1-ol when used tan-1-ol. On-line toxicological databases were searched including
as a fragrance ingredient. Isooctan-1-ol (see Fig. 1; CAS Number those from the Chemical Abstract Services [e.g. ToxCenter (which
26952-21-6) is a fragrance ingredient used in cosmetics, fine fra- in itself contains 18 databases including Chemical Abstracts)],
and the National Library of Medicine [e.g. Medline, Toxnet (which
contains 14 databases)] as well as 26 additional sources (e.g. BIO-
* Corresponding author. Tel.: +1 201 689 8089x123; fax: +1 201 689 8090. SIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance companies
E-mail address: dmcginty@RIFM.org (D. McGinty). were asked to submit all test data.

doi:10.1016/j.fct.2010.05.032
2.9. Water solubility (calculated; EPA, 2010): 1379 mg/l (25 °C).
2.10. UV spectra are not available at RIFM.
3. Usage
Isooctan-1-ol is a fragrance ingredient used in many fragrance

compounds. It may be found in fragrances used in decorative cos-
metics, fine fragrances, shampoos, toilet soaps and other toiletries
as well as in non-cosmetic products such as household cleaners
and detergents. Its use worldwide is in the region of less than
0.01 metric tons per annum (IFRA, 2004). The reported volume of
use is for isooctan-1-ol as used in fragrance compounds (mixtures)
in all finished consumer product categories. The volume of use is
surveyed by IFRA approximately every four years through a com-
prehensive survey of IFRA and RIFM member companies. As such
the volume of use data from this survey provides volume of use
of fragrance ingredients for the majority of the fragrance industry.
Fig. 1. Isooctan-1-ol.
1. Identification
1.1. Synonyms: isooctanol; 6-methylheptan-1-ol.
1.2. CAS Registry Number: 26952-21-6.
1.3. EINECS Number: 248-133-5.
the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford
1.4. Formula: C8H18O.
et al., 2000).
1.5. Molecular weight: 130.31.
2000). The 97.5 percentile use level in formulae for use in cosmet-
ics in general has not been reported. As such the default value of
2.4. Henry’s law (calculated; EPA, 2010): 0.000031 m3/mol
0.02% is used to calculate the maximum daily exposure on the skin
(25 °C).
of 0.0005 mg/kg for high end users of these products (see Table 1).
A maximum skin level is then determined for consideration of
potential sensitization. The exposure is calculated as the percent
on the use of 20% of the fragrance mixture in the fine fragrance
20.1 Pa (25 °C).
consumer product (IFRA, 2007). The maximum skin level that
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing isooctan-1-ol.
Anti-perspirant 0.5 1 1 0.01 .02 0.000001
Bath products 17 0.29 0.001 0.02 .02 0.000001
Body lotion 8 0.71 1 0.004 .02 0.000100
Eau de toilette 0.75 1 1 0.08 .02 0.000200
Face cream 0.8 2 1 0.003 .02 0.000001
Fragrance cream 5 0.29 1 0.04 .02 0.000200
Hair spray 5 2 0.01 0.005 .02 0.000001
Shampoo 8 1 0.01 0.005 .02 0.000001
Shower gel 5 1.07 0.01 0.012 .02 0.000001
Toilet soap 0.8 6 0.01 0.015 .02 0.000001
Total 0.0005
a
b
results from the use of isooctan-1-ol in formulae that go into fine 4.7. Repeated dose toxicity
fragrances has been not been reported. A default value of 0.02%
is used assuming use of the fragrance oils at levels up to 20% in No information available.
the final product.
4. Toxicology data
4.1. Acute toxicity
4.9. Genotoxicity
4.1.1. Oral studies
No information available. No information available.

4.1.3. Inhalation studies
There was no mortality, clinical signs, or autopsy findings when
three female Alderly-Park rats were exposed in whole body expo-
sure chambers. Animals were exposed for up to 6 h a day, 5 days a
material.
weeks (a total of 13 over 4 weeks) to saturated vapor of a mixture
of branched chain alcohols designated isooctan-1-ol, with a boiling
point of 185–189 °C. Concentration was 1 mg/l or 188 ppm (Gage, Conflict of interest statement
1970).
This research was supported by the Research Institute for Fra-
4.2. Skin irritation by the manufacturers of fragrances and consumer products con-
No information available. Institute for Fragrance Materials.
4.3. Mucous membrane (eye) irritation References
No information available. Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,
4.4. Skin sensitization Toxicology 48 (S4), S1–S46.
No information available. Pharmacology 36, 246–252.
Suite™ for MicrosoftÒ Windows, v 4.00 or Insert Version Used. United States
4.5. Phototoxicity and photoallergy Environmental Protection Agency, Washington, DC, USA.
Gage, J.C., 1970. The subacute inhalation toxicity of 109 industrial chemicals. British
Journal of Industrial Medicine 27, 1–18.
4.6. Absorption, distribution and metabolism IFRA (International Fragrance Association), 2004. Use Level Survey, August 2004.
No information available. 2007.

Review
Fragrance material review on isotridecan-1-ol (isomeric mixture)

D. McGinty *, S.P. Bhatia, J. Scognamiglio, C.S. Letizia, A.M. Api
Keywords: A toxicologic and dermatologic review of isotridecan-1-ol (isomeric mixture) when used as a fragrance
Review ingredient is presented. Isotridecan-1-ol (isomeric mixture) is a member of the fragrance structural group
Fragrance
branched chain saturated alcohols. The common characteristic structural elements of the alcohols with
saturated branched chain are one hydroxyl group per molecule, and a C4–C12 carbon chain with one or
several methyl side chains. This review contains a detailed summary of all available toxicology and der-
matology papers that are related to this individual fragrance ingredient and is not intended as a stand-
alone document. A safety assessment of the entire branched chain saturated alcohol group will be pub-
lished simultaneously with this document; please refer to Belsito et al. (2010) for an overall assessment
of the safe use of this material and all other branched chain saturated alcohols in fragrances.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S73
3. Usage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S74
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S75
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S75
4.1.3. Intraperitoneal studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S75
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S76
4.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S77
4.9.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S77
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S77
Introduction
This document provides a summary of the toxicologic review,
E-mail address: dmcginty@RIFM.org (D. McGinty). including all human health endpoints, of isotridecan-1-ol (isomeric

doi:10.1016/j.fct.2010.05.033
mixture) when used as a fragrance ingredient. Isotridecan-1-ol (see 1. Identification

Fig. 1; CAS Number 27458-92-0) is a fragrance ingredient used in
cosmetics, fine fragrances, shampoos, toilet soaps and other toilet- 1.1 Synonyms: Isotridecanol; 11-methyldodecan-1-ol
ries as well as in non-cosmetic products such as household clean- 1.2 CAS registry number: 27458-92-0
ers and detergents. This material has been reported to occur in 1.3 EINECS number: 248-469-2
nature within beef (VCF, 2009). 1.4 Formula: C13H28O
In 2006, a complete literature search was conducted on Isotrid- 1.5 Molecular weight: 200.66
ecan-1-ol. On-line toxicological databases were searched including
those from the Chemical Abstract Services, [e.g., ToxCenter (which 2. Physical properties
in itself contains 18 databases including Chemical Abstracts)], and
the National Library of Medicine [e.g., Medline, Toxnet (which con- 2.1 Physical form: no information available
tains 14 databases)] as well as 26 additional sources (e.g., BIOSIS, 2.2 Boiling point (calculated; EPA, 2010): 279.35 °C
Embase, RTECS, OSHA, ESIS). In addition, fragrance companies were 2.3 Flash point: no information available
asked to submit all test data. 2.4 Henry’s law (calculated; EPA, 2010): 0.000128 atm m3/mol
The safety data on this material has never been reviewed before 25 °C
by RIFM (Research Institute for Fragrance Materials, Inc.). All rele- 2.5 Log Kow (calculated; EPA, 2010): 5.19
vant references are included in this document. More details have 2.6 Refractive index: no information available
been provided for unpublished data. The number of animals, sex 2.7 Specific gravity: no information available
and strain are always provided unless they are not given in the ori- 2.8 Vapor pressure (calculated; EPA, 2010): 0.000462 mm Hg;
ginal report or paper. Any papers in which the vehicles and/or the 0.0615 Pa (25 °C)
doses are not given have not been included in this review. In addi- 2.9 Water solubility (calculated; EPA, 2010): 5.237 mg/l at 25°
tion, diagnostic patch test data with fewer than 100 consecutive 2.10 UV spectra available at RIFM. Does not absorb UV light.
3. Usage
Isotridecan-1-ol (isomeric mixture) is a fragrance ingredient

used in many fragrance compounds. It may be found in fragrances
used in decorative cosmetics, fine fragrances, shampoos, toilet
soaps and other toiletries as well as in non-cosmetic products such
as household cleaners and detergents. Its use worldwide is in the
region of 10–100 metric tons per annum (IFRA, 2004). The reported
volume of use is for isotridecan-1-ol as used in fragrance com-
pounds (mixtures) in all finished consumer product categories.
The volume of use is surveyed by IFRA approximately every four
years through a comprehensive survey of IFRA and RIFM member
companies. As such the volume of use data from this survey pro-
vides volume of use of fragrance ingredients for the majority of
the fragrance industry.
grance ingredient in ten types of the most frequently used personal
care and cosmetic products (anti-perspirant, bath products, body
lotion, eau de toilette, face cream, fragrance cream, hair spray,
shampoo, shower gel, and toilet soap). The concentration of the
fragrance ingredient in fine fragrances is obtained from examina-
tion of several thousand commercial formulations. The upper
Fig. 1. Isotridecan-1-ol (isomeric mixture). This upper 97.5 percentile concentration is then used for all 10
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing isotridecan-1-ol (isomeric mixture).
Anti-perspirant 0.5 1 1 0.01 1.4 0.0012
Bath products 17 0.29 0.001 0.02 1.4 0.00002
Body lotion 8 0.71 1 0.004 1.4 0.0053
Eau de toilette 0.75 1 1 0.08 1.4 0.0140
Face cream 0.8 2 1 0.003 1.4 0.0011
Fragrance cream 5 0.29 1 0.04 1.4 0.0135
Hair spray 5 2 0.01 0.005 1.4 0.0001
Shampoo 8 1 0.01 0.005 1.4 0.0001
Shower gel 5 1.07 0.01 0.012 1.4 0.0001
Toilet soap 0.8 6 0.01 0.015 1.4 0.0002
Total 0.0357
a
b
consumer products. These concentrations are multiplied by the abnormalities were observed. This study was based on the OECD,
amount of product applied, the number of applications per day EU and US EPA OPPTS guidelines (RIFM, 2002a).
for each product type, and a ‘‘retention factor” (ranging from Greim (2000) reported acute oral an LD50 value of isotridecan-1-
0.001 to 1.0) to account for the length of time a product may re- ol (isomeric mixture: 50% branched, 50% linear form) as greater
main on the skin and/or likelihood of the fragrance ingredient than 2.0 g/kg in rats (further information not obtained, ECB, 1995).
being removed by washing. The resultant calculation represents The acute oral LD50 in mice with 30% isotridecan-1-ol (isomeric
the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford mixture) as an aqueous emulsion with tragacanth gum was re-
et al., 2000). ported to be >6.5 ml (6.5 g/kg) body weight. Observations were
This is a conservative calculation of dermal systemic exposure made for 7 days. The clinical signs noted were staggering, acceler-
because it makes the unlikely assumption that a consumer will ated respiration, tremors, and slow recovery. The mortalities were
use these 10 products containing; which are all perfumed with sporadic and late (RIFM, 1963a).
the upper 97.5 percentile level of the fragrance ingredient from a Greim (2000) reported acute oral an LD50 value of isotridecan-1-
fine fragrance type of product (Cadby et al., 2002; Ford et al., ol (isomeric mixture) as 7.257 g/kg in mice (further information
2000). The 97.5% percentile use level in formulae for use in cosmet- not obtained, ECB, 1995; Hoechst, 1961a).
would result in a maximum daily exposure on the skin of
0.0356 mg/kg for high end users.
The acute dermal LD50 of isotridecan-1-ol (Tridecanol: mixed
primary isomers) in male rabbits (n = 4) was reported to be 7.07
(2.33–21.4) ml/kg (7.07; 2.33–24.4 g/kg). Contact time was 24 h
and observation time was 14 days. No additional details were re-
ported (Smyth et al., 1962).
The dermal LD50 for isotridecan-1-ol (Tridecanol: mixed pri-
mary isomers) applied occlusively for 24 h to rabbits (four/dose)
was reported to be >2.6 g/kg. There were no clinical signs indica-
to 20% the final product.
tive of systemic effects at the highest level tested. Dermal irritation
was dose dependent (Scala and Burtis, 1973).
4. Toxicology data
4.1.3. Intraperitoneal studies

The intraperitoneal LD50 of mice with 8% isotridecan-1-ol
(mixed isomers) as an aqueous emulsion with tragacanth gum
4.1.1. Oral studies
was reported to be about 0.6 ml/kg body weight (0.6 g/kg).
The acute oral LD50 of isotridecan-1-ol (1-tridecanol: mixed pri-
Observations included staggering, accelerated respiration, tremors,
mary isomers) in male rats (n = 5) was reported to be 17.2 (12.3–
and slow recovery. Mortalities were sporadic and late. Necropsy
23.9) ml/kg (17.2; 12.3–23.6 g/kg). No additional details were re-
findings included adhesions in the abdominal cavity (RIFM, 1963b).
ported (Smyth et al., 1962; Nishimura et al., 1994).
Scala and Burtis (1973) reported an LD50 for isotridecan-1-ol (1-
tridecanol: mixed primary isomers) of 4.75 g/kg in Sprague–Daw- 4.1.4. Inhalation studies
ley rats (five/dose). The principal clinical signs were central ner- The study of the acute inhalation hazard of isotridecan-1-ol
vous system depression and labored respiration. The depression (isomeric mixture) in rats resulted in no deaths (0/12) and no
included inactivity, ataxia, limb sprawling, depressed righting abnormalities. Animals were exposed for 8 h to atmosphere satu-
and placement reflexes, prostration, and coma. The intensity of rated with vapor at 20 °C (room temperature). For saturation, air
the signs was related to dose. The signs of effect had an early onset, was conducted through a layer of about 5 cm of the product (RIFM,
and recovery was complete by the second or third day. Where 1963c; Smyth et al., 1962).
deaths occurred, they were seen as late as 4 days. No deaths were reported when 10 rats, mice, and guinea pigs
The LD50 of isotridecan-1-ol in Wistar rats was found to be were exposed by whole body inhalation for 6 h to air bubbled
greater than 2 g/kg body weight for male and female rats. Single through isotridecan-1-ol (mixed isomers) to yield a nominal cham-
gavage doses of 2.0 g/kg body weight of isotridecan-1-ol in olive ber concentration of 12 ppm (12 ml/m3) at 30 °C. Clinical signs
oil were given to six (three/sex/group) fasted animals. No mortality indicated moderate local irritation and slight to moderate systemic
occurred in the 2 g/kg groups. Piloerection was the only clinical effects. Local irritation involved the mucous membranes of the
sign observed, in males, 5 h after administration. No clinical signs eyes, nose, throat, and respiratory passages and was manifest as
and findings were observed in the females of the 2 g/kg adminis- blinking, lacrimation, preening, nasal discharge, salivation, gasp-
tration group. The mean body weights of the administration groups ing, and chewing movements. Responses were temporary and all
increased throughout the study period. No macroscopic pathologic animals had recovered within 1 h after termination of exposure.
Table 2
Summary of acute toxicity studies.
Route Species No. animals/dose group LD50 (g/kg) References

Oral Rat 5 17.2 Smyth et al., 1962; Nishimura, 1994
Oral Rat 5 4.75 Scala and Burtis, 1973
Oral Rat 3 >2.0 RIFM, 2002a
Oral Rat N/A >2.0 ECB, 1995 as cited in Greim, 2000
Oral Mouse N/A 6.5 RIFM, 1963a
Oral Mouse N/A 7.257 ECB, 1995; Hoechst, 1961a; as cited in Greim, 2000
Dermal Rabbit 4 7.07 Smyth et al., 1962
Dermal Rabbit 4 >2.6 Scala and Burtis, 1973
Intraperitoneal Mouse N/A 0.6 RIFM, 1963b
Gross necropsy findings were normal in appearance (Scala and Table 4

Burtis, 1973). Summary of eye irritation studies.
Dose Reactions References

(%)
4.2. Skin irritation 100 Irritation was observed. In one animal slight RIFM, 2002b
corneal opacity and loss of corneal tissue
4.2.1. Human studies 100 Slight irritation RIFM, 1963f
In an in vitro human study it was concluded that isotridecan-1- 100 Small area of necrosis on the eye Smyth et al., 1962
100 Moderately irritating Scala and
ol (mixed isomers) does not show a corrosive potential in the Epi-
Burtis, 1973
Derm™ skin corrosivity test (RIFM, 2003a).
4.2.2. Animal studies (see Table 3) 4.3. Mucous membrane (eye) irritation (see Table 4)
Isotridecan-1-ol (mixed isomers) was applied ‘‘at full-strength”
to the closely clipped, intact abdominal skin of albino rabbits (four/ An eye irritation test was conducted in three White New Zea-
group). The exposed area was then covered with an occlusive patch land rabbits subjected to a single dose ocular application of
for 24 h. Doses of 0.10, 0.316, 1.0, or 3.16 ml/kg were administered 0.1 ml of undiluted isotridecan-1-ol (mixed isomers). The ocular
volumetrically and observations for signs of toxicity were made reactions were assessed approximately 1, 24, 48, 72 h and 7 days
once daily for 7 days. Moderate irritation was observed (Scala after application. Slight to moderate conjunctival redness, slight
and Burtis, 1973). conjunctival chemosis and moderate to severe discharge were ob-
A primary skin irritation evaluation was done on the clipped served during the course of the study. In addition in one animal
skin (uncovered) of five albino rabbits with undiluted isotridec- slight corneal opacity and loss of corneal tissue was noted during
an-1-ol (mixed isomers) and resulted in grade 4 (moderate) irrita- the observation period (RIFM, 2002b).
tion (Smyth et al., 1962). An eye irritation test was conducted in rabbits. Undiluted iso-
Undiluted isotridecan-1-ol (mixed isomers) produced irritation tridecan-1-ol (mixed isomers) was applied (1 50 mm3 or
when administered percutaneously to the intact dorsal and ear 50 mg) to the conjunctival sac of the eyelid. The findings after
skin of rabbits. The time of exposure on the dorsal skin was 1, 5, 1 h included slight redness. The findings after 24 h and 8 days were
15, and 20 h, and 20 h for the ears. The skin was checked after nonirritating. No further information (RIFM, 1963d; RIFM, 1963f).
24 h and after 8 days. After 20 h of exposure, the dorsal skin re- Application of to the eyes isotridecan-1-ol (mixed isomers) of
sulted in severe erythema and distinct edema when observed at rabbits produced irritation grade 2 on a ten-grade scale with Grade
24 h, then distinct scarring and severe scaling at 8 days. When 1 a very small area of necrosis from 0.5 ml of an undiluted chem-
the dorsal skin was exposed for 1, 5, or 15 h severe erythema ical in the eye and Grade 5 representing a severe burn from
was observed at 24 h, then scaling at 8 days. Exposure of 20 h to 0.005 ml (Smyth et al., 1962).
the ear resulted in severe erythema at 24 h and severe erythema Six rabbits were given single 0.1 ml application of isotridecan-
and scaring at 8 days (RIFM, 1963d,e). 1-ol (mixed isomers) undiluted. Observations were made after 1,
In order to assess the acute skin irritation potential of isotridec- 4, and 24 h, 2, 3, 4, and 7 days. Moderate irritation was observed
anol-1-ol in White New Zealand rabbits a dermal irritation/corro- (Scala and Burtis, 1973).
sion test was performed according to the method described in
OECD guideline 404. A 0.5 ml sample of the isotridecanol-1-ol 4.4. Skin sensitization
was applied for 4 h to the intact skin of three rabbits, using a patch
of 2.5 cm 2.5 cm, covered with semi-occlusive dressing. After re- No data available.
moval of the patch the application area was washed off. The skin
reactions were assessed immediately after removal of the patch, 4.5. Phototoxicity and photoallergy
approximately 1, 24, 48 and 72 h after removal and then win
weekly intervals until day 14. Slight to marked erythema, slight No data available.
or moderate edema and scaling were observed in almost all ani-
mals during the course of the study. Additionally the described 4.6. Absorption, distribution and metabolism
findings above were partly extended beyond the area of exposure.
Moreover severe scaling and petechiae, both extending beyond the No data available.
area of exposure and thickening of the skin in the regions of the
application area were noted in a single animal. The cutaneous reac- 4.7. Repeated dose toxicity
tions (such as slight erythema) were not reversible in all animals
within study termination of day 14. The average score (24 to Isotridecan-1-ol (isomeric mixture) in polyethylene glycol was
72 h) for irritation was calculated to be 3.0 for erythema and 0.3 given to Alderley Park Wistar-derived rats, five rats treated and
for edema (RIFM, 2003b). 10 controls, by gavage for 14 days. At 1 mmol/kg body weight/
Table 3
Method Dose Species Reactions References

(%)
Single occlusive patch for 24 h to intact skin of 100 Rabbits Moderately irritating Scala and Burtis,
four rabbits 1973
Single uncovered application of 0.01 ml for 24 h 100 Rabbits Moderately irritating Smyth et al., 1962
Percutaneously to the intact dorsal skin for 20 h 100 Rabbits Severe erythema and distinct edema at 24 h. Distinct scarring and severe RIFM, 1963e
scaling at 8 days
4-h semi-occlusive irritation 100 Rabbits Slight to marked erythema, slight or moderate edema and scaling RIFM, 2003b
day (200 mg/kg body weight/day) the liver weight was unaffected, 4.10. Carcinogenicity
no hepatomegaly, peroxisome proliferation, hypolipidemia, or tes-
ticular atrophy was observed (Rhodes et al., 1984). No data available.

4.8. Reproductive and developmental toxicity stand-alone document. Please refer to A Safety Assessment of
Isotridecan-1-ol (isomeric mixture) was tested for its prenatal dients (Belsito et al., 2010) for an overall assessment of this
developmental toxicity in 25 mated female Wistar rats as a solu- material.
tion in olive oil. Gavage administration of 0, 60, 250, or 750 mg/
kg body weight were given on days 6 through day 19 post coitum
(p.c.). A standard dose volume of 5 ml/kg body weight was used for Conflict of interest statement
each group. Food consumption and body weights of the animals
were recorded regularly throughout the study period. On day 20 This research was supported by the Research Institute for Fra-
p.c., blood was taken from all females, then sacrificed and assessed grance Materials, an independent research institute that is funded
by gross pathology (including weight determinations of the uno- by the manufacturers of fragrances and consumer products con-
pened uterus, the liver, the kidneys, the spleen and the placentae). taining fragrances. The authors are all employees of the Research
For each dam, corpora lutea were counted and number and distri- Institute for Fragrance Materials.
bution of implantation sites (differentiated as resorptions, live and
dead fetuses) were determined. The fetuses were removed from References
the uterus, sexed, weighed and further investigated for any exter-
nal findings soft tissue and skeletal findings. In the 750 mg/kg body Ames, B.N., McCann, J., Yamasaki, E., 1975. Methods for detecting carcinogens and
mutagens with the salmonella/mammalian-mincrosome mutagenicity test.
weight/day dose: transient salivation was noted in all rats between Mutation Research 31, 347–363.
treatment days 7–19 p.c.; urine-smeared fur in 4 females on gesta- Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,
tion days 10–13 and 17–20 p.c.; statistically significant reduction Sipes, I.G., Smith, R.L., Tagami, H., 2010. A toxicologic and dermatologic
assessment of Alcohols Branched Chain Saturated when used as fragrance
of food consumption on days 6–10 p.c. (up to about 11% below ingredients. Food and Chemical Toxicology 48 (S4), S1–S46.
the corresponding control value); statistically significant increased Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:
alanine aminotransferase values; statistically significant increased providing estimates for safety evaluation. Regulatory Toxicology and
triglycerides and relative liver weights (about 14% or 18%, respec- EPA (Environmental Protection Agency), 2010. Estimation Programs Interface
tively above control values) were noted; statistically significant de- Suite™ for MicrosoftÒ Windows, v 4.00 or insert version used. United States
creased total protein and globulin concentrations; no substance- Environmental Protection Agency, Washington, DC, USA.
related effects on gestational parameters or fetuses. Substance re-
lated findings in the 250 mg/kg body weight/day group included: Regulatory Toxicology and Pharmacology 31, 166–181.
transient salivation in 17/25 rats immediately after gavaging be- Greim, H. (ed.), 2000. iso-Tridecanol (Isomerengemisch verzweigter primärer C10-
C14-Alkohole). Toxikologisch-arbeitsmedizinische Begründungen von MAK-
tween treatment days 12–19 p.c.; no substance-related effects on
Werten, 30. Lieferung, Wiley-VCH, Weinheim.
gestational parameters or fetuses were noted. No substance-re- IFRA (International Fragrance Association), 2004. Use level survey, August 2004.
lated effects on dams, gestational parameters or fetuses were IFRA (International Fragrance Association), 2007. Volume of use survey, February
noted the 60 mg/kg body weight/day group. 2007.
Nishimura, H., Saito, S., Kishida, F.,Matsuo, M., 1994. Analysis of acute toxicity
Under the conditions of this prenatal developmental toxicity (LD50-value) of organic chemicals to mammals by solubility parameter (delta).
study, the oral administration of isotridecan-1-ol (isomeric mix- 1. Acute oral toxicity to rats. Sangyo Igaku, 36(5), 314–323 (Japanese Journal
ture) to pregnant Wistar rats from implantation to one day prior Industrial Health).
Rhodes, C., Soames, T., Stonard, M.D., Simpson, M.G., Vernall, A.J., Elcombe, C.R.,
to the expected day of parturition (days 6–19 p.c.) elicited some 1984. The absence of testicular atrophy & in vivo & in vitro effects on
signs of maternal toxicity at 750 mg/kg body weight/day. Placental hepatocyte morphology and peroxisomal enzyme activities in male rats
and fetal body weights, the external, soft tissue and/or skeletal following the administration of several alkanols. Toxicology Letters 21, 103–
109.
(including cartilage) examinations of the fetuses revealed no bio- RIFM (Research Institute for Fragrance Materials, Inc.), 1963a. Report on the study
logically relevant differences between the control and the sub- of the acute oral toxicity of isotridecan-1-ol in mice. Unpublished report from
stance-treated groups. Based on these results, the no observed BASF, Report number 55417, RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1963b. Report on the study
adverse effect level (NOAEL) for maternal toxicity is 250 mg/kg
of the acute intraperitoneal toxicity of isotridecan-1-ol in mice. Unpublished
body weight/day, while it is 750 mg/kg body weight/day for prena- report from BASF, Report number 55414, RIFM, Woodcliff Lake, NJ, USA.
tal developmental toxicity (RIFM, 2003c). RIFM (Research Institute for Fragrance Materials, Inc.), 1963c. Report on the study
of the acute inhalation hazard of isotridecan-1-ol in rats (inhalation hazard
test). Unpublished report from BASF, Report number 55415, RIFM, Woodcliff
4.9. Genotoxicity Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1963d. Results of the
analytical toxicology tests with isotridecan-1-ol. Unpublished report from BASF,
4.9.1. In vitro studies Report number 55424, RIFM, Woodcliff Lake, NJ, USA.
4.9.1.1. Bacterial test systems. Isotridecan-1-ol (isomeric mixture) RIFM (Research Institute for Fragrance Materials, Inc.), 1963e. Report on the study
in DMSO was tested for mutagenicity in the Ames test (Ames of the primary irritation/corrosion of isotridecan-1-ol to the intact skin of
rabbits. Unpublished report from BASF, Report number 55426, RIFM, Woodcliff
et al., 1975) (standard plate test and preincubation test) at doses Lake, NJ, USA.
up to 5000 lg/plate both in the presence and absence of a metab- RIFM (Research Institute for Fragrance Materials, Inc.), 1963f. Report on the study of
olizing system obtained from rat liver (S-9 mix) using Salmonella the primary irritation of isotridecan-1-ol to the eye of rabbits. Unpublished
report from BASF, Report number 55431, RIFM, Woodcliff Lake, NJ, USA.
typhimurium strains TA1537, TA 1535, TA100, and TA98. No muta- RIFM (Research Institute for Fragrance Materials, Inc.), 1989. Report on the study of
genicity was observed (RIFM, 1989). Isotridecan-1-ol in the AMES test. Unpublished report from BASF, Report
number 55420, RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 2002a. Isotridecan-1-ol:
4.9.1.2. Studies in mammalian cells. No data available. Acute oral toxicity study in Wistar rats. Unpublished report from BASF, Report
number 55416, RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 2002b. Isotridecan-1-ol:
4.9.2. In vivo studies Acute eye irritation in rabbits. Unpublished report from BASF, Report number
No data available. 55430, RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 2003a Isotridecan-1-ol: Scala, R.A., Burtis, E.G., 1973. Acute toxicity of a homologous series of branched-
EpiDerm skin corrosivity test. Unpublished report from BASF, Report number chain primary alcohols. American Industrial Hygiene Association Journal
55423, RIFM, Woodcliff Lake, NJ, USA. (AIHAJ) 34 (11), 493–499.
RIFM (Research Institute for Fragrance Materials, Inc.), 2003b. Isotridecan-1-ol: Smyth, F., Carpenter, C.P., Weil, M.A., Pozzani, U.C., Striegel, J.A., 1962. Range-finding
Acute dermal irritation/corrosion in rabbits. Unpublished report from BASF, toxicity data: List VI. Industrial Hygiene Association Journal 23, 95–107.
Report number 55427, RIFM, Woodcliff Lake, NJ, USA. VCF (Volatile Compounds in Food): database. In: Nijssen, L.M.; Ingen-Visscher, C.A.
RIFM (Research Institute for Fragrance Materials, Inc.), 2003c. Isotridecan-1-ol: van; Donders, J.J.H. (Eds), – Version 11.1.1 – TNO Quality of Life, Zeist, The
prenatal developmental toxicity study in Wistar rats by oral administration Netherlands, 1963–2009.
(gavage). Unpublished report from BASF, Report number 55432, RIFM,

Review
Fragrance material review on isononyl alcohol

Keywords: A toxicologic and dermatologic review of isononyl alcohol when used as a fragrance ingredient is pre-
Review sented. Isononyl alcohol is a member of the fragrance structural group branched chain saturated alcohols.
Fragrance
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S79
1. Identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S80
2. Physical properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S80
3. Usage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S80
4. Toxicology data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S81
4.1. Acute toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S81
4.2. Skin irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S81
4.3. Mucous membrane (eye) irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S81
4.4. Skin sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S81
4.5. Phototoxicity and photoallergy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S81
4.6. Absorption, distribution, and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S81
4.7. Repeated dose toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S81
4.8. Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S81
4.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S81
4.10. Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S81
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S81
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S81
Introduction In 2006, a complete literature search was conducted on isono-

nyl alcohol. On-line toxicological databases were searched includ-
This document provides a summary of the toxicologic review, ing those from the Chemical Abstract Services [e.g., ToxCenter
including all human health endpoints, of isononyl alcohol when used (which in itself contains 18 databases including Chemical Ab-
as a fragrance ingredient. Isononyl alcohol (see Fig. 1; CAS Number stracts)], and the National Library of Medicine [e.g., Medline, Tox-
27458-94-2) is a fragrance ingredient used in cosmetics, fine fra- net (which contains 14 databases)] as well as 26 additional sources
grances, shampoos, toilet soaps and other toiletries as well as in (e.g., BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance
non-cosmetic products such as household cleaners and detergents. companies were asked to submit all test data.
E-mail address: dmcginty@RIFM.org (D. McGinty). vant references are included in this document. More details have

doi:10.1016/j.fct.2010.05.034
3. Usage
Isononyl alcohol is a fragrance ingredient used in many fra-

cleaners and detergents. Its use worldwide is in the region of 1–
10 metric tons per annum (IFRA, 2004). The reported volume of
use is for isononyl alcohol as used in fragrance compounds (mix-
use is surveyed by IFRA approximately every four years through
a comprehensive survey of IFRA and RIFM member companies.
As such the volume of use data from this survey provides volume
of use of fragrance ingredients for the majority of the fragrance
Fig. 1. Isononyl alcohol. industry.
been provided for unpublished data. The number of animals, sex grance ingredient in ten types of the most frequently used personal
and strain are always provided unless they are not given in the ori- care and cosmetic products (anti-perspirant, bath products, body
ginal report or paper. Any papers in which the vehicles and/or the lotion, eau de toilette, face cream, fragrance cream, hair spray,
doses are not given have not been included in this review. In addi- shampoo, shower gel, and toilet soap). The concentration of the
tion, diagnostic patch test data with fewer than 100 consecutive fragrance ingredient in fine fragrances is obtained from examina-
patients have been omitted. tion of several thousand commercial formulations. The upper
1. Identification consumer products. These concentrations are multiplied by the
1.1 Synonyms: isononanol; 7-methyloctan-1-ol for each product type, and a ‘‘retention factor” (ranging from
1.2 CAS registry number: 27458-94-2 0.001 to 1.0) to account for the length of time a product may re-
1.3 EINECS number: 248-471-3 main on the skin and/or likelihood of the fragrance ingredient
1.4 Formula: C9H20O being removed by washing. The resultant calculation represents
1.5 Molecular weight: 144.58 the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford
et al., 2000).
2. Physical properties because it makes the unlikely assumption that a consumer will
2.1 Physical form: no information available the upper 97.5 percentile level of the fragrance ingredient from a
2.2 Boiling point (calculated; EPA, 2010): 208.49 fine fragrance type of product (Cadby et al., 2002; Ford et al.,
2.3 Flash point: no information available 2000). The 97.5 percentile use level in formulae for use in cosmet-
2.4 Henry’s law (calculated; EPA, 2010): 0.0000412 atm m3/mol ics in general has been reported to be 4.46% (IFRA, 2007), which
25 °C would result in a maximum daily exposure on the skin of
2.5 Log Kow (calculated; EPA, 2010): 3.22 0.1137 mg/kg for high end users.
2.6 Refractive index: no information available A maximum skin level is then determined for consideration of
2.7 Specific gravity: no information available potential sensitization. The exposure is calculated as the percent
2.8 Vapor pressure (calculated; EPA, 2010): 0.0198 mm Hg; concentration of the fragrance ingredient applied to the skin based
2.63 Pa (25 °C) on the use of 20% of the fragrance mixture in the fine fragrance
2.9 Water solubility (calculated; EPA, 2010): 459.7 mg/l (25 °C) consumer product (IFRA, 2007). The average maximum use level
2.10 UV spectra not available at RIFM in formulae that go into fine fragrances has been reported to be
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing isononyl alcohol.
Anti-perspirant 0.5 1 1 0.01 4.46 0.0037
Bath products 17 0.29 0.001 0.02 4.46 0.0001
Body lotion 8 0.71 1 0.004 4.46 0.0169
Eau de toilette 0.75 1 1 0.08 4.46 0.0446
Face cream 0.8 2 1 0.003 4.46 0.0036
Fragrance cream 5 0.29 1 0.04 4.46 0.0431
Hair spray 5 2 0.01 0.005 4.46 0.0004
Shampoo 8 1 0.01 0.005 4.46 0.0003
shower gel 5 1.07 0.01 0.012 4.46 0.0005
Toilet soap 0.8 6 0.01 0.015 4.46 0.0005
Total 0.1136
a
b
0.30% (IFRA, 2007), assuming use of the fragrance oil at levels up to the maternal clinical signs included reduced body weight gain,
20% of the final product. apathy, and nasal discharge. Fetal observations included an in-
creased number of skeletal variations and delayed ossifications.
4. Toxicology data There were no significant differences from control at 144 mg/kg
in either maternal or fetal parameters (Hellwig and Jackh, 1997,
4.1. Acute toxicity and EPA, 1991).
No available information. 4.9. Genotoxicity
4.2. Skin irritation No available information.
No available information. 4.10. Carcinogenicity
4.3. Mucous membrane (eye) irritation No available information.

No available information. stand-alone document. Please refer to A Toxicologic and Dermato-
logic Assessment of Alcohols Branched Chain Saturated When Used
4.4. Skin sensitization as Fragrance Ingredients (Belsito et al., 2010) for an overall assess-
ment of this material.
Conflict of interest statement
This research was supported by the Research Institute for
No available information. Fragrance Materials, an independent research institute that is
funded by the manufacturers of fragrances and consumer products
4.6. Absorption, distribution, and metabolism containing fragrances. The authors are all employees of the
Research Institute for Fragrance Materials.
References
No available information. assessment of alcohols branched chain saturated when used as fragrance
ingredients. Food and Chemical Toxicology 48 (S4), S1–S46.
4.8. Reproductive and developmental toxicity Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:
In a comparative developmental toxicity (OECD TG 414) two EPA (Environmental Protection Agency), 1991. Study of the prenatal toxicity of
different isomeric mixes of isononyl alcohol were administered isononylalcohol 1 and isononylalcohol 2 in rats after oral administration
(gavage). Unpublished report. Report number 34403 (RIFM, Woodcliff Lake, NJ,
by gavage to Wistar rats (10 per group) at 144, 720, 1080, and USA).
1440 mg/kg/d (0, 1, 5, 7.5, and 10 mmol/kg/d) on gestation days EPA (Environmental Protection Agency), 2010. Estimation Programs Interface
6–15. The 1080 mg/kg group was a supplemental group with sup- Suite™ for MicrosoftÒ Windows, v 4.00 or insert version used]. United States
plemental control due to high maternal mortality at 1440 mg/kg/d
in the original study. Both types of isononyl alcohols exhibited a development of a database for safety evaluation of fragrance ingredients.
marked degree of maternal and fetal toxicity at 1080, and Regulatory Toxicology and Pharmacology 31, 166–181.
Hellwig, J., Jackh, R., 1997. Differential prenatal toxicity of one straight-chain and
1440 mg/kg/d and slight effects at 720 mg/kg. Maternal mortality
five branched-chain primary alcohols in rats. Food and Chemical Toxicology 35
was 10/10 for mixture 1 and 3/10 for mixture 2 at 1440 mg/kg/d. (5), 489–500.
Fetal observations for the 1080 mg/kg groups showed increases IFRA (International Fragrance Association), 2004. Use level survey, August 2004.
in resorptions, post-implantation loss, and the number/percent of IFRA (International Fragrance Association), 2007. Volume of use survey, February
2007.
fetuses/litters with malformations or retardations. At 720 mg/kg,

Review
Fragrance material review on 6,8-dimethylnonan-2-ol

Keywords: A toxicologic and dermatologic review of 6,8-dimethylnonan-2-ol when used as a fragrance ingredient is
Review presented. 6,8-Dimethylnonan-2-ol is a member of the fragrance structural group branched chain satu-
Fragrance
rated alcohols. The common characteristic structural elements of the alcohols with saturated branched
chain are one hydroxyl group per molecule, and a C4–C12 carbon chain with one or several methyl side
chains. This review contains the information available on this individual fragrance ingredient and is
not intended as a stand-alone document. A safety assessment of the entire branched chain saturated alco-
hol group will be published simultaneously with this document; please refer to Belsito et al. (2010) for an
overall assessment of the safe use of this material and all other branched chain saturated alcohols in
fragrances.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S82
3. Usage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S83
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S84
Introduction tional sources (e.g. BIOSIS, Embase, RTECS, OSHA and ESIS). In addi-
tion, fragrance companies were asked to submit all test data.
This document provides a summary of the toxicologic review, The safety data on this material has never been reviewed before
all human health endpoints, of 6,8-dimethylnonan-2-ol when used by RIFM (Research Institute for Fragrance Materials Inc.). All rele-
as a fragrance ingredient. 6,8-Dimethylnonan-2-ol (see Fig. 1; CAS vant references are included in this document. More details have
Number 70214-77-6) is a fragrance ingredient used in cosmetics, been provided for unpublished data. The number of animals, sex
fine fragrances, shampoos, toilet soaps and other toiletries as well and strain are always provided unless they are not given in the ori-
as in non-cosmetic products such as household cleaners and ginal report or paper. Any papers in which the vehicles and/or the
detergents. doses are not given have not been included in this review. In addi-
In 2006, a complete literature search was conducted on 6,8- tion, diagnostic patch test data with fewer than 100 consecutive
dimethylnonan-2-ol. On-line toxicological databases were patients have been omitted.
searched including those from the Chemical Abstract Services
[e.g. ToxCenter (which in itself contains 18 databases including
1. Identification
Chemical Abstracts], and the National Library of Medicine [e.g.
Medline, Toxnet (which contains 14 databases)] as well as 26 addi-
1.1. Synonyms: 2-Nonanol, 6,8-dimethyl-; Nonadyl.
1.2. CAS Registry number: 70214-77-6.
1.3. EINECS number: 274-447-7.
* Corresponding author. Tel.: +1 201 689 8089; fax: +1 201 689 8088. 1.4. Formula: C11H24O.
E-mail address: dmcginty@RIFM.org (D. McGinty). 1.5. Molecular weight: 172.12.

doi:10.1016/j.fct.2010.05.035
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 6,8-dimethylnonan-2-ol.
Anti-perspirant 0.5 1 1 0.01 0.05 0.000001
Bath products 17 0.29 0.001 0.02 0.05 0.000001
Body lotion 8 0.71 1 0.004 0.05 0.000200
Eau de toilette 0.75 1 1 0.08 0.05 0.000500
Face cream 0.8 2 1 0.003 0.05 0.000001
Fragrance cream 5 0.29 1 0.04 0.05 0.000500
Hair spray 5 2 0.01 0.005 0.05 0.000001
Shampoo 8 1 0.01 0.005 0.05 0.000001
Shower gel 5 1.07 0.01 0.012 0.05 0.000001
Toilet soap 0.8 6 0.01 0.015 0.05 0.000001
Total 0.0012
a
b

OH amount of product applied, the number of applications per day
Fig. 1. 6,8-Dimethylnonan-2-ol.
2. Physical properties the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford
et al., 2000).
2.1. Physical form: no information available. This is a conservative calculation of dermal systemic exposure
2.2. Boiling point (calculated; EPA, 2010): 217.59. because it makes the unlikely assumption that a consumer will
2.3. Flash point: no information available. use these 10 products containing; which are all perfumed with
2.4. Henry’s law (calculated; EPA, 2010): 0.0000726 atm m3/ the upper 97.5 percentile level of the fragrance ingredient from a
mole. fine fragrance type of product (Cadby et al. 2002, Ford et al.
2.5. Log Kow (calculated; EPA, 2010): 4.06. 2000). The 97.5% percentile use level in formulae for use in cosmet-
2.6. Refractive index: no information available. ics in general has been reported to be 0.5% (IFRA, 2007), which
2.7. Specific gravity: 0.827 g/ml at 20 °C. would result in a maximum daily exposure on the skin of
2.8. Vapor pressure (calculated; EPA, 2010): 0.0252 mm Hg; 0.0012 mg/kg for high end users (see Table 1).
3.36 Pa (25 °C). A maximum skin level is then determined for consideration of
2.9. Water solubility (calculated; EPA, 2010): no information potential sensitization. The exposure is calculated as the percent
available. concentration of the fragrance ingredient applied to the skin based
2.10. UV spectra available at RIFM, peaks at 200–210 nm and on the use of 20% of the fragrance mixture in the fine fragrance
returns to baseline 230–240 nm. Minor absorption from consumer product (IFRA, 2007). The average maximum use level
260 to 320 nm. in formulae that go into fine fragrances has been reported to be
0.009% (IFRA, 2007), assuming use of the fragrance oil at levels
3. Usage up to 20% in the final product.
6,8-Dimethylnonan-2-ol is a fragrance ingredient used in many

fragrance compounds. It may be found in fragrances used in deco-
4. Toxicology data
rative cosmetics, fine fragrances, shampoos, toilet soaps and other
cleaners and detergents. Its use worldwide is in the region of 1–
10 metric tons per annum (IFRA, 2004). The reported volume of
use is for 6,8-dimethylnonan-2-ol as used in fragrance compounds
(mixtures) in all finished consumer product categories. The volume
of use is surveyed by IFRA approximately every 4 years through a
dients Belsito et al. (2010) for an overall assessment of this
comprehensive survey of IFRA and RIFM member companies. As
material.
such the volume of use data from this survey provides volume of
industry.
The dermal systemic exposure in cosmetic products (see Conflict of interest statement
Table 1) is calculated based on the concentrations of the same
fragrance ingredient in 10 types of the most frequently used This research was supported by the Research Institute for
personal care and cosmetic products (anti-perspirant, bath prod- Fragrance Materials, an independent research institute that is
ucts, body lotion, eau de toilette, face cream, fragrance cream, hair funded by the manufacturers of fragrances and consumer products
spray, shampoo, shower gel and toilet soap). The concentration of containing fragrances. The authors are all employees of the
the fragrance ingredient in fine fragrances is obtained from exam- Research Institute for Fragrance Materials.
References EPA (Environmental Protection Agency), 2010. Estimation Programs Interface

assessment of Alcohols Branched Chain Saturated when used as fragrance
ingredients. Food and Chemical Toxicology 48 (S4), S1–S46.
2007.

Review
Fragrance material review on 2-ethyl-1-butanol

D. McGinty *, C.S. Letizia, A.M. Api
Keywords: A toxicologic and dermatologic review of 2-ethyl-1-butanol when used as a fragrance ingredient is pre-
Review sented. 2-Ethyl-1-butanol is a member of the fragrance structural group branched chain saturated alco-
Fragrance
review contains a detailed summary of all available toxicology and dermatology papers that are related to
this individual fragrance ingredient and is not intended as a stand-alone document. A safety assessment
of the entire branched chain saturated alcohol group will be published simultaneously with this docu-
ment; please refer to Belsito et al. (2010) for an overall assessment of the safe use of this material and
all other branched chain saturated alcohols in fragrances.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S86
3. Usage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S86
4.1. Acute toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87
4.1.4. Other studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87
4.2.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87
4.4. Skin densitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87
4.6.1. Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87
4.6.2. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87
4.6.3. Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87
4.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S87
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S88

doi:10.1016/j.fct.2010.05.036
Introduction 1.4. Formula: C6H14O.

This document provides a comprehensive summary of the tox- 1.6. Council of Europe (2000): 2-ethyl-1-butanol was included
icologic review of 2-ethyl-1-butanol when used as a fragrance by the Council of Europe in the list of substances granted B
ingredient including all human health endpoints. 2-Ethyl-1-buta- – information required – 28 day oral study (COE No. 543).
nol (see Fig. 1; CAS Number 97-95-0) is a fragrance ingredient used
in cosmetics, fine fragrances, shampoos, toilet soaps and other toi- 2. Physical properties
letries as well as in non-cosmetic products such as household
cleaners and detergents. This material has been reported to occur
in nature, with highest quantities observed in mushrooms (VCF, 2.1. Physical form: no information available.
2009). 2.2. Boiling point (calculated; EPA, 2010): 145.86 °C.
In 2006, a complete literature search was conducted on isoamyl 2.3. Flash point: no information available.
alcohol. On-line toxicological databases were searched including 2.4. Henry’s law (calculated; EPA, 2010): 0.0000176 atm m3/mol
those from the Chemical Abstract Services [e.g. ToxCenter [which 25 °C.
in itself contains 18 databases including Chemical Abstracts)] and 2.5. Log Kow (calculated; EPA, 2010): 1.75.
the National Library of Medicine [e.g. Medline, Toxnet (which con- 2.6. Refractive index: no information available.
tains 14 databases)] as well as 26 additional sources (e.g. BIOSIS, 2.7. Specific gravity: no information available.
Embase, RTECS, OSHA, ESIS). In addition, fragrance companies were 2.8. Vapor pressure (calculated; EPA, 2010): 1.0 mm Hg (20 °C);
asked to submit all test data. 1.6 mm Hg (25 °C); 213 Pa (25 °C).
The safety data on this material has never been reviewed before 2.9. Water solubility (calculated; EPA, 2010): 11950 mg/l (25 °C).
by RIFM (Research Institute for Fragrance Materials, Inc.). All rele- 2.10. UV spectra not available at RIFM.
3. Usage
2-Ethyl-1-butanol is a fragrance ingredient used in many fra-
cleaners and detergents. Its use worldwide is in the region of less
1. Identification than 0.01 metric tons per annum (IFRA, 2004). The reported vol-
ume of use is for 2-ethyl-1-butanol as used in fragrance com-
1.1. Synonyms: 1-butanol, 2-ethyl-, 2-ethylbutyl alcohol, 2-eth- pounds (mixtures) in all finished consumer product categories.
ylbutan-1-ol. The volume of use is surveyed by IFRA approximately every four
1.2. CAS Registry Number: 97-95-0. years through a comprehensive survey of IFRA and RIFM member
1.3. EINECS Number: 202-621-4. companies. As such the volume of use data from this survey pro-
grance ingredient in 10 types of the most frequently used
Fig. 1. 2-Ethyl-1-butanol. amount of product applied, the number of applications per day
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2-ethyl-1-butanol.
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixturea Ingredientb (mg/kg/day)
Anti-perspirant 0.5 1 1 0.01 0.0003 0.000001
Bath products 17 0.29 0.001 0.02 0.0003 0.000001
Body lotion 8 0.71 1 0.004 0.0003 0.000100
Eau de toilette 0.75 1 1 0.08 0.0003 0.000200
Face cream 0.8 2 1 0.003 0.0003 0.000001
Fragrance cream 5 0.29 1 0.04 0.0003 0.000200
Hair spray 5 2 0.01 0.005 0.0003 0.000001
Shampoo 8 1 0.01 0.005 0.0003 0.000001
Shower gel 5 1.07 0.01 0.012 0.0003 0.000001
Toilet soap 0.8 6 0.01 0.015 0.0003 0.000001
Total 0.0005
a
b
for each product type, and a ‘‘retention factor” (ranging from 0.001 vapors was reported to be 8 h. No additional details were reported
to 1.0) to account for the length of time a product may remain on (Smyth et al., 1954).
the skin and/or likelihood of the fragrance ingredient being re-
moved by washing. The resultant calculation represents the total 4.1.4. Other studies
consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford et al., The acute intraperitoneal ED3 for induction of pronounced
2000). ataxia in rats was reported to be 2.3 mmol/kg (0.24 g/kg) (McCre-
This is a conservative calculation of dermal systemic exposure ery and Hunt, 1978).
use these 10 products containing; which are all perfumed with 4.2. Skin irritation
fine fragrance type of product (Cadby et al. 2002; Ford et al., 4.2.1. Human studies
2000). The 97.5 percentile use level in formulae for use in cosmet- No available information.
ics for 2-ethyl-1-hexanol has been reported to be 0.02% (IFRA,
2007), which would result in a maximum daily exposure on the
4.2.2. Animal studies
skin of 0.0005 mg/kg for high end users (see Table 1).
In a group of 5 rabbits (giant albino, New Zealand rabbits) der-
mal irritation study for 24 h uncovered neat 2-ethyl-1-butanol was
applied at 0.1 ml to clipped skin. Slight to moderate irritation
(grade 2) was reported (Smyth et al., 1954).
4.3. Mucous membrane (eye) irritation
sults from the use of 2-ethyl-1-butanol in formulae that go into
fine fragrances has been not been reported.
In a rabbit eye irritation study, a 1% of 2-ethyl-1-butanol solu-
tion was reported to produce necrosis of the eye (Smyth et al.,
4. Toxicology data 1954).
4.1. Acute toxicity 4.4. Skin densitization
Summary of acute toxicity studies is given in Table 2. No available information.
4.1.1. Oral studies 4.5. Phototoxicity and photoallergy

The acute oral LD50 of 2-ethyl-1-butanol in Carworth-Wistar
male or female rats (5/group) was reported to be 1.85 (1.52– No available information.
2.24) g/kg. Observations were made for 14 days. No additional de-
tails were reported (Smyth et al., 1954). 4.6. Absorption, distribution and metabolism
The acute oral LD50 of 2-ethyl-1-butanol in rats was reported to
be 1.85 g/kg. No additional details were reported (Bar and Griepen- 4.6.1. Absorption
trog, 1967; Nishimura et al., 1994). No available information.
The acute oral LD50 of 2-ethyl-1-butanol in rabbits was reported
to be 1.2 ml/kg (1.2 g/kg). No additional details were reported
4.6.2. Distribution
(Draize et al., 1944).
4.1.2. Dermal studies 4.6.3. Metabolism

The acute dermal LD50 of 2-ethyl-1-butanol in rabbits (4/group) 4.6.3.1. In vivo studies in animals. Kamil et al. (1953a) reported that
was reported to be 1.26 (0.85–1.87) g/kg. Observations were made when 25 mmol (2.55 g) of 2-ethyl-1-butanol was administered by
for 14 days. No additional details were reported (Smyth et al., oral gavage to 3.0 kg rabbits (n = 3), 40% of the administered dose
1954). was excreted in the urine as the glucuronide within 24 h.
The acute dermal LD50 of 2-ethyl-1-butanol in rabbits was re- Furthermore, Kamil et al. (1953b) reported that 2-ethyl-1-buta-
ported to be 2.0 ml/kg (2.0 g/kg). No additional details were re- nol, 2.55 g (3.1 ml), administered by oral gavage to a rabbit was ex-
ported (Draize et al., 1944). creted in the urine (24 h) as diethylacetylglucuronide. A small
amount of methyl-n-propyl ketone was also excreted.
In an acute inhalation study of 2-ethyl-1-butanol in male rats 4.6.3.2. In vitro studies in animals. No available information.
(6/group), the maximum time to death of exposure to concentrated
Table 2
Summary of acute toxicity studies. No available information.
Route Species No. animals/ LD50 References

dose group (g/kg) 4.8. Reproductive and developmental toxicity
Oral Rat 5 1.85 Smyth et al. (1954)
Oral Rat N/A 1.85 Nishimura et al. (1994)
Bar and Griepentrog (1967)
Oral Rabbit N/A 1.2 Draize et al. (1944) 4.9. Genotoxicity
Dermal Rabbit 4 1.26 Smyth et al. (1954)
Dermal Rabbit N/A 2.0 Draize et al. (1944)
4.10. Carcinogenicity Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:
No available information. Council of Europe, 2000. Partial Agreement in the Social and Public Health Field.
Chemically-defined flavouring substances. Group 2.1.3 Aliphatic Alcohols,
branched chain. p. 59, number 543. Council of Europe Publishing, Strasbourg.
This individual Fragrance Material Review is not intended as a Draize, J.H., Woodard, G., Calvery, H.O., 1944. Methods for the study of irritation and
stand-alone document. Please refer to A Safety Assessment of toxicity of substances applied topically to the skin and mucous membranes.
Branched Chain Saturated Alcohols When Used as Fragrance Ingre- Journal of Pharmacology and Experimental Therapeutics 82 (2), 377–390.
Suite™ for MicrosoftÒ Windows, v 4.00 or Insert Version used. United States
material. Environmental Protection Agency, Washington, DC, USA.
Conflict of interest statement Regulatory Toxicology and Pharmacology 31, 166–181.
This research was supported by the Research Institute for Fra- 2007.
grance Materials, an independent research institute that is funded Kamil, I.A., Smith, J.N., Williams, R.T., 1953a. Studies in detoxication. 46. The
by the manufacturers of fragrances and consumer products con- metabolism of aliphatic alcohols. The glucuronic acid conjugation of acyclic
aliphatic alcohols. Biochemical Journal 53, 129–136.
taining fragrances. The authors are all employees of the Research Kamil, I.A., Smith, J.N., Williams, R.T., 1953b. Studies in detoxication. 47. The
Institute for Fragrance Materials. formation of ester glucuronides of aliphatic acids during the metabolism of 2-
ethylbutanol and 2-ethylhexanol. Biochemical Journal 53 (1), 137–140.
McCreery, M.J., Hunt, W.A., 1978. Physico-chemical correlates of alcohol
References intoxication. Neuropharmacology 17, 451–461.
Nishimura, H., Saito, S., Kishida, F., Matsuo, M., 1994. Analysis of acute toxicity
Bar, V.F., Griepentrog, F., 1967. Die Situation in der gesundheitlichen Beurteilung (LD50-value) of organic chemicals to mammals by solubility parameter (delta).
der Aromatisierungsmittel fur Lebensmittel (where we stand concerning the 1. Acute oral toxicity to rats. Sangyo Igaku 36 (5), 314–323 (Japanese Journal
evaluation of flavoring substances from the viewpoint of health). Medizin Industrial Health).
Ernährung 8, 244–251. Smyth, H.F., Carpenter, C.P., Weil, C.S., Pozzani, U.C., 1954. Range-finding toxicity
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H., data. List V. Archives of Industrial Hygiene 10, 61–68.
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chain VCF, 2009. Volatile Compounds in Food: Database/Nijssen, L.M., van Ingen-Visscher,
saturated alcohols when used as fragrance ingredients. Food and Chemical C.A., Donders, J.J.H. (Eds.) – Version 11.1.1. TNO Quality of Life, Zeist, The
Toxicology 48 (S4), S1–S46. Netherlands, 1963–2009.

Review
Fragrance material review on 2,6-dimethyl-4-heptanol

Keywords: A toxicologic and dermatologic review of 2,6-dimethyl-4-heptanol when used as a fragrance ingredient is
Review presented. 2,6-Dimethyl-4-heptanol is a member of the fragrance structural group branched chain satu-
Fragrance
chains. This review contains a detailed summary of all available toxicology and dermatology papers that
are related to this individual fragrance ingredient and is not intended as a stand-alone document. A safety
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S90
3. Usage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S90
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S91
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S91
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S91
4.7.1. Two to 30-day studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S92
4.7.2. Subchronic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S92
4.7.3. Chronic (90+ days) studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S92
4.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S92
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S92

doi:10.1016/j.fct.2010.05.037
1. Identification
1.1. Synonyms: diisobutylcarbinol; 4-heptanol, 2,6-dimethyl-;

2,6-dimethylheptan-4-ol.
1.2. CAS registry number: 108-82-7.
1.3. EINECS number: 203-619-6.
1.4. Formula: C9H20O.
1.6. JECFA (2003): The Joint FAO/WHP Expert Committee on
Food Additives (JECFA No. 303) concluded that the substance
does not present a safety concern at current levels of intake
when used as a flavouring agent.
1.7. FEMA (1970): Flavor and Extract Manufacturers’ Association
states: generally Recognized as Safe as a flavor ingredient –
GRAS 4. (3140) Hall, 1970.
Fig. 1. 2,6,-Dimethyl-4-heptanol. 2. Physical properties

Introduction 2.4. Henry’s law (calculated; EPA, 2010): 0.0000412 atm m3/mol
25 °C.
This document provides a summary of the toxicologic review, 2.5. Log Kow (calculated; EPA, 2010): 3.08.
including all human health endpoints, of 2,6-dimethyl-4-heptanol 2.6. Refractive index: no information available.
when used as a fragrance ingredient. 2,6-Dimethyl-4-heptanol (see 2.7. Specific gravity: no information available.
Fig. 1; CAS No. 108-82-7) is a fragrance ingredient used in cosmet- 2.8. Vapor pressure: (calculated; EPA, 2010): 0.334 mm Hg;
ics, fine fragrances, shampoos, toilet soaps and other toiletries as 44.5 Pa (25 °C).
well as in non-cosmetic products such as household cleaners and 2.9. Water solubility (calculated; EPA, 2010): 613.8 mg/l @ 25 °C.
detergents. 2.10. UV spectra available at RIFM, does not absorb UV light.
In 2006, a complete literature search was conducted on 2,6-di-
methyl-4-heptanol. On-line toxicological databases were searched
including those from the Chemical Abstract Services, e.g. ToxCenter 3. Usage
[which in itself contains 18 databases including Chemical Ab-
stracts)], and the National Library of Medicine [e.g. Medline, Toxnet 2,6-Dimethyl-4-heptanol is a fragrance ingredient used in many
(which contains 14 databases)] as well as 26 additional sources fragrance compounds. It may be found in fragrances used in deco-
(e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance rative cosmetics, fine fragrances, shampoos, toilet soaps and other
companies were asked to submit all test data. toiletries as well as in non-cosmetic products such as household
The safety data on this material has never been reviewed before cleaners and detergents. Its use worldwide is in the region of 10–
by RIFM (Research Institute for Fragrance Materials, Inc.). All rele- 100 metric tons per annum (IFRA, 2004). The reported volume of
vant references are included in this document. More details have use is for 2,6-dimethyl-4-heptanol as used in fragrance compounds
been provided for unpublished data. The number of animals, sex (mixtures) in all finished consumer product categories. The volume
and strain are always provided unless they are not given in the ori- of use is surveyed by IFRA approximately every four years through
ginal report or paper. Any papers in which the vehicles and/or the a comprehensive survey of IFRA and RIFM member companies. As
doses are not given have not been included in this review. In addi- such the volume of use data from this survey provides volume of
tion, diagnostic patch test data with fewer than 100 consecutive use of fragrance ingredients for the majority of the fragrance
patients have been omitted. industry.
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2,6-dimethyl-4-heptanol.
Anti-perspirant 0.5 1 1 0.01 .02 0.000001
Bath products 17 0.29 0.001 0.02 .02 0.000001
Body lotion 8 0.71 1 0.004 .02 0.000100
Eau de toilette 0.75 1 1 0.08 .02 0.000200
Face cream 0.8 2 1 0.003 .02 0.000001
Fragrance cream 5 0.29 1 0.04 .02 0.000200
Hair spray 5 2 0.01 0.005 .02 0.000001
Shampoo 8 1 0.01 0.005 .02 0.000001
Shower gel 5 1.07 0.01 0.012 .02 0.000001
Toilet soap 0.8 6 0.01 0.015 .02 0.000001
Total 0.0005
a
b
Based on a 60 kg adult.
Table 2 Sixteen male and sixteen female rats of the Wistar CF/Gif Car-
Summary of acute toxicity studies. worth strain were given 2,6-dimethyl-4-heptanol with food.
Route Species No. animals/ LD50 References Observations for mortality and or systemic effects were made.
dose group (g/kg) The acute oral LD50 in rats was calculated to be 4.35 g/kg. Necropsy
Oral Rats 5 3.56 Smyth et al. (1949) results done at week 12 showed organ weights and organ histopa-
Oral Rats 32 4.35 Posternak and Vodoz (1975) thology to be within normal limits (Posternak and Vodoz, 1975).
Oral Rats 5,6 or 11 6.5 McOmie and Anderson (1949) Rats (5, 6, or 11/dose) were dosed intra-gastrically with 2.5, 3.7,
Oral Mice 6 or 14 5 McOmie and Anderson (1949)
5.0, 7.5, 10, and 12.5 g/kg in 1% aqueous Tergitol. Observations for
mortality and or systemic effects were made. The acute oral LD50 in
rats was calculated to be 6.5 ml/kg (6.5 g/kg) (McOmie and Ander-
son, 1949).
In the same study as above, mice (6 or 14/dose) were dosed in-
tra-gastrically with 2.5, 5.0, and 10 g/kg in 1% Tergitol. Observa-
tions for mortality and systemic effects were made. The LD50 in
mice was calculated to be 5.0 g/kg (95% CI 2.5–7.5) (McOmie and
Anderson, 1949).
ination of several thousand commercial formulations. The upper 4.1.2. Dermal studies
97.5 percentile concentration is calculated from the data obtained. Five rabbits received a single dermal application of 1, 2, 4 or 8 g/
This upper 97.5 percentile concentration is then used for all 10 kg 2,6-dimethyl-4-heptanol. Observations for mortality and/or sys-
consumer products. These concentrations are multiplied by the temic effects were made for 14 days. The acute dermal LD50 in rab-
amount of product applied, the number of applications per day bits was calculated to be 5.66 g/kg (95% CI 2.51–12.80) (Smyth
for each product type, and a ‘‘retention factor” (ranging from et al., 1949).
main on the skin and/or likelihood of the fragrance ingredient 4.1.3. Inhalation studies
being removed by washing. The resultant calculation represents A group of male and female subjects (n = 12) were exposed by
the total consumer exposure (mg/kg/day) (Cadby et al., 2002; Ford inhalation to 2,6-dimethyl-4-heptanol for 15 min. The sensory re-
et al., 2000). sponse limit and the concentration that produced irritation of the
This is a conservative calculation of dermal systemic exposure mucus membranes of the eyes, nose, or throat were determined.
because it makes the unlikely assumption that a consumer will Less than 5 ppm produced eye irritation in the majority of subjects.
use these 10 products containing; which are all perfumed with At 10 ppm nose and throat were irritated as well (Silverman et al.,
the upper 97.5 percentile level of the fragrance ingredient from a 1946).
fine fragrance type of product (Cadby et al., 2002; Ford et al., Groups of an unspecified number of rats were exposed to a sat-
2000). The 97.5% percentile use level in formulae for use in cosmet- urated vapor of two samples of 2,6-dimethyl-4-heptanol. The max-
ics in general has not been reported. As such the default value of imum period of exposure to both samples one and two that did not
0.02% is used to calculate the maximum daily exposure on the skin result in any deaths was 8 h (Smyth et al., 1949).
of 0.0005 mg/kg for high end users of these products. Ten mice were exposed by inhalation to 2 mg/l of 2,6-dimethyl-
A maximum skin level is then determined for consideration of 4-heptanol as a saturated vapor-air mixture. No deaths were re-
potential sensitization. The exposure is calculated as the percent ported after the 12-h exposure (McOmie and Anderson, 1949).
on the use of 20% of the fragrance mixture in the fine fragrance 4.2. Skin irritation
sults from the use of 2,6-dimethyl-4-heptanol in formulae that 4.2.1. Human studies
go into fine fragrances has not been reported. A default value of No available information.
0.02% is used, assuming use of the fragrance oil at levels up to
20% in the final product. 4.2.2. Animal studies (see Table 3)
The primary skin irritation of neat 2,6-dimethyl-4-heptanol was
4. Toxicology data evaluated on groups of five rabbits. Scoring similar to the Draize
method was used, with grades ranging from 1 to 10. A grade of 1
4.1. Acute toxicity (see Table 2) was observed; this indicates there was no irritation from the undi-
luted material (Smyth et al., 1949).
4.1.1. Oral studies Seven 5 h applications of neat 2,6-dimethyl-4-heptanol were
Five rats per dose were given a single dose of 2,6-dimethyl-4- made to the intact skin of two rabbits over a period of 21 days.
heptanol at 1, 2, 4, and 8 g/kg. Observations for mortality and or Observations included definite erythema after the 2nd exposure,
systemic effects were made for 14 days. The acute oral LD50 in rats areas of flaking after the 4th exposure, and cracking of the skin
was calculated to be 3.56 g/kg (95% CI 1.43–8.86) (Smyth et al., with bleeding fissures after the 7th exposure (McOmie and
1949). Anderson, 1949).
Table 3
Method Dose (%) Species Reactions References

Dermal application 100% Rabbit 0/5 No irritation Smyth et al. (1949)
Dermal application 100% Rabbit Definite erythema, flaking, and bleeding fissures McOmie and Anderson (1949)
Dermal application 100% Rabbit 2/5 erythema and slight edema McOmie and Anderson (1949)
Table 4 sumption was measured on a weekly basis, and efficiency of food

Summary of eye irritation studies. utilization (EFU) was calculated for pairs of rats (as housed). Hema-
Dose (%) Vehicle Reactions References tological examinations and blood urea determinations were car-
100% NA Irritation observed Smyth et al. (1949) ried out on 50% of the animals at week seven, and on all the
NA NA Irritation observed McOmie and Anderson (1949) animals at the end of the treatment period. All animals were sacri-
ficed at the end of the study, and a gross necropsy was conducted
at that time. The liver and kidneys were weighed, and a histological
examination was conducted. No adverse effects were observed,
The cuff method was used for acute dermal exposure in five rab-
and no changes of any biological significance were observed (Pos-
bits. Animals were given 4 h semi-occlusive applications of neat
ternak and Vodoz, 1975).
2,6-dimethyl-4-heptanol from 3.9–9.4 ml/kg. Two of the five rab-
bits showed some erythema and slight edema (McOmie and
Anderson, 1949).
4.3. Mucous membrane (eye) irritation (see Table 4)
4.9. Genotoxicity
An ocular irritation study was conducted with two samples of
neat 2,6-dimethyl-4-heptanol. Groups of five rabbits per dose were
used, and the test material was applied to the corneas. The re-
tracted eyelids were released approximately 1 min after the instil-
lation, and the eyes were stained with fluorescein 18–24 h later.
The eyes were examined and scored according to a 10-point scale.
Both samples of 2,6-dimethyl-4-heptanol were assigned a score of
2, which was equivalent to 0.5 ml of the neat material producing
injury of 1–5 points. Prior to the fluorescein staining, an injury of
stand-alone document. Please refer to A Safety Assessment of Alco-
one point was equivalent to iritis and five points was equivalent
hols Branched Chain Saturated when used as fragrance ingredients
to corneal opacity. After fluorescein staining, one point was equiv-
(Belsito et al., 2010) for an overall assessment of this material.
alent to necrosis on less than 5% of the cornea and five points was
equivalent to necrosis on 63–87% of the cornea (Smyth et al.,
1949).
2,6-Dimethyl-4-heptanol was tested in one rabbit. Moderate
This research was supported by the Research Institute for Fra-
Irritation was observed within the first 24 h, but returned to nor-
mal by the 72nd hour (McOmie and Anderson, 1949).
4.4. Skin sensitization
Institute for Fragrance Materials.
References
4.5. Phototoxicity and photoallergy Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,
No available information. saturated alcohols when used as fragrance ingredients. Food and Chemistry
Toxicology 48 (S4), S1–46.
4.6. Absorption, distribution and metabolism providing estimates for safety evaluation. Regulatory Toxicology and
EPA (Environmental Protection Agency), 2010. Estimation programs interface
suite™ for MicrosoftÒ Windows, v 4.00 or insert version used. United States
4.7. Repeated dose toxicity FEMA (Flavor and Extract Manufacturers Association), 1970. Recent progress in the
consideration of flavoring ingredients under the food additives amendment 4.
GRAS substances. Food Technology, 24(5), 25–34.
4.7.1. Two to 30-day studies Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria for
No available information. development of a database for safety evaluation of fragrance ingredients.
IFRA (International Fragrance Association), 2004. Use level survey, August 2004.
4.7.2. Subchronic studies IFRA (International Fragrance Association), 2007. Volume of use survey, February
No available information. 2007.
JECFA (Joint Expert Committee on Food Additives), 2003. Safety evaluation of
certain food additives. Who Food Additives Series:42. Prepared by the Fifty-First
4.7.3. Chronic (90+ days) studies Meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA).
A 12-week oral study was conducted on groups of 32 Wistar CF/ World Health Organization, Geneva 1999.
Gif Carworth strain rats (16 per sex), and the treated animals were McOmie, W.A., Anderson, H.H., 1949. Comparative toxicologic effects of some
isobutyl carbinols and ketones. University California Publications Pharmacology
fed a diet containing 2,6-dimethyl-4-heptanol mixed with micro- 2 (17), 217–230.
crystalline cellulose. The controls were only fed the basic diet, Posternak, J.M., Vodoz, C.A., 1975. Toxicology tests on flavouring matters. II.
but both the test and control animals were allowed access to food Pyrazines and other compounds. Food and Cosmetics Toxicology 13, 487–490.
Silverman, L., Schultz, H.F., First, M.W., 1946. Further studies on sensory response to
ad libitum. The daily intake of the test material was estimated to
certain industrial solvent vapors. The Journal of Industrial Hygiene and
be 11 mg/kg bodyweight per day. Individual body weights were re- Toxicolology 28, 262–266.
corded prior to the test and weekly thereafter. Observations of Smyth, H.F., Carpenter, C.P., Weil, C.S., 1949. Range-finding toxicity data, list III. The
physical appearance and behavior were made daily. Food con- Journal of Industrial Hygiene and Toxicolology 31 (1), 60–62.

Review
Fragrance material review on 3-methyl-1-pentanol

Keywords: A toxicologic and dermatologic review of 3-methyl-1-pentanol when used as a fragrance ingredient is
Review presented. 3-Methyl-1-pentanol is a member of the fragrance structural group branched chain saturated
Fragrance
alcohols. The common characteristic structural elements of the alcohols with saturated branched chain
are one hydroxyl group per molecule, and a C4 to C12 carbon chain with one or several methyl side chains.
This review contains a detailed summary of all available toxicology and dermatology papers that are
related to this individual fragrance ingredient and is not intended as a stand-alone document. A safety
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S94
3. Usage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S94
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95
4.1.3. Other studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95
4.2.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95
4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95
4.4.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95
4.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S95
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S96

doi:10.1016/j.fct.2010.05.038
1.6. JECFA (1998): The Joint FAO/WHP Expert Committee on

Food Additives (JECFA No. 263) concluded that the substance
does not present a safety concern at current levels of intake
when used as a flavoring agent.
1.7. FEMA (1990): Flavor and Extract Manufacturers’ Association
states: Generally Recognized as Safe as a flavor ingredient –
GRAS 15 (3762).
Fig. 1. 3-Methyl-1-pentanol. 2. Physical properties

Introduction 2.2. Boiling point (calculated; EPA, 2010): 145.86 °C.
This document provides a summary of the toxicologic review, 2.4. Henry’s law (calculated; EPA, 2010): 0.0000176 atm m3/mol
including all human health endpoints, of 3-methyl-1-pentanol 25 °C.
when used as a fragrance ingredient. 3-Methyl-1-pentanol (see 2.5. Log Kow (calculated; EPA, 2010): 1.75.
Fig. 1; CAS Number 589-35-5) is a fragrance ingredient used in cos- 2.6. Refractive index: no information available.
metics, fine fragrances, shampoos, toilet soaps and other toiletries 2.7. Specific gravity: no information available.
as well as in non-cosmetic products such as household cleaners 2.8. Vapor pressure (calculated; EPA, 2010): 0.7 mm Hg (20 °C);
and detergents. This material has been reported to occur in nature, 1.7 mm Hg (25 °C); 227 Pa (25 °C).
with quantities observed in the mangifera species of mango (VCF, 2.9. Water solubility (calculated; EPA, 2010): 11950 mg/l (25 °C).
2009). 2.10. UV spectra available at RIFM, peaks at 200–210 nm and
In 2006, a complete literature search was conducted on 3- returns to baseline at 280–290 nm.
methyl-1-pentanol. On-line toxicological databases were searched
including those from the Chemical Abstract Services [e.g. ToxCen-
3. Usage
ter [which in itself contains 18 databases including Chemical Ab-
stracts)] and the National Library of Medicine [e.g. Medline,
3-Methyl-1-pentanol is a fragrance ingredient used in many fra-
Toxnet (which contains 14 databases)] as well as 26 additional
sources (e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fra-
grance companies were asked to submit all test data.
cleaners and detergents. Its use worldwide is in the region of less
than 0.01 metric tons per annum (IFRA, 2004). The reported vol-
ume of use is for 3-methyl-1-pentanol as used in fragrance com-
pounds (mixtures) in all finished consumer product categories.
The volume of use is surveyed by IFRA approximately every four
years through a comprehensive survey of IFRA and RIFM member
companies. As such the volume of use data from this survey pro-
1. Identification is calculated based on the concentrations of the same fragrance
ingredient in 10 types of the most frequently used personal care
1.1. Synonyms: 2-ethyl-4-butanol; 1-pentanol, 3-methyl; and cosmetic products (anti-perspirant, bath products, body lotion,
methyl pentanol-3. eau de toilette, face cream, fragrance cream, hair spray, shampoo,
1.2. CAS Registry Number: 589-35-5. shower gel, and toilet soap). The concentration of the fragrance
1.3. EINECS Number: 209-644-9. ingredient in fine fragrances is obtained from examination of several
1.4. Formula: C6H14O. thousand commercial formulations. The upper 97.5 percentile
1.5. Molecular weight: 102.18. concentration is calculated from the data obtained. This upper 97.5
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 3-methyl-1-pentanol.
Product type Grams applied Applications per day Retention factor Mixture/product (%) Ingredient/mixturea Ingredientb (mg/kg/day)
Anti-perspirant 0.5 1 1 0.01 0.0006 0.000001
Bath products 17 0.29 0.001 0.02 0.0006 0.000001
Body lotion 8 0.71 1 0.004 0.0006 0.000001
Eau de toilette 0.75 1 1 0.08 0.0006 0.000010
Face cream 0.8 2 1 0.003 0.0006 0.000001
Fragrance cream 5 0.29 1 0.04 0.0006 0.000010
Hair spray 5 2 0.01 0.005 0.0006 0.000001
Shampoo 8 1 0.01 0.005 0.0006 0.000001
Shower gel 5 1.07 0.01 0.012 0.0006 0.000001
Toilet soap 0.8 6 0.01 0.015 0.0006 0.000001
Total 0.00002
a
b
percentile concentration is then used for all 10 consumer products. applications were made in a three week period. Little or no irrita-
These concentrations are multiplied by the amount of product ap- tion was found in all 41 male and female volunteers (RIFM, 1973).
and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account for 4.2.2. Animal studies
the length of time a product may remain on the skin and/or likeli- A group of three albino rabbits were given 0.5 ml of 0.5% 3-
hood of the fragrance ingredient being removed by washing. The methyl-1-pentanol in 99.5% Alcohol SDA 39C and observed at the
resultant calculation represents the total consumer exposure (mg/ end of the 24 h contact period and again 48 h later. Erythema
kg/day) (Cadby et al., 2002; Ford et al., 2000). and edema were not observed in any of the three rabbits tested
This is a conservative calculation of dermal systemic exposure and therefore 3-methyl-1-pentanol cannot be considered a pri-
because it makes the unlikely assumption that a consumer will mary irritant (RIFM, 1972).
the upper 97.5 percentile level of the fragrance ingredient from a 4.3. Mucous membrane (eye) irritation
2000). The 97.5 percentile use level in formulae for use in cosmet- No information available.
would result in a maximum daily exposure on the skin of 4.4. Skin sensitization
0.00002 mg/kg for high end users of these products (Table 1).
A maximum skin level is then determined for consideration of 4.4.1. Human studies
potential sensitization. The exposure is calculated as the percent 4.4.1.1. Induction studies. A repeated insult patch test was con-
concentration of the fragrance ingredient applied to the skin based ducted to determine if 3-methyl-1-pentanol would induce dermal
on the use of 20% of the fragrance mixture in the fine fragrance sensitization in human volunteers. During the induction phase
consumer product (IFRA, 2007). The maximum skin level in formu- 0.5 ml was applied onto a Webril swatch and applied to the upper
lae that go into fine fragrances has been reported to be 0.0002% arms of each volunteer for 24 h. Induction applications were made
(IFRA, 2007), assuming use of the fragrance oil at levels up to for a total of 9 applications during 3 week period. Following a two
20% in the final product. week rest period, a challenge patch was applied to the original site
as well as a fresh site. Patches were applied as in the induction
4. Toxicology data phase and kept in place for 24 h after which time they were re-
moved. Reactions to the challenge were scored at 48 and 72 h after
4.1. Acute toxicity (see Table 2) application. There was no sensitization reactions observed during
the challenge phase (RIFM, 1973).
4.1.1. Oral studies
The acute oral LD50 of 3-methyl-1-pentanol in mice was re- 4.4.1.2. Cross-sensitization. No information available.
ported to be >2 g/kg. Mortality was 0, 0, 1, and 10 of 10 mice at
0.5, 1.0, 2.0, and 4.0 g/kg. At the top dose 8/10 animals died within 4.4.1.3. Diagnostic studies. No information available.
24 h. Surviving animals were observed for 14 days post-dosing
(RIFM, 1982). 4.4.2. Animal studies
No information available. 4.5. Phototoxicity and photoallergy
4.1.3. Other studies No information available.

The acute intraperitoneal LD50 of 3-methyl-1-pentanol in mice
was reported to be >0.25 g/kg. Mortality was 0, 0, 8, 9, 10, and 10 4.6. Absorption, distribution and metabolism
of 10 mice at 0.125, 0.25, 0.5, 1.0, 2.0, and 4.0 g/kg. At the 0.5,
1.0, 2.0, and 4.0 g/kg, 7, 9, 10, and 10 animals, respectively, died No information available.
within 24 h. Surviving animals were observed for 14 days post-
dosing (RIFM, 1982). 4.7. Repeated dose toxicity
4.2. Skin irritation No information available.
4.2.1. Human studies 4.8. Reproductive and developmental toxicity

Irritation was evaluated during the induction phase in a human
repeated insult patch test (HRIPT). An application of 0.5 ml with No information available.
0.5% 3-methyl-1-pentanol in 99.5% alcohol SDA 39C on a 1 1-
inch Webril patch was administered to the upper arms of the 4.9. Genotoxicity
panelists and removed after 24 h. Irritation was scored 48 h after
initial application and a new patch reapplied at that time. Nine No information available.
Table 2
Summary of acute toxicity studies.
Route Species No. animals/ LD50 (g/kg) References
dose group
Oral Mice 10 >2.0 RIFM (1982)
Intraperitoneal Mice 10 >0.25 RIFM (1982)
Branched Chain Saturated Alcohols When Used as Fragrance
Ingredients (Belsito et al., 2010) for an overall assessment of this FEMA (Flavor and Extract Manufacturers Association), 1990. Recent progress in the
consideration of flavoring ingredients under the food additives amendment. 15.
material.
GRAS substances. Food Technol. 44 (2). 78, 80, 82, 84, 86.
Conflict of interest statement Development of a database for safety evaluation of fragrance ingredients. Regul.
Toxicol. Pharm. 31, 166–181.
This research was supported by the Research Institute for Fra- IFRA (International Fragrance Association), 2007. Volume of Use Survey, February
grance Materials, an independent research institute that is funded 2007.
JECFA (Joint Expert Committee on Food Additives), 1998. Safety Evaluation of
by the manufacturers of fragrances and consumer products con- Certain Food Additives. Who Food Additives Series: 40. Prepared by the Forty-
taining fragrances. The authors are all employees of the Research ninth Meeting of the Joint FAO/WHO Expert Committee on Food Additives
Institute for Fragrance Materials. (JECFA). World Health Organization, Geneva.
RIFM (Research Institute for Fragrance Materials, Inc.), 1972. Skin Irritation Study
with 3-Methyl-1-pentanol in Rabbits. Unpublished Report from International
References Flavors and Fragrances. Report Number 53594. RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1973. Repeated Insult Patch
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H., Test with 3-Methyl-1-pentanol. Unpublished Report from International Flavors
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched chain and Fragrances. Report Number 53593 RIFM, Woodcliff Lake, NJ, USA.
saturated alcohols when used as fragrance ingredients. Food Chem. Toxicol. 48 RIFM (Research Institute for Fragrance Materials, Inc.), 1982. 14-Day LD50 Study on
(S4), S1–S46. 3-Methyl-1-pentanolin Mice. Private Communication to FEMA. Unpublished
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients: Report from H.W. Engler B. Bahler. Report Number 9019. RIFM, Woodcliff Lake,
providing estimates for safety evaluation. Regul. Toxicol. Pharma. 36, 246–252. NJ, USA.
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface VCF, 2009. (Volatile Compounds in Food): Database/Nijssen, L.M., van Ingen-
Suite™ for MicrosoftÒ Windows, v 4.00 or Insert Version used. United States Visscher, C.A., Donders, J.J.H. (Eds.), – Version 11.1.1. TNO Quality of Life, Zeist,
Environmental Protection Agency, Washington, DC, USA. The Netherlands, 1963–2009.

Review
Fragrance material review on 2-methylbutanol

Keywords: A toxicologic and dermatologic review of 2-methylbutanol when used as a fragrance ingredient is pre-
Review sented. 2-Methylbutanol is a member of the fragrance structural group branched chain saturated alco-
Fragrance
review contains a detailed summary of all available toxicology and dermatology papers that are related to
this individual fragrance ingredient and is not intended as a stand-alone document. A safety assessment
of the entire branched chain saturated alcohol group will be published simultaneously with this docu-
ment; please refer to Belsito et al., 2010 for an overall assessment of the safe use of this material and
all other branched chain saturated alcohols in fragrances.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S98
3. Usage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S99
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S99
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S99
4.1.4. Intraperitoneal studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S99
4.1.5. Other studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S99
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S99
4.2.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S100
4.6.1. Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S100
4.6.2. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S100
4.6.3. Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S100
4.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S100
* Corresponding author. Tel.: +1 201 689 8089; fax: +1 201 689 8088.

doi:10.1016/j.fct.2010.05.039
4.9.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S100

4.9.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S100
4.10. Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S100
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S100
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . S101
Introduction diagnostic patch test data with fewer than 100 consecutive pa-
tients have been omitted.
This document provides a comprehensive summary of the tox-
icologic review, including all human health endpoints, of 2-meth-
ylbutanol when used as a fragrance ingredient. 2-Methylbutanol 1. Identification
(see Fig. 1; CAS Number 137-32-6) is a fragrance ingredient used
in cosmetics, fine fragrances, shampoos, toilet soaps and other 1.1. Synonyms: active amyl alcohol; 1-butanol, 2-methyl-; sec-
toiletries as well as in non-cosmetic products such as household butylcarbinol; (±) 2-methyl-1-butanol; 2-methylbutyl alco-
cleaners and detergents. This material has been reported to occur hol; 2-methylbutan-1-ol.
in nature, with highest quantities observed in hop oil (VCF, 1.2. CAS registry number: 137-32-6.
2009). 1.3. EINECS number: 205-289-9.
In 2006, a complete literature search was conducted on 2-meth- 1.4. Formula: C5H12O.
ylbutanol. On-line toxicological databases were searched including 1.5. Molecular weight: 88.15.
those from the Chemical Abstract Services, [e.g., ToxCenter (which 1.6. Council of Europe (2000): 2-methylbutanol was included
in itself contains 18 databases including Chemical Abstracts)], and by the Council of Europe in the list of substances granted
the National Library of Medicine [e.g., Medline, Toxnet (which con- B – information required – 28 day oral study (COE No. 2346).
tains 14 databases)] as well as 26 additional sources (e.g., BIOSIS, 1.7. FEMA (2001): Flavor and Extract Manufacturers’ Association
Embase, RTECS, OSHA, ESIS). In addition, fragrance companies were states: Generally Recognized as Safe as a flavor ingredient –
asked to submit all test data. GRAS 20.
The safety data on this material has never been reviewed by 1.8. JECFA (2004): The Joint FAO/WHO Expert Committee on
RIFM (Research Institute for Fragrance Materials, Inc.). All relevant Food Additives (JECFA No. 1199) concluded that the sub-
references are included in this document. More details have been stance does not present a safety concern at current levels
provided for unpublished data. The number of animals, sex and of intake when used as a flavouring agent.
strain are always provided unless they are not given in the original
report or paper. Any papers in which the vehicles and/or the doses 2. Physical properties
are not given have not been included in this review. In addition,
(25 °C).
2.8. Vapor pressure (calculated; EPA, 2010): 2.5 mm Hg (20 °C);
4.54 mm Hg (25 °C); 606 Pa (25 °C).
2.9. Water solubility (calculated; EPA, 2010): 32,200 mg/l
(25 °C).
Fig. 1. 2-Methylbutanol. 2.10. UV spectra available at RIFM, peaked at 200–215 nm range
and returns to baseline at 220–225 nm.
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2-methylbutanol.
Anti-perspirant 0.5 1 1 0.01 0.007 0.000010
Bath products 17 0.29 0.001 0.02 0.007 0.000001
Body lotion 8 0.71 1 0.004 0.007 0.000030
Eau de toilette 0.75 1 1 0.08 0.007 0.000070
Face cream 0.8 2 1 0.003 0.007 0.000010
Fragrance cream 5 0.29 1 0.04 0.007 0.000070
Hair spray 5 2 0.01 0.005 0.007 0.000001
Shampoo 8 1 0.01 0.005 0.007 0.000001
Shower gel 5 1.07 0.01 0.012 0.007 0.000001
Toilet soap 0.8 6 0.01 0.015 0.007 0.000001
Total 0.0002
a
b
Table 2
3. Usage Summary of acute toxicity studies.
Route Species NO. animals/ LD50 References

2-Methylbutanol is a fragrance ingredient used in many fra-
dose group (g/kg)
grance compounds. It may be found in fragrances used in decorative
Oral Rat 5 4.92 Smyth et al. (1962)
cosmetics, fine fragrances, shampoos, toilet soaps and other toilet-
ries as well as in non-cosmetic products such as household cleaners Oral Rat N/A 4.01 Rowe and McCollister (1982)
and detergents. Its use worldwide is in the region of 0.01–0.1 metric Oral Rat 10 (5/sex) 4.17 RIFM (1979)
tons per annum (IFRA, 2004). The reported volume of use is for 2- Oral Rat 10 (5/sex) >5.0 RIFM (1985)
methylbutanol as used in fragrance compounds (mixtures) in all
Dermal Rabbit N/A 3.54 RIFM (1979)
finished consumer product categories. The volume of use is sur-
veyed by IFRA approximately every 4 years through a comprehen-
sive survey of IFRA and RIFM member companies. As such the
volume of use data from this survey provides volume of use of fra- The acute oral LD50 was reported to be 4.17 g/kg based on mortal-
grance ingredients for the majority of the fragrance industry. ity (1/10) at 3.16 g/kg and (8/10) at 5.0 g/kg (RIFM, 1979).
The dermal systemic exposure in cosmetic products (see Table Wistar rats (5/sex) were given a single oral dose 3.0 or 5.0 g/kg
1) is calculated based on the concentrations of the same fragrance of 2-methylbutanol by gavage and observed for 14 days. No ani-
ingredient in ten types of the most frequently used personal care mals died, and the LD50 was determined to be greater than 5.0 g/
and cosmetic products (anti-perspirant, bath products, body lotion, kg (RIFM, 1985).
shower gel, and toilet soap). The concentration of the fragrance 4.1.2. Dermal studies
ingredient in fine fragrances is obtained from examination of sev- The acute dermal LD50 of 2-methylbutanol in rabbits (n = 4) was
eral thousand commercial formulations. The upper 97.5 percentile reported to be 3.54 ml/kg (3.54 g/kg). Contact time was 24 h and
concentration is calculated from the data obtained. This upper 97.5 observation time was 14 days. No additional details were reported
percentile concentration is then used for all 10 consumer products. (Smyth et al., 1962; RIFM, 1979).
These concentrations are multiplied by the amount of product ap- An acute dermal LD50 value was reported to be 2.89 for 2-
plied, the number of applications per day for each product type, methyl-1-butanol (Rowe and McCollister, 1982).
and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account
for the length of time a product may remain on the skin and/or 4.1.3. Inhalation studies
likelihood of the fragrance ingredient being removed by washing. The maximum time for exposure of rats (6/dose) to concen-
The resultant calculation represents the total consumer exposure trated vapors of 2-methylbutanol without mortality was 8 h. The
(mg/kg/day) (Cadby et al., 2002, Ford et al., 2000). chemical was administered undiluted, unless a lesser concentra-
This is a conservative calculation of dermal systemic exposure tion was necessary. Then the solution was made in water, or corn
because it makes the unlikely assumption that a consumer will oil (Smyth et al., 1962).
use these 10 products containing; which are all perfumed with Rats were exposed to 2-methylbutanol by inhalation of satu-
the upper 97.5 percentile level of the fragrance ingredient from a rated atmosphere at 20 °C for 7 h. Mortality was not observed,
fine fragrance type of product (Cadby et al., 2002, Ford et al., but escape behavior and intermittent respiration was noted (RIFM,
2000). The 97.5% percentile use level in formulae for use in cosmet- 1979).
ics in general has been reported to be 0.007% (IFRA, 2007), which No mortality was observed when six rats were exposed to 2-
would result in a maximum daily exposure on the skin of methylbutanol by inhalation of saturated vapors for 8 h. No further
0.0002 mg/kg for high end users. information available (Rowe and McCollister, 1982).
potential sensitization. The exposure is calculated as the percent 4.1.4. Intraperitoneal studies
concentration of the fragrance ingredient applied to the skin based Mice were given 2-methylbutanol at doses of 200, 700, or
on the use of 20% of the fragrance mixture in the fine fragrance 2000 mg/kg by intraperitoneal injection and observed for 14 days.
consumer product (IFRA, 2007). The average maximum use level All animals in the 2000 mg/kg and 9/10 at 700 mg/kg died. The
in formulae that go into fine fragrances has been reported to be LD50 was estimated to be greater than 200 mg/kg but less than
0.001% (IFRA, 2007), assuming use of the fragrance oil at levels 700 mg/kg (RIFM, 1979).
up to 20% in the final product. Rats were given 2-methylbutanol at doses of 1000, or 2000 mg/
kg by intraperitoneal injection and observed for 14 days. Animals
4. Toxicology data in the 2000 mg/kg showed respiratory arrest and death. At
1000 mg/kg the rats showed sedation, irritation of the peritoneum
4.1. Acute toxicity (see Table 2) and injury of the lungs (Haggard et al., 1945 as cited in Greim,
2008).
4.1.1. Oral studies
The acute oral LD50 of 2-methylbutanol in rats (n = 5) was 4.1.5. Other studies
reported to be 4.92 (3.75–6.46) ml/kg (4.92 g/kg). No additional In isolated perfused livers of rats, 65.1 mmol 2-methylbutanol/l
details were reported (Smyth et al., 1962). were cytotoxic as evidenced by the release of liver enzymes into
The acute oral LD50 of 2-methylbutanol in rats (not specified) the perfusate. The alcohols decreased the content of ATP in the li-
was reported to be 1000 mg/kg. No additional details were re- ver. The content of oxidized glutathione was increased. Lipid per-
ported (Nishimura et al., 1994). oxidation was not observed (Strubelt et al., 1999).
The acute oral LD50 of 2-methylbutanol in rats (not specified)
was reported to be 4.01 g/kg. No additional details were reported 4.2. Skin irritation
(Rowe and McCollister, 1982).
2-Methylbutanol was given to Sprague dawley rats (5/sex) at 4.2.1. Human studies
doses of 1.47, 2.15, 3.16, or 5.0 g/kg and observed for 14 days. No available information.
4.2.2. Animal studies contain aldehydes or ketones, but did yield 9.6% of non-reducing
In a rabbit dermal irritation study (n = 5) undiluted 2-methyl- glucuronide (Kamil et al., 1953).
butanol resulted in Grade 2 irritation defined as the least visible
capillary injection from the undiluted material (Smyth et al., 1962). 4.6.3.2. In vitro studies in animals. Rat liver microsomes metabo-
In a rabbit dermal irritation study with two rabbits, undiluted lized 2-methylbutanol to yield approximately 8 nmol aldehyde
2-methylbutanol resulted in Grade 4.7 or moderate irritation with per minute per mg protein and 13 nmol glucuronide per min per
some necrosis observed (RIFM, 1979). mg protein. The km and Vmax for glucuronidation were 2 mmol/l
and 18 nmol/min/mg protein, respectively. The km and Vmax for
4.3. Mucous membrane (eye) irritation microsomal oxidation were 4.6 mmol/l and 3.6 nmol/min/mg pro-
tein, respectively. The microsomes were obtained from male Spra-
In a rabbit eye irritation study, 2-methylbutanol resulted in gue–Dawley rats that had been pre-treated for 2 weeks with 10%
Grade 8 injury where corneal necrosis was observed (Smyth ethanol in the drinking water (Iwersen and Schmoldt, 1995).
et al., 1962).
In a rabbit eye irritation study (n = 6), undiluted 2-methylbuta- 4.7. Repeated dose toxicity
nol resulted in some turbidity at the cornea, inflammation on the
iris, and redness of the conjunctivae after observations for 72 h No available information.
(RIFM, 1979).
When a 0.005 ml of undiluted 2-methylbutanol (or an excess of 4.8. Reproductive and developmental toxicity
a 15% solution in propylene glycol; not specified) was instilled into
the eyes of rabbits moderate to severe burns and corneal necrosis No available information.
was observed (Rowe and McCollister, 1982).
4.9. Genotoxicity
4.4. Skin sensitization
4.9.1. In vitro studies
No available information. 4.9.1.1. Bacterial test systems. Light absorption and luminescent
umu tests were used to investigate the genotoxicity of 2-methylbu-
tanol with Salmonella typhimurium TA1535/pSK1002 and TA1535/
pTL210. Results showed the umu test for light absorption of
TA1535/pSK102 to be negative, where as the umu test for lumines-
cent TA1535/pTL210 to be positive (Nakajima et al., 2006).
4.6. Absorption, distribution and metabolism 4.9.1.2. Studies in mammalian cells. In a study of the cytotoxic and
genotoxic effects of a number of alcohols and ketones, 2-methylbu-
4.6.1. Absorption tanol had an IC50 (Inhibitory concentration resulting in 50% reduc-
No available information. tion in colony formation) of 31 mM for human lung carcinoma cell
line A549. At 45 and 90 mM concentration of 2-methylbutanol,
4.6.2. Distribution there was no difference from controls in alkaline comet assay tail
No available information. moment in either A549 cells or Chinese hamster V79 cells. The co-
met assay could not be performed in human peripheral blood cells
4.6.3. Metabolism due to cytotoxicity. At methylbutanol concentrations of 23 and
4.6.3.1. In vivo studies in animals (see Table 3). Following intraperi- 45 mM, there was no difference, in the micronucleus test, from
toneal administration of 1 g/kg undiluted 2-methylbutanol to rats; controls in induction of micronuclei in V79 cells with or without
blood was drawn for analysis 1 h after the first administration and the addition of hepatic S-9 from Aroclor induced rats. Finally an
at subsequent intervals. There was total elimination of 7.6%, 5.6% HPRT with Chinese hamster V70 fibroblast cells at concentrations
was recovered unchanged in the expired air and 2.0% unchanged up to 46 mM (the highest non-toxic concentration) mutagenicity
in the urine. Disappearance from blood was rapid, with neither was not observed (Kreja and Seidel, 2001, 2002a,b).
alcohol nor aldehyde detected after 10 h (Haggard et al., 1945).
Oxidation to the aldehyde and glucuronidation was demon- 4.9.2. In vivo studies
strated for 2-methylbutanol with microsomes from rats pre-trea- No available information.
ted with ethanol (Iwersen and Schmoldt, 1995).
2-Methylbutanol was administered to large chinchilla rabbits 4.10. Carcinogenicity
(n = 3) by oral gavage at 25 m-mol/rabbit. Collected urine did not
Table 3 This individual Fragrance Material Review is not intended as a

Summary of in vivo animal studies.
Route Species Results References Branched Chain Saturated Alcohols When Used as Fragrance Ingre-
Intraperitoneal Rat 5.6% was recovered unchanged in Haggard dients (Belsito et al., 2010) for an overall assessment of this
the expired air and 2.0% et al. (1945) material.
unchanged in the urine
Oral (drinking Rat Oxidation to the aldehyde and Iwersen and
water) glucuronidation was Schmoldt Conflict of interest statement
demonstrated (1995)
Oral (gavage) Rabbit Excess glucuronide excretion Kamil et al. This research was supported by the Research Institute for Fra-
represented 9.6% of the (1953)
administered dose
taining fragrances. The authors are all employees of the Research Prepared by the Joint FAO/WHO Expert Committee on Food Additives (JECFA).
WHO Food Additives Series: 52. IPCS, WHO, Geneva.
Kamil, I.A., Smith, J.N., Williams, R.T., 1953. Studies in detoxication. 46. The
metabolism of aliphatic alcohols. The glucuronic acid conjugation of acyclic
aliphatic alcohols. Biochem. J. 53, 129–136.
References Kreja, L., Seidel, H.J., 2001. Toxicology study of some often detected microbial
volatile organic compounds (MVOC). Umweltmed Forsch Prax. 6 (3), 159–163.
Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H., Kreja, L., Seidel, H.J., 2002a. Evaluation of the genotoxic potential of some microbial
Sipes, I.G., Smith, R.L., Tagami, H., 2010. A safety assessment of branched volatile organic compounds (MVOC) with the comet assay, the micronucleus
chain saturated alcohols when used as fragrance ingredients. Food Chem assay and the HPRT gene mutation assay. Mutat. Res. 513 (1–2), 143–150.
Toxicol. 48 (S4), S1–S46. Kreja, L., Seidel, H.J., 2002b. On the cytotoxicity of some microbial volatile organic
Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients: compounds as studied in the human lung cell line A549. Chemosphere 49 (1),
providing estimates for safety evaluation. Regul.Toxicol. Pharm. 36, 246–252. 105–110.
Council of Europe, 2000. Partial Agreement in the Social and Public Health Field. Nakajima, D., Ishii, R., Kageyama, S., Onji, Y., Mineki, S., Morooka, N., Takatori, K.,
Chemically-defined flavouring substances. Group 2.1.3 Aliphatic alcohols, Goto, S., 2006. Genotoxicity of microbial volatile organic compounds. J. Health
branched chain. p. 60, number 2346. Council of Europe Publishing, Strasbourg. Sci. 52 (2), 148–153.
EPA (Environmental Protection Agency), 2010. Estimation Programs Interface Nishimura, H., Saito, S., Kishida, F., Matsuo, M., 1994. Analysis of acute toxicity
Suite™ for MicrosoftÒ Windows, v 4.00 or insert version used]. United States (LD50-value) of organic chemicals to mammals by solubility parameter (delta).
Environmental Protection Agency, Washington, DC, USA. 1. Acute oral toxicity to rats. Sangyo Igaku 36 (5), 314–323 (Japanese Journal
FEMA (Flavor and Extract Manufacturers Association), 2001. GRAS flavoring Industrial Health).
substances 20. Food Technol. 55 (12), 1-17. RIFM (Research Institute for Fragrance Materials, Inc.), 1979. Acute toxicity studies
Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria for on 2-methylbutanol. Unpublished report from BASF, Report number 55366.
development of a database for safety evaluation of fragrance ingredients. Regul. RIFM, Woodcliff Lake, NJ, USA.
Toxicol. Pharm. 31, 166–181. RIFM (Research Institute for Fragrance Materials, Inc.), 1985. Report on the acute
Greim, H. (Ed.), 2008. Pentanol-Isomeren. Toxikologisch-arbeitsmedizinische oral toxicity of 2-methylbutanol in rats. Unpublished report from BASF, Report
Begründungen von MAK-Werten, Lieferung 44. Wiley-VCH, Weinheim. number 55365. RIFM, Woodcliff Lake, NJ, USA.
Haggard, H.W., Miller, D.P., Greenberg, L.A., 1945. The amyl alcohols and their Rowe, V.K., McCollister, S.B, 1982. Alcohols. In: Industrial Hygiene and Toxicology,
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(1), 1–14. Smyth, H.F., Carpenter, C.P., Weil, C.S., Pozzani, U.C., Striegel, J.A., 1962. Range-
IFRA (International Fragrance Association), 2004. Use Level Survey, August 2004. finding toxicity data: list VI. Am. Ind. Hyg. Assoc. J. (AIHAJ) 23, 95–107.
IFRA (International Fragrance Association), 2007. Volume of Use Survey, February Strubelt, O., Deters, M., Pentz, R., Siegers, C.P., Younes, M., 1999. The toxic and
2007. metabolic effects of 23 aliphatic alcohols in the isolated perfused rat liver.
Iwersen, S., Schmoldt, A., 1995. ADH Independent metabolism of aliphatic alcohols: Toxicol. Sci. (formerly Fundam. Appl. Toxicol.) 49 (1), 133–142.
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Review
Fragrance materials review on isoamyl alcohol

D. McGinty *, A. Lapczynski, J. Scognamiglio, C.S. Letizia, A.M. Api
Keywords: A toxicologic and dermatologic review of isoamyl alcohol when used as a fragrance ingredient is pre-
Review sented. Isoamyl alcohol is a member of the fragrance structural group branched chain saturated alcohols.
Frangrance
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S103
1. Identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S103
2. Physical properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S103
3. Usage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S103
4. Toxicology data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S104
4.1. Acute toxicity (see Table 2). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S104
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S104
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S105
4.1.3. Intravenous studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S105
4.1.4. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S105
4.2. Skin irritation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S105
4.2.1. Human studies (see Table 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S105
4.2.2. Animal studies (see Table 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S105
4.3. Mucous membrane (eye) irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S105
4.4. Skin sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S105
4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S105
4.4.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S105
4.5. Phototoxicity and photoallergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S105
4.6. Absorption, distribution, and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S105
4.6.1. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S105
4.6.2. Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S106
4.7. Repeated dose toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S106
4.7.1. Subchronic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S106
4.7.2. Chronic studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S106
4.8. Reproductive and developmental . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S107
4.9. Genotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S107
4.9.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S107
4.9.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S107

doi:10.1016/j.fct.2010.05.040
4.10. Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S107

4.11. Neurotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S108
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S108
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S108
Introduction 1. Identification
This document provides a comprehensive summary of the tox-

icologic review of isoamyl alcohol when used as a fragrance ingre- 1.1. Synonyms: 1-butanol, 3-methyl-; isobutyl carbinol; isopent-
dient including all human health endpoints. Isoamyl alcohol (see anol; isopentyl alcohol; 3-methyl-1-butanol; 3-methylb-
Fig. 1; CAS Number 123-51-3) is a fragrance ingredient used in cos- utan-1-ol.
metics, fine fragrances, shampoos, toilet soaps, and other toiletries 1.2. CAS Registry Number: 123-51-3.
as well as in non-cosmetic products such as household cleaners 1.3. EINECS Number: 204-633-5.
and detergents. It is a colorless liquid with a disagreeable alcohol 1.4. Formula: C5H12O.
odor only becoming a pleasant fruity-winey odor at high dilutions 1.5. Molecular weight: 88.15.
(Arctander, 1969). This material has been reported to occur in nat- 1.6. Council of Europe (2000): isoamyl alcohol was included by
ure, with the highest quantities observed in the brassica species of the Council of Europe in the list of substances granted A –
mustard (VCF, 2009). may be used in foodstuffs (COE Number 51).
In 2006, a complete literature search was conducted on isoamyl 1.7. FDA: isoamyl alcohol was approved by the FDA as flavor (21
alcohol. On-line toxicological databases were searched including CFR 172.515).
those from the Chemical Abstract Services [e.g. ToxCenter (which 1.8. FEMA (1965): Flavor and Extract Manufacturers’ Association
in itself contains 18 databases including Chemical Abstracts)], states: Generally Recognized as Safe as a flavor ingredient –
and the National Library of Medicine [e.g. Medline, Toxnet (which GRAS 3 (2057).
contains 14 databases)] as well as 26 additional sources (e.g. BIO- 1.9. JECFA (1996): the Joint FAO/WHO Expert Committee on
SIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance companies Food Additives (JECFA) concluded that the substance does
were asked to submit all test data. not present a safety concern at current levels of intake when
The safety data on this material was last reviewed by Opdyke used as a flavoring agent (52).
(1979). All relevant references are included in this document. More 1.10. OSHA: isoamyl alcohol was listed by the Occupational Safety
details have been provided for unpublished data. The number of and Health Administration as PEL-TWA 100 ppm, 360 mg/
animals, sex, and strain are always provided unless they are not gi- m3 (for primary and secondary).
ven in the original report or paper. Any papers in which the vehi-
cles and/or the doses are not given have not been included in this 2. Physical properties
review. In addition, diagnostic patch test data with fewer than 100
consecutive patients have been omitted. 2.1. Physical form: colorless liquid with a disagreeable alcohol
odor and pungent, repulsive taste.
2.2. Flash point: 109 °F; CC.
2.3. Boiling point: 132 °C.
(25 °C).
2.5. Log Kow (measured; EPA, 2010): 1.16.
2.6. Specific gravity: 0.81.
2.7. Refractive index: 1.4.
2.8. Vapor pressure (calculated; EPA, 2010): 3.84 mm Hg at
(25 °C); 512 Pa (25 °C).
2.9. Water solubility (calculated; EPA, 2010): 41,580 mg/l at
25 °C.
Fig. 1. Isoamyl alcohol. 2.10. UV spectra available at RIFM. Does not absorb UV light.
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing isoamyl alcohol.
Anti-perspirant 0.5 1 1 0.01 0.01 0.000001
Bath products 17 0.29 0.001 0.02 0.01 0.000001
Body lotion 8 0.71 1 0.004 0.01 0.000001
Eau de toilette 0.75 1 1 0.08 0.01 0.000100
Face cream 0.8 2 1 0.003 0.01 0.000001
Fragrance cream 5 0.29 1 0.04 0.01 0.000100
Hair spray 5 2 0.01 0.005 0.01 0.000001
Shampoo 8 1 0.01 0.005 0.01 0.000001
Shower gel 5 1.07 0.01 0.012 0.01 0.000001
Toilet soap 0.8 6 0.01 0.015 0.01 0.000001
Total 0.0002
a
b
Table 2 This is a conservative calculation of dermal systemic exposure

Summary of acute toxicity studies. because it makes the unlikely assumption that a consumer will
Route Species Number LD50 (g/kg) References use these 10 products containing; which are all perfumed with
of animals/ the upper 97.5 percentile level of the fragrance ingredient from a
dose group fine fragrance type of product (Cadby et al., 2002; Ford et al.,
Oral Mice 4 >2.0 RIFM (2008) 2000). The 97.5 percentile use level in formulae for use in cosmet-
Oral Rat N/A 4.36 Golovinskaya (1976) ics in general has been reported to be 0.01% (IFRA, 2007), which
Oral Rat 4 1.3 (male) Purchase (1969)
would result in a conservative calculated maximum daily exposure
4.0 (female) on the skin of 0.0002 mg/kg for high end users of these products
Oral Rat 5 7.1 Smyth et al. (1969) (see Table 1).
Oral Rat N/A >5.0 RIFM (1979) A maximum skin level is then determined for consideration of
Oral Rabbit 10–35 3.44 Munch (1972)
Dermal Rabbit 10 >5.0 RIFM (1976a)
Dermal Rabbit 4 3.97 Smyth et al. (1969) concentration of the fragrance ingredient applied to the skin based
Dermal Rabbit 6 4.0 RIFM (1979) on the use of 20% of the fragrance mixture in the fine fragrance
Intravenous Mice N/A 0.23 Chvapil et al. (1962) consumer product (IFRA, 2007). The maximum skin level that re-
sults from the use of isoamyl alcohol in formulae that go into fine
fragrances has been reported to be 0.012% (IFRA, 2007), assuming
use of the fragrance oil at levels up to 20% in the final product.
3. Usage
4. Toxicology data
Isoamyl alcohol is a fragrance ingredient used in decorative cos-
metics, fine fragrances, shampoos, toilet soaps, and other toiletries 4.1. Acute toxicity (see Table 2)
as well as in non-cosmetic products such as household cleaners
and detergents. Its use worldwide is in the region 0.1–1.0 metric 4.1.1. Oral studies
tons/annum (IFRA, 2004). The reported volume of use is for iso- As a preliminary study for a mouse micronucleus test, acute oral
amyl alcohol as used in fragrance compounds (mixtures) in all fin- toxicity was evaluated with four (2/sex) animals. The NMRI mice
ished consumer product categories. The volume of use is surveyed were treated orally with the 0.1, 0.5, 1.0, or 2.0 g/kg of isoamyl
by IFRA approximately every four years through a comprehensive alcohol and examined for acute toxic symptoms at intervals of
survey of IFRA and RIFM member companies. As such the volume around 1, 2–4, 6, 24, 30, and 48 h after administration. At the high-
of use data from this survey provides volume of use of fragrance est dose of 2.0 g/kg bodyweight the toxic effects observed were a
ingredients for the majority of the fragrance industry. reduction in spontaneous activity, eyelid closure, and ruffled fur.
The dermal systemic exposure in cosmetic products (see Table 1) No mortality was observed at the highest dose which indicated
is calculated based on the concentrations of the same fragrance the LD50 to be greater than 2.0 g/kg (RIFM, 2008).
ingredient in 10 types of the most frequently used personal care The acute oral LD50 of isoamyl alcohol in rats was reported to be
and cosmetic products (anti-perspirant, bath products, body lotion, 4.36 g/kg (no further details provided) (Golovinskaya, 1976).
eau de toilette, face cream, fragrance cream, hair spray, shampoo, The oral LD50 of isoamyl alcohol in rats was reported to be 1.3 g/
shower gel, and toilet soap). The concentration of the fragrance kg (no further details provided) (Nishimura et al., 1994).
ingredient in fine fragrances is obtained from examination of several The acute oral (gavage) LD50 was evaluated in groups of 4 rats
thousand commercial formulations. The upper 97.5 percentile con- with isoamyl alcohol at a dose range of 0.325–4.95 and 0.81–
centration is calculated from the data obtained. This upper 97.5 per- 12.0 g/kg (concentration not reported) in polyethylene glycol 200
centile concentration is then used for all 10 consumer products. for male and female, respectively. Deaths in female rats occurred
These concentrations are multiplied by the amount of product ap- 4 h after high doses (4.95 and 12.0 g/kg); none died in the 10 days
plied, the number of applications per day for each product type, after the lower doses (0.81 and 2.0 g/kg). Males receiving the high-
and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account for est doses of 4.95 g/kg and a group receiving 12.0 g/kg died within
the length of time a product may remain on the skin and/or likeli- 4 h, and several at the lower doses of 0.81 and 2.0 g/kg died
hood of the fragrance ingredient being removed by washing. The 1–5 days later. Histological examination of the liver revealed
resultant calculation represents the total consumer exposure (mg/ hyperemia but very few degenerative changes. Females receiving
kg/day) (Cadby et al., 2002; Ford et al., 2000). 4.95 g/kg showed cloudy swelling and cast formation in the cortex
Table 3
Summary of human skin irritation studies.
Method Concentration Results References

Reactions Frequency (%)
48 h closed patch test 8% in petrolatum 0/25 0 RIFM (1976b)
5 min, occlusive patch test 75% in water 12/12 100 Wilkin and Fortner (1985a)
5 min, occlusive patch test 75% in water 3/3 100 Wilkin and Fortner (1985b)
5 min, occlusive patch test 75% in a hydrophilic ointment 12/12 100 Wilkin and Stewart (1987)
Table 4
Method Dose (%) Species Reactions References

Single application of 5.0 g/kg 100 Rabbit Marked erythema and moderate edema RIFM (1976)
0.01 ml aliquot applied to the clipped skin 100 Rabbit Irritation observed Smyth et al. (1969)
Single application 100 Rabbit Very irritating RIFM (1979)
and a few pyknotic tubular cells in the medulla section of the kid- 4.2. Skin irritation
ney. In females receiving 12.0 g/kg, the cortex showed signs of
necrosis with some tubular cells showing pyknosis. In males pyk- 4.2.1. Human studies (see Table 3)
nosis and hyperemia were seen in the outer zone of the medulla In a pre-test for a human maximization study, a 48 h closed
in all groups, and tubular necrosis was seen in the cortex after patch test was conducted on the volar forearms or backs of 25 vol-
the two highest doses (2.0 and 4.95 g/kg). The calculated LD50 unteers with 8% isoamyl alcohol in petrolatum. No irritation was
was 4.0 g/kg (95% limits: 2.45–6.17 g/kg) for female and 1.3 g/kg observed (RIFM, 1976b).
(95% limits: 0.67–2.41 g/kg) for male (Purchase, 1969). Patch tests were conducted on 27 (groups of 12, 12, and 3)
Groups of five Carworth-Wistar male rats were administered a healthy volunteers with 75% aqueous solution of isoamyl alcohol.
single dose of undiluted isoamyl alcohol by gavage. The oral LD50 Patches were applied to the subjects’ forearms, and were removed
of was reported to be 7.1 g/kg with limits of 4.82–10.4 g/kg (Smyth after being occluded for 5 min. Irritation reactions were observed
et al., 1969). in all volunteers (Wilkin and Fortner, 1985a,b; Wilkin and Stewart,
Isoamyl alcohol was reported to have an LD50 greater than 5.0 g/ 1987).
kg in Sprague Dawley rats. The animals were given doses of 2.15 or
5.0 g/kg and observed for 14 days (RIFM, 1979). 4.2.2. Animal studies (see Table 4)
The acute oral (gavage) LD50 of isoamyl alcohol was reported to Irritation was evaluated during a dermal LD50 study. A single
be 39 mmol/kg (3.45 g/kg). Administration was via stomach tube application of 5.0 g/kg of neat isoamyl alcohol was made to 10 rab-
from a 50 ml syringe to groups of 10–35 rabbits (Munch, 1972). bits. Marked or moderate edema were observed in 10/10 rabbits
(RIFM, 1976a).
4.1.2. Dermal studies Primary skin irritation was determined using groups of five al-
The acute dermal LD50 of isoamyl alcohol was evaluated in 10 bino rabbits. A 0.01 ml aliquot of isoamyl alcohol was applied to
rabbits. Each animal received a single dermal application of undi- the clipped skin of the animals undiluted or as a solution in water,
luted isoamyl alcohol at a dose of 5.0 g/kg. Clinical signs and/or propylene glycol or acetone. Irritation reactions were observed
mortality were observed over a 14 day period. No deaths were ob- (Smyth et al., 1969).
served. Clinical signs included flaccidity, ataxia, loss of righting re- Isoamyl alcohol was reported to be very irritating when applied
flex and diarrhea. The LD50 was reported to be greater than 5.0 g/kg undiluted to the skin of six rabbits. Irritation resolved after 8 days
(RIFM, 1976a). (RIFM, 1979).
The acute dermal LD50 was evaluated in groups of four male al-
bino New Zealand rabbits. Undiluted isoamyl alcohol at 0.1 ml was 4.3. Mucous membrane (eye) irritation
applied to the clipped trunk, and kept in place beneath an imper-
vious plastic film for 24 h (doses and skin area not provided). The An eye irritation test was conducted in five rabbits per dose. Iso-
LD50 was reported to be 3.97 g/kg with limits of 2.93–5.37 g/kg amyl alcohol (0.5 ml aliquot) was tested undiluted or as a solution
(Smyth et al., 1969). in propylene glycol and water. Irritant effects were observed
Isoamyl alcohol was reported to have a dermal LD50 of 4 ml/kg (Smyth et al., 1969).
(4 g/kg) in rabbits. The animals were given undiluted doses of An eye irritation test was conducted in two rabbits with undi-
isoamyl alcohol and observed for 8 days (RIFM, 1979). luted isoamyl alcohol. Irritation was observed up to 8 days in one
rabbit (RIFM, 1979).
4.1.3. Intravenous studies
The intravenous LD50 of isoamyl alcohol in water was deter- 4.4. Skin sensitization
mined in female white H strain mice. Using an approximate gra-
phic probit method, the LD50 was calculated to be 2.64 mmol/kg 4.4.1. Human studies
(233 mg/kg; no further details provided) (Chvapil et al., 1962). A maximization study was conducted on 25 (5 male, 20 female)
The hemodynamic effects of isoamyl alcohol were studied in 56 volunteers. Isoamyl alcohol at 8% in petrolatum was applied under
anesthetized, open chest dogs. The material was administered i.v. occlusion to the volar forearms or backs for five alternate days,
at a constant rate for 40–150 min. The infusion of 20 mg/kg/min 48 h periods. The sites were pre-treated for 24 h with 2.5% aqueous
decreased heart rate, systemic arterial pressure, and myocardial sodium lauryl sulfate (SLS) under occlusion. The challenge phase
contraction force progressively and markedly. All dogs died during was conducted after a rest period of 10–14 days at sites pre-treated
the first hour of infusion (Nakano and Kessinger, 1972). for 1 h with 5–10% SLS. The challenge patch was removed after
Isoamyl alcohol was injected into the vein of cat, under a light 48 h, and the site was read at the patch removal and 24 h after
ether anesthesia, to determine the lethal dose. In terms of the pure the patch removal. No reactions were observed (RIFM, 1976b).
alcohol of 0.26 ml/kg (260 mg/kg) was determined to be lethal
(Macht, 1920). 4.4.2. Animal studies
No data available.
Smyth et al. (1969) reported no death up to 8 h when concen- 4.5. Phototoxicity and photoallergy
trated vapors of isoamyl alcohol were exposed to rats by
inhalation. No data available.
Sensory irritation was evaluated in four Swiss male mice via
measurement of changes in respiratory rate during a 10 min expo- 4.6. Absorption, distribution, and metabolism
sure to isoamyl alcohol. The concentration of isoamyl alcohol that
caused a 50% decrease in the respiratory rate (RD50) of mice was 4.6.1. Distribution
4452 ppm with 95% confidence limits of 2885–12,459 (Kane 4.6.1.1. Human studies. Respiratory uptake of isoamyl alcohol was
et al., 1980). investigated in four healthy volunteers. Test air concentration
Rats inhaled isoamyl alcohol as a steam vapor in an enriched was 25–200 ppm and it was inhaled for 10 min. The mean uptake
atmosphere at 20 °C. After a 7 h exposure, no animals died (RIFM, (determined using calculations based on exhalation percentages of
1979). isoamyl alcohol to mixed exhaled air) for the last 5 min of the test
1
respiration was 63% and the mean respiratory rate was 15.3 min 4.7. Repeated dose toxicity
(Kumagai et al., 1998).
4.7.1. Subchronic studies
Groups of 10 Ash/CSE rats (5/sex) were administered 500 or
1000 mg/kg of isoamyl alcohol dissolved in corn oil by gavage,
4.6.1.2. Animal studies. Groups of 10 rats per dose received 600 mg 7 days a week for 6 weeks. A group of 10 controls (5/sex) were
of 20% isoamyl alcohol/l solution (either in ethanol or water) by administered corn oil alone. Observations included mortality,
intraperitoneal injection in four equally divided portions of behavior, bodyweight, food and water consumption, renal concen-
2.5 ml/100 g of bodyweight, at 15 min intervals. Two hours after tration, organ weights, and gross pathology. Blood was examined
administration, the blood concentration of isoamyl alcohol with for hemoglobin content, packed cell volume, and counts of erythro-
ethanol was maximal. It declined thereafter and was still detect- cytes, reticulocytes, as well as total and differential leukocytes. Ser-
able at 10 h but not at 12 h. When isoamyl alcohol was adminis- um was analyzed for the content of urea, glucose, total protein, and
tered in water, its presence in the blood was discernible 2 h after albumin as well as activities of glutanic–oxalacetic and glutamic–
administration but not thereafter (Greenberg, 1970). pyruvic trasaminases and lactic dehydrogenase. With 500 mg/kg,
A single dose of 2.0 g/kg of isoamyl alcohol, in an aqueous solu- a significant increase in the hemoglobin concentration and red
tion of 20%, was given orally to fasted six Wistar WAG rats. Blood blood cell count of test females was observed when compared to
and urine were collected for up to 8 h for measurement of test the controls, but the increases were not dose-related. With
material levels. The blood level in mg/100 ml was 7 at 15 min, 9 1000 mg/kg, a lower pituitary weight in males was observed, but
at 30 min, 17 at 1 h, 8 at 1.5 h, 7 at 2 h, 3 at 4 h, and 1 at 8 h. Uri- when expressed relative to bodyweight, the decrease was not evi-
nary excretion was 0 (Gaillard and Derache, 1965). dent. At both doses, red patches on the lungs of male and female
After intraperitoneal administration of 1000 mg bodyweight, treated animals and control animals were found at the necropsy.
the concentration of isoamyl alcohol in blood declined within 5 h Histopathological examination of the lungs revealed lymphocyte
to non-detectable levels. An elimination half-life was not calcu- cuffing of the bronchi, but the incidence and severity were similar
lated. For isoamyl alcohol 1.2% was excreted via urine and expired in both the test and control animals. The authors have concluded
air. Compared to other amyl alcohols tested by the authors, pri- the NOAEL to be 1000 mg/kg in females and 500 mg/kg in males
mary alcohols were eliminated from the blood more quickly than (Carpanini et al., 1973).
secondary and tertiary alcohols (Haggard et al., 1945). Groups of 20 SPF-Wistar, Chbb:THOM rats (10/sex) were
administered isoamyl alcohol in drinking water at 1000 ppm
(80 mg/kg), 4000 ppm (320 mg/kg), and 16,000 ppm
4.6.2. Metabolism (1280 mg/kg) for 90 days. A group of 20 controls (10/sex) were
4.6.2.1. Human studies. The glucuronidation of isoamyl alcohol and administered drinking water alone. Parameters evaluated included
other short-chained aliphatic alcohols was investigated in vitro bodyweight, food and water consumption, clinical signs, mortality,
with human liver microsomes. The Vmax value was 3.3 nmol/min/ hematology, clinical chemistry, gross and microscopic pathology.
mg protein and the Km was determined as 13.3 mM. The glucuron- The erythrocyte count was slightly elevated in males treated with
idation increased with chain length (C2–C5) of the alcohols studied 4000 ppm (320 mg/kg). With 16,000 ppm (1280 mg/kg), an in-
(Jurowich et al., 2004). crease in the erythrocyte count, a decrease in the mean corpuscular
The rate of oxidation of isoamyl alcohol by human skin alcohol volume, and a decrease in the mean corpuscular hemoglobin con-
dehydrogenase was 183.3 nM/mg protein/min (Wilkin and Stew- tent of the blood in male rats were observed. Compared to the con-
art, 1987). trols, a significant deviation from the control group leukocyte
count was observed in males at 1000 ppm (80 mg/kg), and in the
prothrombin time in females treated with 4000 and 16,000 ppm
(320 and 1280 mg/kg). However, these observed effects did not ap-
4.6.2.2. Animal studies. A single oral (gavage) dose of 25 mmol/3 kg pear to be relevant to the treatment. Ectopia of thymus tissue in
rabbit (734.6 mg/kg) of isoamyl alcohol in water was given to the region of the thyroid gland was observed in five males treated
three chinchilla rabbits. Increases in the urinary excretion of glucu- with 16,000 ppm (1680 mg/kg). The no-observable-adverse-effect-
ronides were monitored. Of the dose, 9% was excreted in the urine level (NOAEL) of isoamyl alcohol was concluded to be 4000 ppm
(at 24 h) as the glucuronide. The urine did not contain aldehydes or (320 mg/kg) in males and 16,000 ppm (1680 mg/kg) in females
ketones (Kamil et al., 1953). (Schilling et al., 1997; RIFM, 1991).
In isolated perfused livers of rats, 65.1 mmol isoamyl alcohol/l
were cytotoxic as evidenced by the release of liver enzymes into 4.7.2. Chronic studies
the perfusate. The alcohols decreased the content of ATP in the li- Groups of 30 Ash/CSE rats (15/sex) were administered 150, 500,
ver. The content of oxidized glutathione was increased. Lipid per- and 1000 mg/kg of isoamyl alcohol dissolved in corn oil by gavage,
oxidation was not observed (Strubelt et al., 1999). 7 days a week for 17 weeks. A group of 30 controls (15/sex) were
Age-dependent glucuronidation activity was demonstrated administered corn oil alone. Observations included mortality,
in vitro in the olfactory mucosa of 1 day, 1 week, 2 week, 3 month, behavior, bodyweight, food and water consumption, hematology,
12 month, and 24 month old male Wistar rats with isoamyl alcohol serum analysis, urinalysis, renal concentration, organ weights,
(Leclerc et al., 2002). and gross pathology. Microscopic pathology was examined for
Oxidation to the aldehyde and glucuronidation was demon- the highest dose only. There were no effects associated with treat-
strated for isoamyl alcohol with microsomes from rats pre-treated ment in the results of the hematological examinations, serum anal-
with ethanol (Iwersen and Schmoldt, 1995). yses, urinary cell counts, renal concentration tests, or organ
The rate of oxidative metabolism of isoamyl alcohol was about weights. A slight reduced rate of bodyweight gain at the highest
0.1 mmol/g liver in rat liver homogenate and about 0.05 mM/g per- dose level was shown to be due to a reduced food intake. Two rats
fused rat liver (Hedlund and Kiessling, 1969). in the highest dose level died, but histopathological examination
The Km-values of isoamyl alcohol with alcohol dehydrogenase showed that these deaths were due to dosing into the lungs and
from human and horse liver were 0.07 and 0.08 mM, respectively not to any toxic effects of isoamyl alcohol. A female rat given
(Pietruszko et al., 1973). 500 mg/kg/day developed a lipoma, which was not considered to
be due to treatment. The other histopathological changes seen 4.9. Genotoxicity

were related to mild infections in the animals and not to isoamyl
alcohol. The NOAEL was concluded to be 1000 mg/kg/day (Carpa- 4.9.1. In vitro studies
nini et al., 1973). 4.9.1.1. Bacterial test systems. Isoamyl alcohol was negative in a
Astill et al. (1996) gave 0 (water), 0 (vehicle), 50, 200, or umu test for light absorption in Salmonella typhimurium TA1535/
750 mg/kg bodyweight/day in 0.005% cremophor EL to B6C3F1 pSK1002 at concentrations in which growth inhibition was 650%.
mice (50/sex). For 18 months, 5 days a week, animals were treated However, isoamyl alcohol was positive when tested in a umu test
with isoamyl alcohol by gavage. Increased mortality, and decreases for luminescence with S. typhimurium TA1535/pTL210 at concen-
in bodyweight gains, and food consumption were observed at trations in which growth inhibition was 650% (Nakajima et al.,
750 mg/kg as well as fatty liver and hyperplasia of the forestomach 2006).
epithelium. A systemic NOAEL of 200 mg/kg bodyweight was
determined. 4.9.1.2. Studies in mammalian cells (see Table 5). A Comet assay was
conducted on human lung carcinoma A549 cells and human
4.8. Reproductive and developmental peripheral blood pB cells. Induced DNA damage was only observed
at cytotoxic concentrations of isoamyl alcohol such as 23, 46, and
Groups of 25 pregnant rats were exposed to a vapor–air mixture 91 mM (Kreja and Seidel, 2002).
of isoamyl alcohol at concentrations of 0.5, 2.5, and 10 mg/l, 6 h/ An alkaline single cell gel electrophorese assay (comet assay)
day from gestation day (GD) 6–15. In rats exposed to 10 mg/l body- was conducted on Chinese hamster V79 fibroblasts, and DNA dam-
weight gain was decreased between GD 6 and 9 and increased be- age induced by isoamyl alcohol was observed at cytotoxic concen-
tween GD 12–15, however no biologically relevant or trations of 23, 46, and 91 mM (Kreja and Seidel, 2002).
concentration related differences were apparent among the A micronucleus assay was conducted on Chinese hamster fibro-
groups. At 0.5 mg/l fetal examination revealed skeletal changes: blast V79 cells, with isoamyl alcohol at concentrations of 5, 9, and
malformations of the sternebrae and/or the vertebral column. With 23 mM in the presence and absence of metabolic activation (S9).
2.5 mg/l, the observed fetal anomalies included soft tissue changes No genotoxic effects were produced at any of the tested concentra-
such as a globular shaped heart and dextrocardia, and skeletal tions (Kreja and Seidel, 2002).
changes: malformations of the sternebrae and/or the vertebral col- No mutagenicity was produced in a hypoxanthine–guanine
umn. At 10 mg/l observed fetal anomalies included external phosphoribosyltransferase (HPRT) assay conducted on Chinese
changes such as polydactyly and skeletal changes: malformations hamster lung fibroblast cell line V79, with 51.5 mM of isoamyl
of the sternebrae and/or the vertebral column. With all the tested alcohol in the presence or absence of metabolic activation (S9)
concentrations, retardations such as incomplete or missing ossifi- (Kreja and Seidel, 2002).
cation of hyoid, skull bones, metacarpal or metatarsal bones, verte-
bral bodies, and/or sternebrae were observed. The NOAEL for dams 4.9.2. In vivo studies
was 2.5 and 10 mg/l for the fetuses (Klimisch and Hellwig, 1995; An in vivo micronucleus assay was conducted with bone mar-
RIFM, 1990a). row cells of NMRI mice with isoamyl alcohol at doses of 500,
As a part of the same experiment, groups of 15 pregnant Hima- 1000, and 2000 mg/kg. Ten animals (5/sex) were evaluated at 24
layan rabbits Chbbb:HM per dose were exposed to 0.5, 2.5, and and 48 h after a single administration for the occurrence of micro-
10 mg/l isoamyl alcohol on gestation days 7–19. At 10 mg/l a slight nuclei. There was no increase in the frequency of detected micro-
retardation of bodyweight increase was observed throughout the nuclei. Isoamyl alcohol was determined to be non-mutagenic in
whole exposure period and was significant on GD 7–10. Also, at the micronucleus assay (RIFM, 2008).
10 mg/l an indication of an irritant eye effect (reddish, lid closure,
or slight discharge) was also observed during the exposure period. 4.10. Carcinogenicity
In fetuses pseudoankylosis and soft tissue changes such as hypo-
plasia of the gall bladder, bipartite ovary, dilated renal pelvis, A group of 15 Wistar rats were administered 0.1 ml/kg (0.1 g/
and/or separate origin of carotids were observed at all doses. How- kg) of isoamyl alcohol by gavage, twice a week up to the time of
ever, it was noted that these findings occurred at a similar inci- their spontaneous deaths. The average total dosage was 27 ml
dence rate in historical controls. Observed skeletal changes (27 g). The 25 controls were treated with 1 ml/kg (1 g/kg) of a
included malformations of the sternebrae and/or the vertebral col- 0.9% NaCl solution, twice weekly. The animals were weighed at
umn, the sternum and the ribs. They were seen in all groups with- regular intervals, and most were subjected to hematological test-
out apparent dose relationships or statistically significant ing. At the time of spontaneous death, a necropsy, histological
differences between the groups. The only significant differences examinations of all organs, vertebrae, and femur, and additional
of note were due to the increased incidence of two specific types hematological tests were conducted. The average survival time of
of soft tissue variation (the separated origin of carotids and traces the control animals was 643 days. A wide spectrum of tumors
of interventricular foramen/septum membranaceum) which oc- was observed from bladder carcinoma, carcinoma of the kidney
curred without a clear concentration relationship. The NOAEL for pelvis, adenocarcinoma of the proventriculum to benign tumors
dams was 2.5 and 10 mg/l for the fetuses (Klimisch and Hellwig, such as papillomae and occasional incipient infiltrative growth.
1995; RIFM, 1990b). The number of malignant and benign tumors found was 0 and 3,
Table 5
Summary of studies in mammalian cells.
Test system Concentration (mM) Results References

Comet assay Human lung carcinoma A549 cells 23, 46, and 91 Not genotoxic Kreja and Seidel (2002)
Comet assay Human lung peripheral blood pB cells 46 and 91 Not genotoxic Kreja and Seidel (2002)
Comet assay Chinese hamster fibroblast V79 cells 23 and 91 Not genotoxic Kreja and Seidel (2002)
Micronucleus assay Chinese hamster fibroblast V79 cells 5, 9, and 23 Not genotoxic Kreja and Seidel (2002)
HPRT assay Chinese hamster lunch fibroblast V79 cells 51.5 Not genotoxic Kreja and Seidel (2002)
respectively. The average survival time of test animals was Astill, B.D., Gingell, R., Guest, D., Hellwig, J., Hodgson, J.R., Kuettler, K., Mellert, W.,
Murphy, S.R., Sielken Jr., R.L., Tyler, T.R., 1996. Oncogenicity testing of 2-
527 days, and the number of malignant and benign tumors found
was 4 and 3, respectively (Gibel et al., 1975). Toxicology 31 (1), 29–41.
As a part of the same experiment group of 24 Wistar rats were Belsito, D., Bickers, D., Bruze, M., Calow, P., Greim, H., Hanifin, J.M., Rogers, A.E.,
subcutaneously administered 0.04 ml/kg (0.04 g/kg) of isoamyl Saurat, J.H., Sipes, I.G., Tagami, H., 2010. A safety assessment of branched chain
saturated alcohols when used as fragrance ingredients. Food Chem. Toxicol. 48
alcohol, once a week up to the time of their spontaneous deaths. (S4), S1–S46.
The average total dosage was 3.8 ml (3.8 g/kg). The controls were Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:
subcutaneously treated with 1 ml/kg (1 g/kg) of a 0.9% NaCl solu- providing estimates for safety evaluation. Regulatory Toxicology and
tion, twice weekly. The average survival time of the control ani- Carpanini, F.M.B., Gaunt, I.F., Kiss, I.S., Grasso, P., Gangolli, S.D., 1973. Short-term
mals was 643 days, and the number of malignant and benign toxicity of isoamyl alcohol in rats. Food and Cosmetics Toxicology 11 (5), 713–
tumors found was 0 and 2, respectively. The average survival time 724.
Chvapil, M., Zahradnik, R., Cmuchalova, B., 1962. Influence of alcohols and
of test animals was 592 days, and the number of malignant and be- potassium salts of xanthogenic acids on various biological objects. Archives of
nign tumors found was 10 and 5, respectively. The tumors con- International Pharmacodyn 135 (3–4), 330–343.
sisted of pancreas adenomas, adenomas of the proventriculus Council of Europe, 2000. Partial Agreement in the Social and Public Health Field.
Partial Agreement in the Social and Public Health Field. Chemically-defined
and of suprarenal glands, spleen fibromas to the benign small pap- Flavouring Substances. Group 2.1.3 Aliphatic Alcohols, Branched Chain, vol. 51.
illomas or fibroadenomas (Gibel et al., 1975). Council of Europe Publishing, Strasbourg. p. 58.
4.11. Neurotoxicity Environmental Protection Agency, Washington, DC, USA.
FDA (Food and Drug Administration). Code of Federal Regulations, 21 CFR 172.515.
Title 21 – Food and Drugs, vol. 3. Food and Drug Administration, Department of
Male albino SPF rats derived from the Wistar strain, or female Health and Human Services. Part 172 – Food Additives Permitted for Direct
mice of the H strain were used to study the neurotoxicity of iso- Addition to Food for Human Consumption. Subpart F – Flavoring Agents and
amyl alcohol. Whole body exposures were carried out in 80-l glass Related Substances, 515 – Synthetic Flavoring Substances and Adjuvants
(Chapter I).
chambers with 1 rat or 2 mice. In total 16 rats (4/group) or 32 mice FEMA (Flavor and Extract Manufacturers Association), 1965. Recent progress in the
were exposed. Less than 1 min after removal from the exposure consideration of flavoring ingredients under the food additives amendment 3.
box, a short electrical impulse was applied through ear electrodes GRAS substances. Food Technology 19 (2, Part 2), 151–197.
to the animals to measure the biological effect of isoamyl alcohol. development of a database for safety evaluation of fragrance ingredients.
Of the six time characteristics recorded, duration of toxic extension Regulatory Toxicology and Pharmacology 31, 166–181.
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solvents: isoeffective air concentrations of 48 compounds evaluated in rats and
sitive and reproducible response measures. All animals were given
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Most animals went through 3–4 exposure to each concentration, beverages, in the rat. Travaux de la Société de Pharmacie de Montpellier 25 (1),
51–62.
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homovanillic acid (HVA), norepinephrine, 3-methoxy-4-hydroxy- ketones: their metabolic fates and comparative toxicities. The Journal of
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the conditions of this study, a single dose of 325 mg/kg adminis- in rat liver and their effect on the mitochondrial oxidation of various substrates.
tered by gavage to rats resulted in increases in 5HIAA in the mid- Acta Pharmacologica et Toxicologica 27, 381–396.
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Branched Chain Saturated Alcohols When Used as Fragrance Ingre- JECFA (Joint Expert Committee on Food Additives), 1996. Safety evaluation of
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Review
Fragrance material review on 2,6-dimethyl-2-heptanol

Keywords: A toxicologic and dermatologic review of 2,6-dimethyl-2-heptanol when used as a fragrance ingredient is
Review presented. 2,6-Dimethyl-2-heptanol is a member of the fragrance structural group branched chain satu-
Fragrance
chains. This review contains a detailed summary of all available toxicology and dermatology papers that
are related to this individual fragrance ingredient and is not intended as a stand-alone document. A safety
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S111
1. Identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S111
2. Physical properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S111
3. Usage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S111
4. Toxicology data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S112
4.1. Acute toxicity (see Table 2). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S112
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S112
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S112
4.2. Skin irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S112
4.2.1. Human studies (see Table 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S112
4.2.2. Animal studies (see Table 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S112
4.3. Mucous membrane (eye) irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S113
4.4. Skin sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S113
4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S113
4.4.2. Maximization studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S113
4.4.3. Diagnostic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S113
4.4.4. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S113
4.5. Phototoxicity and photoallergy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S113
4.5.1. Phototoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S113
4.5.2. Photoallergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S114
4.6. Absorption, distribution and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S114
4.7. Repeated dose toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S114
4.8. Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S114
4.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S114
4.10. Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S114
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S114
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S114

doi:10.1016/j.fct.2010.05.041
This document provides a summary, including all human health

endpoints, of the toxicologic review of 2,6-dimethyl-2-heptanol 2.1. Physical form: a colorless liquid with a fresh, woody, floral
when used as a fragrance ingredient. 2,6-Dimethyl-2-heptanol odor.
(see Fig. 1; CAS Number 13254-34-7) is a fragrance ingredient used 2.2. Boiling point (calculated; EPA, 2010): 172.11 °C.
in cosmetics, fine fragrances, shampoos, toilet soaps and other toi- 2.3. Flash point: 145°F; CC.
letries as well as in non-cosmetic products such as household 2.4. Henry’s law (calculated; EPA, 2010): 0.0000412 atm m3/mol
cleaners and detergents. It is a colorless liquid with a fresh, woody, 25 °C.
floral odor. 2.5. Log Kow: 3.0 at 45 °C.
In 2006, a complete literature search was conducted on 2,6-di- 2.6. Refractive index: 1.4259.
methyl-2-heptanol. On-line toxicological databases were searched 2.7. Specific gravity: 0.8135.
including those from the Chemical Abstract Services, [e.g., ToxCen- 2.8. Vapor pressure (calculated; EPA, 2010): 0.2 mm Hg (20 °C);
ter (which in itself contains 18 databases including Chemical Ab- 0.364 mm Hg (25 °C); 48.5 Pa (25 °C).
stracts)], and the National Library of Medicine [e.g., Medline, 2.9. Water solubility (calculated; EPA, 2010): 572 mg/l (25 °C).
Toxnet (which contains 14 databases)] as well as 26 additional 2.10. UV spectra available at RIFM, does not absorb UV light.
sources (e.g., BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fra-
grance companies were asked to submit all test data. 3. Usage
The safety data on this material was last reviewed by Ford et al.
(1992). All relevant references are included in this document. More 2,6-Dimethyl-2-heptanol is a fragrance ingredient used in many
details have been provided for unpublished data. The number of fragrance compounds. It may be found in fragrances used in deco-
animals, sex and strain are always provided unless they are not gi- rative cosmetics, fine fragrances, shampoos, toilet soaps and other
ven in the original report or paper. Any papers in which the vehi- toiletries as well as in non-cosmetic products such as household
cles and/or the doses are not given have not been included in this cleaners and detergents. Its use worldwide is in the region of 10–
review. In addition, diagnostic patch test data with fewer than 100 100 metric tons per annum (IFRA, 2004). The reported volume of
consecutive patients have been omitted. use is for 2,6-dimethyl-2-heptanol as used in fragrance compounds
of use is surveyed by IFRA approximately every four years through
1. Identification a comprehensive survey of IFRA and RIFM member companies. As
such the volume of use data from this survey provides volume of
1.1. Synonyms: dimetol; freesiol; 2-heptanol, 2,6-dimethyl-; lol- industry.
itol; 2,6-dimethylheptan-2-ol. The dermal systemic exposure in cosmetic products (see Table 1)
1.2. CAS Registry number: 13254-34-7. is calculated based on the concentrations of the same fragrance
1.3. EINECS number: 236-244-1. ingredient in ten types of the most frequently used personal care
1.4. Formula: C9H20O. and cosmetic products (anti-perspirant, bath products, body lotion,
1.5. Molecular weight: 144.26. eau de toilette, face cream, fragrance cream, hair spray, shampoo,
and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account for
the length of time a product may remain on the skin and/or likeli-
HO hood of the fragrance ingredient being removed by washing. The
resultant calculation represents the total consumer exposure (mg/
Fig. 1. 2,6-Dimethyl-2-heptanol. kg/day) (Cadby et al., 2002; Ford et al., 2000).
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2,6-dimethyl-2-heptanol.
Anti-perspirant 0.5 1 1 0.01 2.41 0.00200
Bath products 17 0.29 0.001 0.02 2.41 0.00004
Body lotion 8 0.71 1 0.004 2.41 0.00910
Eau de toilette 0.75 1 1 0.08 2.41 0.02410
Face cream 0.8 2 1 0.003 2.41 0.00190
Fragrance cream 5 0.29 1 0.04 2.41 0.02330
Hair spray 5 2 0.01 0.005 2.41 0.00020
Shampoo 8 1 0.01 0.005 2.41 0.00020
Shower gel 5 1.07 0.01 0.012 2.41 0.00030
Toilet soap 0.8 6 0.01 0.015 2.41 0.00030
Total 0.0614
a
b
This is a conservative calculation of dermal systemic exposure Table 3

because it makes the unlikely assumption that a consumer will Summary of human irritation studies.
use these 10 products containing; which are all perfumed with Method Dose Vehicle Results References
the upper 97.5 percentile level of the fragrance ingredient from a (%)
fine fragrance type of product (Cadby et al., 2002; Ford et al., Maximization 10 Petrolatum No irritation RIFM (1976b)
2000). The 97.5 percentile use level in formulae for use in cosmet- (pre-test)
ics in general has been reported to be 2.41 (IFRA, 2007), which Phototoxicity 10 1:1 Ethanol/acetone No irritation RIFM (1983)
(control)
would result in a maximum daily exposure on the skin of HRIPT (pre-test) 2 Dimethyl phthalate No irritation RIFM (1969)
0.0614 mg/kg for high end users (see Table 1). HRIPT (pre-test) 5 Alcohol SDA 39C No irritation RIFM (1971a)
A maximum skin level is then determined for consideration of HRIPT (pre-test) 5 Alcohol SDA 39C No irritation RIFM (1972)
on the use of 20% of the fragrance mixture in the fine fragrance trol site. No effects were observed in any of the subject’s exposed
consumer product (IFRA, 2007). The average maximum use level to 10% 2,6-dimethyl-2-heptanol in 1:1 ethanol/acetone without
in formulae that go into fine fragrances has been reported to be irradiation (irritancy control sites) (RIFM, 1983).
1.40% (IFRA, 2007), assuming use of the fragrance oil at levels up A preliminary primary irritation study was conducted prior to
to 20% in the final product. the associated Human Repeated Insult Patch Test (HRIPT) to
determine irritation potential of 2,6-dimethyl-2-heptanol. A pilot
4. Toxicology data group of 10 healthy male and female subjects, ranging in age
from 18 to 72 were used. The 10 subjects in the pilot group be-
4.1. Acute toxicity (see Table 2) came part of the full complement of 57 subjects that started
the associated HRIPT. By the end of the induction period, these
4.1.1. Oral studies 10 individuals had had 11 induction applications as compared
Ten rats were given a single dose of 2,6-dimethyl-2-heptanol at to the remaining individuals who were subjected to 10 induction
5.0 g/kg. Observations for mortality and or systemic effects were applications. At 2% 2,6-dimethyl-2-heptanol no effects were ob-
made. At 5.0 g/kg, 2/10 deaths occurred within the first day. Symp- served (RIFM, 1969).
toms observed between 2 and 24 h were lethargy (in 3/8 rats), Irritation was assessed with a panel of 10 volunteers during
ataxia, piloerection (in 2/8 rats), and some loss of righting reflex. preliminary test for an HRIPT. The test patch consisted of a 1 1
At necropsy two of the rats showed redness through the lungs inch Webril swatch and 0.5 ml aliquot of 5% 2,6-dimethyl-2-hept-
and stomach. The acute oral LD50 in rats was resolved to be greater anol in alcohol SDA 39C. A series of nine 24 h exposures over three
than 5.0 g/kg (RIFM, 1976a). successive weeks caused little to no irritation (RIFM, 1971a).
Rats were orally given 2,6-dimethyl-2-heptanol as a 31.6–50% A preliminary primary irritation study was conducted prior to
emulsion in olive oil. Observations for mortality and/or systemic the associated Repeated Insult Patch Test to determine irritation
effects were made. The acute oral LD50 in rats was calculated to potential. Thirty-five subjects (10 males and 25 females) com-
be greater than 6.8 g/kg (RIFM, 1979). pleted the study. The test patch was a 1 inch square of Webril
swatch with 0.5 ml of 5% 2,6-dimethyl-2-heptanol in alcohol SDA
39C. A series of nine 24 h exposures over three successive weeks
caused little to no irritation (RIFM, 1972).
The acute LD50 in rabbits exceeded 5.0 g/kg based on 0 deaths in
10 animals tested at that dose. Ten rabbits received a single dermal
application at a dose level of 5.0 g/kg bodyweight. Mortality and/or 4.2.2. Animal studies (see Table 4)
systemic effects were not observed (RIFM, 1976a). As part of an associated acute toxicity study with a 5 g/kg neat
application of 2,6-dimethyl-2-heptanol, rabbits were observed for
4.2. Skin irritation irritation. Slight redness in 2, moderate redness in 8, slight edema
in 1, and moderate edema in 9 animals was observed (RIFM,
4.2.1. Human studies (see Table 3) 1976a).
In an irritation screen for a maximization test, 10% 2,6-di- 2,6-Dimethyl-2-heptanol was applied to the intact and abraded
methyl-2-heptanol in petrolatum was applied to the forearms or skin of six rabbits. The undiluted material produced strong irrita-
backs of 25 subjects for 48 h under occlusion. No irritation was ob- tion. The Primary Irritation Index was reported as 5.13. (RIFM,
served (RIFM, 1976b). 1979).
Irritation was assessed during an associated phototoxicity To determine the degree of irritation with 5% 2,6-dimethyl-2-
study. Six healthy female volunteers, 20–40 years old were used. heptanol, dermal occluded patches (0.5 ml) were applied to the
The vehicle was 1:1 ethanol/acetone. Prior to the application of clipped intact and abraded skin of three rabbits. Animals were
2,6-dimethyl-2-heptanol, 36 test sites (each 2 cm2) were marked
on the back (1.5 cm apart). 2,6-Dimethyl-2-heptanol was then ap-
Table 4
plied in a dose volume of 0.025 ml/2 cm2 in 1:1 ethanol/acetone.
The right hand test site was covered and served as an irritancy con-
(%)
Table 2 Dermal 100 Rabbits Slight to moderate RIFM (1976a)
Summary of acute toxicity studies. application erythema and edema
Dermal 100 Rabbits Strong irritation RIFM (1979)
Route Species No. animals/ LD50 (g/kg) References
application observed
dose group
Dermal 5 Rabbits No irritation RIFM (1972)
Oral Rats 10 5.0 RIFM (1976a) application
Oral Rats NA 6.8 RIFM (1979) Phototoxicity 10 Guinea No irritation RIFM (1981a,b)
Dermal Rabbits 10 5.0 RIFM (1976a) (control) Pigs
immobilized for the 24 h exposure, and then evaluated 48 h after phases of these studies. Under these conditions, 5% 2,6-dimethyl-
removal. Irritation was not observed (RIFM, 1971b). 2-heptanol in alcohol SDA 39C was not considered a sensitizer in
A minimum of four groups of four albino guinea pigs were patch humans subjects (RIFM, 1971b, 1972).
tested to both flanks for a reaction time of 48 h. Four hours after
the removal of the patches, the left flanks of the two experimental 4.4.2. Maximization studies
groups (A and B) were irradiated with UV-A or UV-B light. Groups C A human maximization (MAX) test was conducted on 25 healthy
and D were controls, where C did not receive radiation and group D volunteers (19 female and 6 males), ages 18–43 years old. Applica-
was not pre-treated. No reactions were observed in the control tion was on the volar forearm or back of all subjects for five alternate
Group C where animals were treated with 10% 2,6-diemthyl-2- days, 48 h periods. The patch site was pre-treated for 24 h with 2.5%
heptanol but not irradiated (RIFM, 1981a,b). aqueous SLS under occlusion. Following a 10-day rest period, a chal-
lenge patch of 10% 2,6-dimethyl-2-heptanol was applied to a differ-
4.3. Mucous membrane (eye) irritation ent site for a 48 h period under occlusion. Prior to challenge, 5–10%
SLS was applied to the site for one hour before application of 2,6-di-
Undiluted 2,6-dimethyl-2-heptanol produced strong irritation methyl-2-heptanol. The challenge site was read at patch removal
when applied to the surface of the rabbit eye. The Primary Irrita- and 24 h thereafter. There were no instances of contact sensitization
tion Index was reported as 29.8. Further details reported in Ger- by 2,6-dimethyl-2-heptanol (RIFM, 1976a).
man (RIFM, 1979).
Aliquots of 0.1 ml 2,6-dimethyl-2-heptanol at 5% in alcohol SDA 4.4.2.1. Cross-sensitization. No data available on this material.
39C were instilled into the eyes of three healthy albino rabbits.
Both the treated and control eyes were examined every 24 h for 4.4.3. Diagnostic studies
4 days, then again on the 7th day. Moderate conjunctival irritation No data available on this material.
such as redness, chemosis, and discharge were observed, but re-
turned to normal by day 7 (RIFM, 1971c). 4.4.4. Animal studies
4.4.4.1. Maximization test. A guinea pig maximization test accord-
ing to the Kligman (1969) method was conducted. Induction con-
4.4. Skin sensitization sisted of a series of six intradermal injections of 10% 2,6-
dimethyl-2-heptanol with and without FCA, followed six to eight
4.4.1. Human studies days later with a 48 h occluded patch application. Animals were
4.4.1.1. Induction studies (see Table 5). challenged 12–14 days later by an occluded 24 h (20% in acetone)
patch application. Reactions were read 24 and 48 h after patch re-
4.4.1.2. Human repeated insult patch test. Human Repeated Insult moval. Positive reactions were not observed (Watanabe et al.,
Patch Tests (HRIPT) were conducted to determine if 2,6-di- 1988).
methyl-2-heptanol would induce dermal sensitization in human
volunteers. Patches were applied to the inner surface of the right 4.4.4.2. Local Lymph Node Assay (LLNA). No data available on this
and left deltoid area of each subject. Patches were occluded and re- material.
mained in place for 48 h. The patches were then removed and read
for any reactions. Alternating rotation of the sites was made for a 4.5. Phototoxicity and photoallergy
total of 10 applications. A 2-week rest period followed the applica-
tion of the last patch. After the rest period, the challenge patch was 4.5.1. Phototoxicity
applied in the identical manner that the previous patches were ap- 4.5.1.1. Human studies. A test was performed on six female volun-
plied, except that the test patch was applied in duplicate, one to teers to determine the phototoxic potential of 2,6-dimethyl-2-
the inner surface of each deltoid area. Patches remain in place for heptanol. The light source was a bank of four ‘blacklight’ fluores-
48 h after which time they were removed and scored for reactions. cent tubes with an emission spectrum of 320–400 mm housed in
Fifty-three subjects (35 female and 18 male) ranging in age a reflector unit. Prior to the application 36 test sites (2 cm2) with
from 18 to 72, completed the study. 2,6-Dimethyl-2-heptanol a 1.5 separation between each were marked on the back using a
(0.5 cc) in dimethyl phthalate was applied to individual absorbent metal stamp and Gentian Violent solution. The sites were loaded
patches. At 72 and 144 h readings were made to detect any de- by micro-pipette with the test material at a dose of 0.25 ml per
layed/retarded responses. Five minor adhesive tape reactions were 2 cm2 area. Thirty minutes later the sites were exposed to UV A-
recorded but not repeated during the challenge tests. There were irradiation. Observations were made at 4, 24, 48, and 72 h after
no sensitization reactions observed in any of the 53 subjects during the application. No evidence was noted to indicate that at a con-
the challenge phase of the study. Under the conditions of the study, centration of 10% the material will produce a phototoxic reaction
2% 2,6-dimethyl-2-heptanol in dimethyl phthalate was not consid- in humans (RIFM, 1983).
ered a sensitizer in humans subjects (RIFM, 1969).
A 1 1 inch Webril swatch with 0.5 ml of 5% 2,6-dimethyl-2- 4.5.1.2. Animal studies. A minimum of four groups of four albino
heptanol was applied to the upper arms of 45 subjects (33 female, guinea pigs were patch tested on both flanks for a reaction time
12 male) ranging in age from 16 to 60. There were no sensitization of 48 h. Four hours after the removal of the patches, the left flanks
reactions observed in any of the 45 subjects during the challenge of the two experimental groups (A and B) were irradiated with UV-
A or UV-B light. Groups C and D were controls, where C did not re-
ceive radiation and group D was not pre-treated. The light sources
Table 5
were both Westinghouse FS 40. The ‘‘black lamp” had a spectrum
Summary of human skin sensitization studies.
between 320 and 400 nm and a radiation time of 30 min; whereas
Test method Test concentration Results References the ‘‘sunlamp” had a spectrum of 280–370 nm and radiation time
HRIPT 2 0/53 RIFM (1969) of 15 min. Skin reactions were measured 4, 24, and 48 h after radi-
HRIPT 5 0/10 RIFM (1971) ation. Slight irritation was observed 4 h after application of 10%
0/35 RIFM (1972)
2,6-dimethyl-2-heptanol in ethanol in 1/8 animals in Group A, B
MAX 10 0/25 RIFM (1976a)
and D. However, by 48 h all irritation had cleared (RIFM, 1981a).
4.5.2. Photoallergy by the manufacturers of fragrances and consumer products con-

4.5.2.1. Human studies. No data available on this material. taining fragrances. The authors are all employees of the Research
4.5.2.2. Animal studies. Guinea pigs of both sexes, divided in groups
of eight animals each, were shaved on the upper dorsal area. About References
one hour later, 0.1 ml of 10% 2,6-dimethyl-2-heptanol in rectified
alcohol was applied to 8 cm2 of the test area. After this pretreat- Belsito, D., Bickers, D., Bruze, M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H.,
ment, the animals were exposed to the UV B-irradiation for 150 saturated alcohols when used as fragrance ingredients. Food Chem. Toxicol. 48
and thereafter to UV A-irradiation for 4 h (Westinghouse black (S4), S1–S46.
light tubes) from a distance of 25 cm. The application of the test Cadby, P., Troy, W., Vey, M., 2002. Consumer exposure to fragrance ingredients:
providing estimates for safety evaluation. Regul. Toxicol. Pharm. 36, 246–252.
material and the following irradiation were performed every sec- EPA (Environmental Protection Agency), 2010. Estimation Programs Interface
ond day, a total of nine times in 18 days. Observations for irritation Suite™ for MicrosoftÒ Windows, v 4.00 or insert version used]. United States
were made 24 h after each application. After a 10-day rest period Environmental Protection Agency, Washington, DC, USA.
Ford, R.A., Api, A.M., Letizia, C.S., 1992. Monographs on fragrance raw materials, 2,6-
the guinea pigs were again shaved on both flanks and the test area dimethyl-2-heptanol. Food Chem. Toxicol. 30 (Suppl.), 23.
was marked. A 0.025 ml sample was applied to a 2 cm2 area. Then Ford, R., Domeyer, B., Easterday, O., Maier, K., Middleton, J., 2000. Criteria for
only the left flank was irradiated. Observations were made and 24 development of a database for safety evaluation of fragrance ingredients. Regul.
Toxicol. Pharm. 31, 166–181.
and 48 h after the challenge. At 10% 2,6-dimethyl-2-heptanol in
rectified alcohol showed no photosensitizing potential under the IFRA (International Fragrance Association), 2007. Volume of Use Survey, February
conditions of this test (RIFM, 1981b). 2007.
Kligman, A.M., 1969. The identification of contact allergens by animal assay. The
guinea pig maximization test. J. Invest. Dermatol. 52 (3), 268–276.
4.6. Absorption, distribution and metabolism RIFM (Research Institute for Fragrance Materials, Inc.), 1969. Sensitization and
irritation studies of 2,6-dimethyl-2-heptanol. Unpublished report from
No data available on this material. Givaudan, 30 June. Report number 41345. RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1971a. Eye irritation study
with 2,6-dimethyl-2-heptanol in rabbits. Unpublished report from International
4.7. Repeated dose toxicity Flavors and Fragrances, Report number 53500. RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1971b. Repeated insult patch
test with 2,6-dimethyl-2-heptanol. Unpublished report from International
No data available on this material. Flavors and Fragrances, Report number 53498. RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1971c. Skin irritation study
4.8. Reproductive and developmental toxicity with 2,6-dimethyl-2-heptanol in rabbits. Unpublished report from International
Flavors and Fragrances, Report number 53501. RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1972. Repeated insult patch
No data available on this material. test with 2,6-dimethyl-2-heptanol. Unpublished report from International
Flavors and Fragrances, Report number 53499. RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1976a. Acute toxicity studies
4.9. Genotoxicity
in rats, mice, rabbits and guinea pigs. RIFM report number 2019, October 08.
RIFM, Woodcliff Lake, NJ, USA.
No data available on this material. RIFM (Research Institute for Fragrance Materials, Inc.), 1976b. Report on human
maximization studies. RIFM report number 1797, November 04. RIFM,
4.10. Carcinogenicity RIFM (Research Institute for Fragrance Materials, Inc.), 1979. Acute toxicity studies
on 2,6-dimethyl-2-heptanol. Unpublished report from BASF, 08 February.
No data available on this material. Report number 4458. RIFM, Woodcliff Lake, NJ, USA.
RIFM (Research Institute for Fragrance Materials, Inc.), 1981a. Guinea pig assay of
photosensitizing potential of 2,6-dimethyl-2-heptanol. Unpublished report
This individual Fragrance Material Review is not intended as a from Givaudan, 09 July. Report number 41343. RIFM, Woodcliff Lake, NJ, USA.
stand-alone document. Please refer to A Safety Assessment of RIFM (Research Institute for Fragrance Materials, Inc.), 1981b. Determination of
phototoxicity of 2,6-dimethyl-2-heptanol in guinea pigs. Unpublished report
Branched Chain Saturated Alcohols When Used as Fragrance Ingre- from Givaudan, 07 April. Report number 41346. RIFM, Woodcliff Lake, NJ, USA.
dients (Belsito et al., 2010) for an overall assessment of this RIFM (Research Institute for Fragrance Materials, Inc.), 1983. 2,6-Dimethyl-2-
material. heptanol: Phototoxicity test on a fragrance raw material in humans.
Unpublished report from Givaudan, 23 September. Report number 41344.
RIFM, Woodcliff Lake, NJ, USA.
Watanabe, S., Kinosaki, A., Kawasaki, M., Yoshida, T., Kaidbey, K., 1988. The contact
sensitizing potential of (+)- and ()-hydroxycitronellal. In flavors and
fragrances: a world perspective. Proceedings of 10th International Congress of
This research was supported by the Research Institute for Fra- Essential Oils, 11/86, pp. 1029–1038.

Review
Fragrance material review on 2-ethyl-1-hexanol

Keywords: A summary of the safety data available for 2-ethyl-1-hexanol when used as a fragrance ingredient is pre-
Review sented. 2-Ethyl-1-hexanol is a member of the fragrance structural group branched chain saturated alco-
Fragrance
hols in which the common characteristic structural element is one hydroxyl group per molecule, and a C4
to C12 carbon chain with one or several methyl side chains. This review contains a detailed summary of all
available toxicology and dermatology papers that are related to this individual fragrance ingredient and is
not intended as a stand-alone document. A safety assessment of the entire branched chain saturated alco-
hol group will be published simultaneously with this document; please refer to Belsito et al. (2010) for an
overall assessment of the safe use of this material and all other branched chain saturated alcohols in
fragrances.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S116
1. Identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S116
2. Physical properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S116
3. Usage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S116
4. Toxicology data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S117
4.1. Acute toxicity (see Table 2). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S117
4.1.1. Oral studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S117
4.1.2. Dermal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S117
4.1.3. Intraperitoneal (ip) studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S117
4.1.4. Inhalation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S118
4.2. Skin irritation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S118
4.2.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S118
4.2.2. Animal studies (see Table 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S118
4.3. Mucous membrane (eye) irritation (see Table 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S118
4.4. Skin sensitization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S118
4.4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S118
4.4.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S119
4.5. Phototoxicity and photoallergy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S119
4.6. Absorption, distribution and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S119
4.6.1. Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S119
4.6.2. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S119
4.6.3. Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S119
4.7. Repeated dose toxicity (see Table 6) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S120
4.7.1. Two to 30-day studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S120
4.7.2. Subchronic (31–90 days) studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S122
4.7.3. Chronic (90+ days) studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S122
4.8. Reproductive and developmental toxicity (see Table 7) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S123
4.9. Genotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S124
4.9.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S124
4.9.2. In vivo studies (see Table 10) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S125

doi:10.1016/j.fct.2010.05.042
4.10. Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S125

4.10.1. In vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S125
4.10.2. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S125
4.11. Miscellaneous studies (see Table 12) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S125
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S127
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . S127
This document provides a summary of the toxicologic review,

including all human health endpoints, of 2-ethyl-1-hexanol when 1.1. Physical form: Colorless, oily liquid with mild, sweet and
used as a fragrance ingredient. 2-Ethyl-1-hexanol (see Fig. 1; CAS slightly floral-rosy odor.
Number 104-76-7) is a fragrance ingredient used in cosmetics, fine 1.2. Boiling point (calculated; EPA, 2010): 188.52 °C.
fragrances, shampoos, toilet soaps and other toiletries as well as in 1.3. Flash point: 167°F;CC.
non-cosmetic products such as household cleaners and detergents. 1.4. Henry’s law (calculated; EPA, 2010): 0.000031 atm m3/mol
It is a colorless, oily liquid with mild, sweet and slightly floral-rosy 25 °C.
odor of considerable tenacity (Arctander, 1969). This material has 1.5. Log Kow (calculated): 2.73.
been reported to occur in nature, with highest quantities observed 1.6. Refractive index: no information available.
in tea (VCF, 2009). 1.7. Specific gravity: 0.833.
In 2007, a complete literature search was conducted on 2-ethyl- 1.8. Vapor pressure (calculated; EPA, 2010): 0.06 mm Hg (20 °C);
1-hexanol. On-line toxicological databases were searched includ- 0.185 mm Hg (25 °C); 24.6 Pa (25 °C).
ing those from the Chemical Abstract Services, [e.g. ToxCenter 1.9. Water solubility (calculated; EPA, 2010): 1379 mg/l (25 °C).
(which in itself contains 18 databases including Chemical Ab- 1.10. UV spectra available at RIFM, peaks at 210–215 nm and
stracts)], and the National Library of Medicine [e.g. Medline, Toxnet returns to baseline at 400 nm; minor absorption from 290–
(which contains 14 databases)] as well as 26 additional sources 400 nm.
(e.g. BIOSIS, Embase, RTECS, OSHA, ESIS). In addition, fragrance
companies were asked to submit all test data. 3. Usage
The safety data on this material was last reviewed by Opdyke,
1978. All relevant references are included in this document. More 2-Ethyl-1-hexanol is a fragrance ingredient used in many fra-
details have been provided for unpublished data. The number of grance compounds. It may be found in fragrances used in decora-
animals, sex and strain are always provided unless they are not gi- tive cosmetics, fine fragrances, shampoos, toilet soaps and other
ven in the original report or paper. Any papers in which the vehi- toiletries as well as in non-cosmetic products such as household
cles and/or the doses are not given have not been included in this cleaners and detergents. Its use worldwide is in the region of
review. In addition, diagnostic patch test data with fewer than 100 0.1–1.0 metric tons per annum (IFRA, 2004). The reported volume
consecutive patients have been omitted. of use is for 2-ethyl-1-hexanol as used in fragrance compounds
1. Identification of use is surveyed by IFRA approximately every four years through
a comprehensive survey of IFRA and RIFM member companies. As
1.1. Synonyms: 2-Ethylhexanol; 1-hexanol, 2-ethyl- such the volume of use data from this survey provides volume of
1.2. CAS registry number: 104-76-7. use of fragrance ingredients for the majority of the fragrance
1.3. EINECS number: 203-234-3. industry.
1.4. Formula: C8H18O. The dermal systemic exposure in cosmetic products (see Table 1)
1.5. Molecular weight: 130.23. is calculated based on the concentrations of the same fragrance
1.6. JECFA (1998): The Joint FAO/WHO Expert Committee on ingredient in ten types of the most frequently used personal care
Food Additives (JECFA No. 267) concluded that the substance and cosmetic products (anti-perspirant, bath products, body lotion,
does not present a safety concern at current levels of intake eau de toilette, face cream, fragrance cream, hair spray, shampoo,
when used as a flavoring agent. shower gel, and toilet soap). The concentration of the fragrance
1.7. FEMA (1970): Flavor and Extract Manufacturers’ Association ingredient in fine fragrances is obtained from examination of sev-
states: Generally Recognized as Safe as a flavor ingredient – eral thousand commercial formulations. The upper 97.5 percentile
GRAS 4 (3151). concentration is calculated from the data obtained. This upper 97.5
percentile concentration is then used for all 10 consumer products.
and a ‘‘retention factor” (ranging from 0.001 to 1.0) to account
for the length of time a product may remain on the skin and/or
likelihood of the fragrance ingredient being removed by washing.
The resultant calculation represents the total consumer exposure
(mg/kg/day) (Cadby et al., 2002; Ford et al., 2000).
HO the upper 97.5 percentile level of the fragrance ingredient from a
Fig. 1. 2-Ethyl-1-hexanol. 2000). The 97.5 percentile use level in formulae for use in cosmet-
Table 1
Calculation of the total human skin exposure from the use of multiple cosmetic products containing 2-ethyl-1-hexanol.
Anti-perspirant 0.5 1 1 0.01 0.02 0.000020
Bath products 17 0.29 0.001 0.02 0.02 0.000001
Body lotion 8 0.71 1 0.004 0.02 0.000080
Eau de toilette 0.75 1 1 0.08 0.02 0.000200
Face cream 0.8 2 1 0.003 0.02 0.000020
Fragrance cream 5 0.29 1 0.04 0.02 0.000190
Hair spray 5 2 0.01 0.005 0.02 0.000001
Shampoo 8 1 0.01 0.005 0.02 0.000001
Shower gel 5 1.07 0.01 0.012 0.02 0.000001
Toilet soap 0.8 6 0.01 0.015 0.02 0.000001
Total 0.0005
a
b
ics for 2-ethyl-1-hexanol has been reported to be 0.02% (IFRA, In a study primarily addressing the toxicity of diethylhexyl
2007), which would result in a maximum daily exposure on the phthalate, it was reported that the oral LD50 of 2-ethyl-1-hexanol
skin of 0.0005 mg/kg for high end users (see Table 1). in 90–120 g male Wistar rats is 7.1 (5.5–9.1) g/kg. No additional
A maximum skin level is then determined for consideration of details are reported (Shaffer et al., 1945).
potential sensitization. The exposure is calculated as the percent The oral LD50 of 2-ethyl-1-hexanol in rats was reported to be
concentration of the fragrance ingredient applied to the skin based 3.2 g/kg. No additional details are reported (Bar and Griepentrog,
on the use of 20% of the fragrance mixture in the fine fragrance 1967; Dave and Lidman, 1978).
consumer product (IFRA, 2007). The average maximum use level The oral LD50 of 2-ethyl-1-hexanol in rats was reported to be
in formulae that go into fine fragrances has been reported to be 3.29 (2.87–3.79) g/kg (Schmidt et al., 1973).
0.008% (IFRA, 2007), assuming use of the fragrance oil at levels The oral LD50 for 2-ethyl-1-hexanol in Sprague–Dawley rats (5/
up to 20% of the final product. dose) was reported to be 3.73 g/kg. The principal clinical signs
were central nervous system depression and labored respiration.
The depression included inactivity, ataxia, limb sprawling, de-
4. Toxicology data pressed righting and placement reflexes, prostration, and coma.
The intensity of the signs was related to dose. The signs of effect
4.1. Acute toxicity (see Table 2) had an early onset, and recovery was complete by the second or
third day. Where deaths occurred, they were seen in the first
4.1.1. Oral studies 24 h. Gross necropsy revealed some evidence of gastrointestinal
In a study with a total of 85 rats, it was determined that the irritation (Scala and Burtis, 1973).
lethal dose of 2-ethyl-1-hexanol by oral gavage was 3.2 g/kg In a study to investigate the mechanism of action for induction
(Hodge, 1943). of peroxisome proliferation by several compounds including 2-
In a structure–activity study of a large number of organic sol- ethyl-1-hexanol, it was reported that a single dose of 100 mg/kg
vents, it was reported that the oral LD50 of 2-ethyl-1-hexanol in administered by oral gavage to Fischer 344 rats resulted in no dif-
rats was 2.049 g/kg (Nishimura et al., 1994). ference from controls in hepatic acyl CoA oxidase or catalase activ-
The acute oral LD50 of 2-ethyl-1-hexanol in groups of five ity 5 h after dosing (Bojes and Thurman, 1994).
non-fasted, Carworth–Wistar male rats was reported to be 2.46
(1.82–3.33) g/kg. No additional details were reported (Smyth 4.1.2. Dermal studies
et al., 1969). The dermal LD50 of 2-ethyl-1-hexanol in groups of four male al-
bino New Zealand rabbits was reported to be 2.38 (1.7–3.34) g/kg.
No additional details are reported (Smyth et al., 1969).
Table 2 The dermal LD50 of 2-ethyl-1-hexanol in 10 rabbits was re-
Summary of acute toxicity studies. ported to be >5.0 g/kg. One of 10 animals died on day 12, but the
Route Species No. LD50 References necropsy was reported to be normal in the animal that died. Skin
animals/ (g/kg) irritation with moderate redness and edema was reported in all
dose group 10 animals (RIFM, 1977).
Oral Rat 5–15 3.2 Hodge (1943) The dermal LD50 for 2-ethyl-1-hexanol applied occlusively for
Oral Rat N/A 2.049 Nishimura et al. (1994) 24 h to rabbits (4/dose) was reported to be >2.6 g/kg. There were
Oral Rat 5 2.46 Smyth et al. (1969) no clinical signs indicative of systemic effects at the highest level
Oral Rat N/A 7.1 Shaffer et al. (1945)
Oral Rat N/A 3.2 Bar and Griepentrog
tested. Dermal irritation was dose-dependent (Scala and Burtis,
(1967) 1973).
Dave and Lidman (1978)
Schmidt et al. (1973) 4.1.3. Intraperitoneal (ip) studies
Oral Rat 5 3.73 Scala and Burtis (1973)
In a study with 102 mice, it was determined that the lethal ip
Dermal Rabbit 4 2.38 Smyth (1969)
Dermal Rabbit 10 >5.0 RIFM (1977) dose in mice was approximately 0.78 g/kg. 2-Ethyl-1-hexanol
Dermal Rabbit 4 >2.6 Scala and Burtis (1973) was also administered to 101 rats as ip injections to determine
Intraperitoneal Rat 5–15 0.65 Hodge (1943) an LD50 of 0.65 g/kg. Clinical signs included irregular gait, dragging
Intraperitoneal Rat 5 0.5– Dave and Lidman (1978) of hind limbs, gasping without cyanosis, insensibility and sleepi-
1.0
Intraperitoneal Mice 5–15 0.78 Hodge (1943)
ness at high doses. The 2-ethyl-1-hexanol was rapidly anaesthetic
in mice as well as rats (Hodge, 1943).
Dave and Lidman (1978) reported a literature value from the rabbits. Observations were made at 1, 4, and 24 h and 2, 3, 4, and
Handbook of Toxicology of 0.65 g/kg for the ip LD50 of 2-ethyl-1- 7 days. Median irritation scores according to the Draize system
hexanol in rats. In a separate study, Sprague–Dawley rats (5/sex/ were 19, 20, and 0 at 24 h, 72 h, and 7 days, respectively. Corneal
dose) were given undiluted 2-ethyl-1-hexanol at doses of 0.05, dullness, opacity (widespread corneal opacity), vascularization,
0.1, 0.5, 1.0, or 5.0 g/kg. Observations were made continuously over irritates, conjunctival erythema, chemosis, and discharge were all
14-days. The ip LD50 was reported to be between 0.5 and 1.0 g/kg. observed (Scala and Burtis, 1973).
At doses of 1.0 and 5.0 g/kg coma and death were observed in the Application of 2-ethyl-1-hexanol to the eyes of rabbits pro-
rats within two hours. At 0.5 g/kg, the animals went into comas in duced irritation Grade 5 on a 10-Grade scale with Grade 5 repre-
5 min, but then recovered and survived throughout the experimen- senting ‘‘severe burn” from 0.005 ml of undiluted material and
tal period. At the post-mortem examinations, no pathological Grade 10 representing severe burn from 0.5 ml of a 1% solution
changes were noted. with propylene glycol or water (Smyth et al., 1969; Carpenter et
al., 1946).
4.1.4. Inhalation studies In a TSCA 8(e) submission, it was reported that 2-ethyl-1-hexa-
No deaths were reported when 10 rats, mice, and guinea pigs nol produced persistent corneal effects in rabbits (EPA, 1991,
were exposed by whole body inhalation for 6 h to air bubbled 1992).
through 2-ethyl-1-hexanol to yield a nominal chamber concentra- Draize rabbit eye irritation scores of 9, 30, 39, 35, and 51 were
tion of 227 ppm (ml/m3). Clinical signs indicated moderate local reported for 1%, 3%, 10%, 30%, and 100% 2-ethyl-1-hexanol, respec-
irritation and slight to moderate systemic effects. Local irritation tively, in a study designed to evaluate the predictive value of
involved the mucous membranes of the eyes, nose, throat, and changes in corneal thickness for quantitating eye irritation
respiratory passages and was manifest as blinking, lacrimation, (Kennah et al., 1989).
preening, nasal discharge, salivation, gasping, and chewing move- Schmidt et al. (1973) conducted an eye irritation study in rab-
ments. Responses were temporary and all animals had recovered bits with a single application of 2-ethyl-1-hexanol, undiluted or
within 1 h after termination of exposure. Gross necropsy findings in solution with oil at 50%, 25%, or 12.5%. Reactions were graded
were confined to areas of slight hemorrhage in the lungs. All other after 18–24 h. There were no effects on the cornea for all concen-
tissues and organs were normal in appearance (Scala and Burtis, trations, and at 12.5%. Conjunctival redness, swelling, lacrimation,
1973). and discharge were observed at remaining concentrations. These
effects did not reverse within 96 h with the undiluted concentra-
4.2. Skin irritation tion (Schmidt et al., 1973).
4.2.1. Human studies 4.4. Skin sensitization

In a maximization test pre-screen, 2-ethyl-1-hexanol at 4% was
applied to the backs of 29 healthy male volunteers for 48 h under 4.4.1. Human studies
occlusion. No subject had any irritation (RIFM 1976). 4.4.1.1. Induction studies.
4.4.1.1.1. Human repeated insult patch test (HRIPT). No informa-
4.2.2. Animal studies (see Table 3) tion available.
Uncovered application of undiluted 2-ethyl-1-hexanol to the
4.4.1.1.2. Maximization studies. In a human maximization study
clipped skin on the underbelly of five rabbits for 24 h produced
involving 29 subjects, 2-ethyl-1-hexanol was applied in petrola-
irritation Grade 3 (moderate) on a 10-Grade scale with Grade 2
tum at 4% under occlusion to the forearms for a total of five alter-
representing the least visible capillary injection from undiluted
nate days, 48 h periods. Each application was preceded by a 24 h
material, Grade 6 representing necrosis from undiluted material,
occlusive treatment of the patch sites with 5% aqueous sodium lau-
and Grade 10 representing necrosis from a 0.01% solution with pro-
ryl sulfate. Following a 10–14 day rest period, challenge patches
pylene glycol or water (Smyth et al., 1969).
were applied to fresh sites on the scapular back under occlusion
In an acute dermal toxicity test in which 0.10, 0.316. 1.00, and
for 48 h. The challenge sites were pretreated for 30 min with a
3.16 mg/kg of undiluted 2-ethyl-1-hexanol was applied occlusively
5% aqueous sodium lauryl sulfate solution. Challenge sites were
for 24 h to the clipped intact abdominal skin of rabbits, 2-ethyl-1-
evaluated at 48 and 72 h, there were no positive reactions to 2-
hexanol was reported to cause moderate dermal irritation (Scala
ethyl-1-hexanol (RIFM, 1976).
and Burtis, 1973).
In an acute dermal toxicity test in which 5 g/kg was applied to the
skin of rabbits, moderate redness and edema was observed in all 10
treated animals. No additional details are reported (RIFM, 1977). Table 4
Summary of eye irritation studies.
4.3. Mucous membrane (eye) irritation (see Table 4) Dose (%) Vehicle Reactions References
100 – Severe eye irritant Scala and Burtis
2-Ethyl-1-hexanol was reported to be a severe eye irritant when (1973)
applied undiluted in a 0.1 ml dose to the left eye of each of six 100 – Severe burn Smyth et al.
(1969)
Table 3 Carpenter and
Summary of animal irritation studies. Smyth (1946)
N/A N/A Persistent corneal effects EPA (1992)
Method Dose (%) Species Reactions References 100, 30, 10, PEGa Eye irritation observed at all Kennah et al.
Patch test 100 Rabbits Moderate Smyth et al. (1969) 3, or 1 concentrations (1989)
irritation 100, 50, 25, N/A No effects to the cornea Schmidt et al.
Patch test 100 Rabbits Moderate Scala and Burtis (1973) 12.5 Conjunctival redness, swelling, (1973)
irritation lacrimation, and discharge
Patch test 100 Rabbits Moderate RIFM (1977) 100%: not reversed at 96h
erythema and 12.5%: no effects observed
edema a
PEG, polyethylene glycol.
4.4.1.1.3. Cross-sensitization. No information available. recovered in CO2 matched the amount of unlabeled 2-heptanone
4.4.1.1.4. Diagnostic studies. No information available. plus 4-heptanone recovered from urine in study in which both la-
beled and unlabeled compound were administered, suggesting
4.4.2. Animal studies that both types of metabolite may have been derived from the ma-
No information available. jor urinary metabolite, 2-ethylhexanoic acid, by decarboxylation,
following partial beta-oxidation. The radio-labeled CO2 appeared
4.5. Phototoxicity and photoallergy not to be derived from acetate (urinary acetic acid and liver and
brain cholesterol were not labeled) or by reductive decarboxyl-
No information available. ation (heptane was not present). Other identified metabolites were
2-ethyl-5-hydroxyhexanoic acid, 2-ethyl-5-ketohexanoic acid, and
4.6. Absorption, distribution and metabolism 2-ethyl-1,6-hexadecanoic acid. Only about 3% of the dose was ex-
creted unchanged. In vitro incubation with mammalian alcohol
4.6.1. Absorption dehydrogenase resulted in a Vmax of 0.30 lmol/min/mg protein
In a comparison of in vitro percutaneous absorption in rat and and a Km value of 0.74 mM (Albro, 1975).
human skin (n = 12 for rat and human skin), it was reported that In a study of DNA binding of diethylhexylphthalates and related
the absorption rates were 0.22 ± 0.09 and 0.038 ± 0.014 mg/cm2/h compounds, it was reported that radio-labeled 2-ethyl-1-hexanol
in rat and human skin. The permeability constants were 2.59 ± was not bound to hepatic DNA of Fischer 344 rats 24 h following
1.10 10 4 cm/h for rats and 4.54 ± 1.66 10 5 cm/h for humans. oral gavage administration (Albro et al., 1982).
The ratio of the permeability constants (rat/human) of 5.78 indi- It was reported that oral administration of 2.55 g of 2-ethyl-1-
cates that 2-ethyl-1-hexanol penetrated full thickness rat skin hexanol to a rabbit resulted in urinary excretion (24 h) of the glu-
more rapidly than it penetrated human stratum corneum (Barber curonide of alpha-ethylhexanoic acid (Kamil et al., 1953).
et al., 1992). It was reported that urinary glucuronide ester accounted for
Dermal absorption in the rat was determined to be 5.2% of a 86.9% of a 25 mMol dose of 2-ethyl-1-hexanol administered by ga-
dose of 1000 mg 2-ethyl-1-hexanol/kg body weight applied for vage to a rabbit weighing approximately 3 kg (Kamil et al., 1953).
6 h. An absorption rate of 0.57 mg/cm2/h and a terminal half-life In the same ADME study, two groups of Fischer 344 rats (4/
of 77 h were calculated (Deisinger et al., 1994). group) received a 6 h dermal application (1 g/kg) of 14C labeled
2-ethyl-1-hexanol. Pyrex glass containment cells (exposure area
4.6.2. Distribution of 2.27 cm2) were covered and adhered to the clipped back of eight
No information available. rats. Blood pharmacokinetics were studied on four of the eight rats.
Dermal dosing resulted in only about 5% absorption of the applied
4.6.3. Metabolism dose. Dermal dosing led to a recovery of 1.41% of the dose in silica
4.6.3.1. In vivo studies in animals. Single oral gavage administration gel breath traps compared to 0.25–0.28% following oral dosing. The
of 14C labeled 2-ethyl-1-hexanol was given to Fischer 344 rats (4/ small portion of the dose that was absorbed dermally was elimi-
group) at 50 mg/kg so that absorption, distribution, metabolism, nated primarily in the urine, with smaller amounts eliminated in
and elimination (ADME) could be studied. A repeated oral dose the feces, and as 14CO2 in the breath. Urinary metabolites elimi-
of 50 mg/kg (unlabeled 2-ethyl-1-hexanol) was also given to rats nated were predominately glucuronides of oxidized metabolites,
for 14 consecutive days. On the final (15th day) the rats were given including glucuronides of 2-ethyladipic acid, 2-ethylhexanoic acid,
a 50 mg/kg dose of 14C labeled 2-ethyl-1-hexanol. All applications 5-hydroxy-2-ethylhexanoic acid, and 6-hydroxy-2-ethylhexanoic
were neat. The oral doses were eliminated rapidly, predominantly acid (Deisinger et al., 1994, 1993).
in urine and feces. Urinary excretion accounted for 56–60% of the An i.v. injection of 2-ethyl-1-hexanol (1 mg/kg in saline) was gi-
administered dose, with all but about 2% of administered dose ex- ven to two groups of Fischer 344 rats (4/group). Blood pharmaco-
creted in the first 24 h. Urinary metabolites eliminated were pre- kinetics was studied on four of the eight rats; on the other four rats
dominately glucuronides of oxidized metabolites, including ADME was evaluated. Urinary excretion was rapid with 53% of the
glucuronides of 2-ethyladipic acid, 2-ethylhexanoic acid, 5-hydro- dose recovered within 8 h of dosing. The next largest portions
xy-2-ethylhexanoic acid, and 6-hydroxy-2-ethylhexanoic acid. Fe- recovered were from the sodium hydroxide breath traps at 22.9%
cal excretion accounted for 13–15% of the dose, primarily between and fecal excretion at 3.8%. The terminal half-life was estimated
8 and 24 h after dosing. Sodium hydroxide breath traps accounted to be 60 h (Deisinger et al., 1993, 1994).
for 8–14% of the dose, primarily in the first 24 h. Silica gel breath Asano and Yamakawa (1950) reported that following a subcuta-
traps accounted 0.25–0.28% following oral dosing. There was some neous injection to rabbits with 11 g of 2-ethyl-1-hexanol over
evidence of metabolic saturation at the high dose, and no evidence 10 days, a volatile urinary metabolite (believed to be 2-ethylcapro-
of metabolic induction following pretreatment with unlabeled ic acid) and a non-volatile metabolite (believed to be the bis-p-
compound for 14 days. The total recovery for the low, high, and re- phenylphenacyl ester of 2-ethyl adipic acid) was formed. Their
peated doses ranged was 94–97% (Deisinger et al., 1994, 1993). assessment was based on comparison of the melting points of
Single oral gavage administration of 14C labeled 2-ethyl-1-hex- the isolated metabolites and synthesized compounds.
anol was given to Fischer 344 rats (4/group) at 500 mg/kg so that
absorption, distribution, metabolism, and elimination (ADME)
could be studied. After oral administration to rats, 69–75% of a 4.6.3.2. In vitro studies in animals (see Table 5). Primary rat hepato-
dose of 500 mg 14C-labeled 2-ethyl-1-hexanol/kg body weight cyte cultures were used to compare the effects of some alkyl phthal-
was excreted in the urine within 96 h. About 13–15% of the dose ate esters on peroxisomal enzyme activities. Linear diesters and
was excreted in the feces and about the same amount was exhaled. their constituent monoesters and alcohols were compared with
More than 50% of the dose was excreted within 24 h (Deisinger branched chain 2-eythylhexyl derivatives. There was no significant
et al., 1993, 1994). difference between 2-ethyl-1-hexanol treated and control cells in
2-Ethyl-1-hexanol was efficiently absorbed following oral activities of cyanide-insensitive palmitoyl-CoA oxidation, a specific
administration of a 14C labeled dose and was rapidly excreted in peroxisomal marker. Yet, there was a six fold increase with 1 mM 2-
respiratory CO2 (6–7%), feces (8–9%), and urine (80–82%) with ethyl-1-hexanol on carnitine acyl transferase activity (P < 0.01). The
essentially complete elimination in 28 h. The amount of radiolabel authors concluded that the measurement of carnitine acyl transfer-
Table 5
Summary of in vitro animal studies.
Test system in vitro Species Concentration Results References

Hepatocyte cultures Rat 0.2 or 1 mM (DMSO) No significant differences in peroxisomal enzyme activities Gray et al. (1983)
Liver, lung, and kidney Rat 40 mg (DEHP) and 20 mg Tween Hydrolyses DEHP to mono-(2-ethylhexyl)phthalate and 2- Carter et al.
homogenates 80 ethylhexanol (1974)
ase alone was not an adequate criterion for assessing peroxisomal In contrast to treatment with DEHP and MEHP, treatment with
effects in cultured hepatocytes (Gray et al., 1983). 2-ethyl-1-hexanol at dietary levels of 50–2500 ppm (5–250 mg/kg
It was reported that 2-ethyl-1-hexanol is one of the metabolites body weight/day) for 7 days did not prevent orotic acid induced
produced from diethylhexyl phthalate by rat liver, lung, and kidney hepatic triglyceride accumulation. Also, the hepatic enzymes in-
homogenates (Carter et al., 1974). volved in lipid transport and metabolism did not increase (Morton
and Rubin, 1979).
4.7. Repeated dose toxicity (see Table 6) Fischer 344 rats (10/sex/dose) were treated by oral gavage with
undiluted 2-ethyl-1-hexanol for 5 days, followed by 2 days un-
4.7.1. Two to 30-day studies treated, followed by 4 days treated at 0, 100, 330, 1000, or
4.7.1.1. Dermal studies. 2-Ethyl-1-hexanol was administered by oc- 1500 mg/kg/day. The NOEL was 100 mg/kg/d. At 100 mg/kg/day,
cluded patch doses to Fischer 344 rats for five days, followed by no treatment related effects were observed for any in-life, clinical
2 days untreated, followed by 4 days treated at 0, 500, or pathology, gross necropsy, or histopathology parameters. Treat-
1000 mg/kg/day. Treatment-related clinical signs of toxicity were ment-related dose-dependent effects seen at 330 mg/kg/day and
restricted to the skin at the treatment site and included exfoliation higher included hypoactivity, ataxia, prostration, delayed righting
(minimal severity) at both doses and transient erythema (days reflex, muscle twitch, lacrimation, and urine stained fur. Food con-
4–7) (graded as barely perceptible) at the high dose. There were sumption and body weights were decreased. Total leukocytes and
no differences from control in food consumption, water consump- lymphocytes and spleen weight and size were decreased. Lymphoid
tion, body weight, or weight gain. There was a statistically signifi- necrosis in the spleen and thymic atrophy and lymphoid cell degen-
cant decrease in lymphocytes compared to control for females at eration in the thymus were also observed. Liver weight was in-
the high dose and statistically significant increases in triglycerides creased. Stomach weight was increased and histopathological
for both males and females at both doses. There was a statistically findings of the stomach included hyperkeratosis, mucosal hyper-
significant reduction in absolute spleen weight at 1000 mg/kg/day plasia, edema, exocytosis, and gastritis. Absolute and relative testes
and in females only at 500 mg/kg/day. Spleen weight relative to weights were decreased at the highest dose. Absolute and relative
both body weight and brain weight were also reduced in females kidney weights were increased at 1000 mg/kg/day, and relative kid-
at both 500 and 1000 mg/kg/day. There were no other effects on ney weight was increased at 1500 mg/kg/day. However, there were
absolute or relative organ weights in males. There is no discussion no histopathological findings in testes or kidneys (EPA, 1992b).
of gross necropsy or histopathological findings. (EPA, 1992b; 2-Ethyl-1-hexanol was administered to Fischer 344 rats via the
Weaver et al., 1989). drinking water continuously for 9 days at 0, 308 ppm (half-satu-
For 12 days, 2-ethyl-1-hexanol was applied to the shaved backs rated) and 636 ppm (saturated). Mean intake was estimated to
of 10 rats at 2 ml/kg body weight/day (1600 mg/kg body weight/ be 61.1 and 151.1 mg/kg/day for males and 73.4 and 173.5 mg/
day). Observations included a decrease in absolute and relative kg/day for females at the low and high doses, respectively. There
thymus weights, liver granulomas, bronchiectasis in the lung, renal were no clinical signs of toxicity and no differences from control
tubular epithelial necroses, edematous heart and testes, as well as in food consumption, body weight, or weight gain. There were sta-
decreased spermatogenesis (Schmidt et al., 1973). tistically significant increases in water consumption for both dose
levels. There were no alterations in hematology or clinical chemis-
4.7.1.2. Oral studies. 2-Ethyl-1-hexanol was included in a study to try parameters. There were no effects on absolute or relative organ
further investigate the relationship between peroxisome prolifera- weights. Exposure of Fischer 344 rats to 2-ethyl-1-hexanol in
tion and induction of cytosolic epoxide hydrolase in mouse liver. drinking water for 9 days at the maximum possible concentration
Male C57BI/6 mice were given 10,000 ppm (1500 mg/kg body did not result in any significant toxicological changes (EPA, 1992b;
weight/day) of 2-ethyl-1-hexanol in their diet for 4 days. At this Weaver et al., 1989).
dose microsomal epoxide hydrolases were unaffected, but activity The administration of 2-ethyl-1-hexanol to male Swiss–Web-
of the cytosolic epoxide hydrolases increased (Lundgren et al., 1988). ster mice (6/group) in the diet at a concentration of 2%
In a study of the hepatic effects of DEHP and its metabolites, (2857 mg/kg body weight/day) for 10 days resulted in a significant
2-ethyl-1-hexanol was administered by oral gavage to male Wistar increase in absolute liver weight, significantly raised activities of
rats for 7 days at 850, 1335, and 1425 mg/kg/day. Livers were ex- cytoplasmic and microsomal epoxide hydrolases and glutathione-
cised for biochemical and histological evaluations. 2-Ethyl-1-hexa- S-transferase and a significant increase in the cytoplasmic and
nol, like DEHP, resulted in decreased glucose-6-phosphatase microsomal protein content of the liver (Hammock and Ota, 1983).
activity. An increase in relative liver weight, biphenyl-4-hydroxy- 2-Ethyl-1-hexanol was microencapsulated in the diet at doses
lase activity, and cytochrome P-450 content per mg microsomal of 0.46%, 0.92%, 1.38% or 2.75% (a mean daily substance intake of
protein, was observed when compared to controls. Additionally, 500, 980, 1430, or 2590 mg/kg body weight/day in 10 males and
there was a similar increase in histochemical alcohol dehydroge- 540, 1060, 1580, or 2820 mg/kg body weight/day in 10 females)
nase activity in the centrilobular area of the liver lobule, and elec- for 11 days. All groups exhibited reductions in feed consumption,
tronmicroscopy studies showed an increase in microbodies and cholesterol, triglycerides and alanine-aminotransferases. Increased
dilation of the endoplasmic reticulum. In contrast to DEHP, relative stomach and liver weights were also observed. Overall the
succinate dehydrogenase activity was not decreased and aniline- authors felt the NOEL under these study conditions was less than
4-hydroxylase activity was not increased by 2-ethyl-1-hexanol 0.46% (500, or 540 mg/kg/day) microcapsules in the feed of male
treatment compared to controls (Lake, 1974, 1975). and female rats (EPA, 1992c).
Table 6
Summary of repeated dose studies.

9 day Dermal 0, 500, or 1000 mg/kg/day Rat P500 mg/kg Body weight/day: exfoliation (minimal severity), EPA (1992b)
(occluded) spleen weight decreased; serum triglycerides increased (females); Weaver et al. (1989)
1000 mg/kg body weight: transient erythema (days 4–7) (graded
as barely perceptible), decreased absolute spleen weight,
lymphocytes decreased
12 day Dermal 2 ml/kg Body weight/day Rat Absolute and relative thymus weights decreased, liver Schmidt et al. (1973)
(1600 mg/kg body weight/ granulomas, bronchiectasis in the lung, renal tubular epithelial
day) necroses, edematous heart and testes and decreased
spermatogenesis
4 day Oral (In food) 10,000 ppm (1500 mg/kg Mice Activity of the cytosolic epoxide hydrolases increased. Lundgren et al. (1988)
body weight/day)
7 day Oral (gavage) 800, 1335, or 1425 mg/kg/ Rat Decreased: glucose-6-phosphatase activity Lake (1974, 1975)
day Increased: liver weight, biphenyl-4-hydroxylase activity, and
cytochrome P-450
7 day Oral (In food) 5–250 mg/kg/day Rat No effects Morton and Rubin
(1979)
9 day Oral (gavage) 0, 100, 330, 1000, 1500 mg/ Rat NOEL 100 mg/kg/day EPA (1992b)
kg/day
9 day Oral (drinking 61.1 or 151.1 mg/kg/day Rat Significant increase in water consumption EPA (1992b), Weaver
water) (males) et al. (1989)
73.4 or 173.5 mg/kg/day
(females)
10 days Oral (in food) 2857 mg/kg body weight/ Mice 2857 mg/kg body weight/day: absolute liver weight, activities of Hammock and Ota
day cytoplasmic and microsomal epoxide hydrolase and glutathione- (1983)
S-transferase and the cytoplasmic and microsomal protein
content of the liver increased
11 day Oral (in food) 500, 980, 1430, or 2590 mg/ Rat NOAEL < 500 (m) or 540 (f) mg/kg bodyweight/day P 500 (m) or EPA (1992c)
kg/day (males) 540 (f) mg /kg/d: relative stomach weights increased females (f);
540, 1060, 1580, or triglycerides and alanine aminotransferase decreased, males (m);
2820 mg/kg/day (females) feed consumption significantly decreased (m)
11 day Oral (gavage) Nine doses in propylene Mice NOEL between 100 and 330 mg/kg body weight/day EPA (1992d)
glycol of 100, 330, 1000, or Toxic effects in the 330 – 1500 mg/kg dosage groups
1500 mg/kg/day
11 day Oral (gavage) 0, 100, 330, 1000 or Rats and Mice Decreased (rat) body weights at 1500 mg/kg Astill et al. (1996a)
1500 mg/kg/day Increased relative liver/stomach weights, and gross lesions (rats)
at 1000 and 1500 mg/kg/day. Kidney weights were increased in
females at 330 mg/kg/day.
11 day Oral (gavage) Nine doses: 0, 100, 330, B6C3F1 mice Systemic NOAEL 100 mg/kg body weight/day EPA (1992e)
1000, or 1500 mg/kg body (10/sex) 300 mg/kg body weight/day: acanthosis with hyperkeratosis in
weight/day, in an aqueous the forestomach; P 1000 mg/kg body weight/day: relative liver
emulsion in Cremophor EL (males) and stomach weights (female) increased, hypertrophy of
hepatocytes; 1/20 deaths.
abdominal or lateral position and loss of consciousness; clinical
chemistry and hematology, no substance-related changes; 5/20
deaths.
14 day Oral (gavage) 0–1750 mg/kg/day Rats and mice Marked toxicity at the highest dose Kieth et al. (1992)
14 day Oral (gavage) 130 mg/kg/day Rat No hepatomegaly, peroxisome proliferation, hypolipidemia, or Rhodes et al. (1984)
testicular atrophy
21 day Oral (In food) 20 mg/kg/day Rat Decreased serum cholesterol and triglyceride levels Moody and Reddy
(1982)
21 day Oral 833 mg/kg/day Rat Increased liver weights Yamada (1974)
21 day Oral (gavage) 950 mg/kg/day Rat Increased absolute and relative liver weights. Slightly increased Hodgson (1987)
hepatic peroxisome levels and pCoA activity
21 day Oral (gavage 1000, 1500 mg/kg body Rat 1000 mg/kg body weight/day: 30% increase in liver-to-body- Barber and Topping
weight/day weight ratio; peroxisome cell fraction and peroxisome density in (1995)
the liver increase 500 mg/kg body weight/day: mortality
22 day Oral (gavage) 0, 330, 660, 930 mg/kg body Rat 930 mg/kg: body weight on day 17 decreased, mortality: 1/10 Schmidt et al. (1973)
weight in sunflower oil,
controls 10 ml oil/kg body
weight
90 day (inhaled) 15, 40, 120 ppm Rat No substance-related effects were observed NOAEL: 120 ppm Klimisch et al. (1998)
91 day Oral (gavage) 0, 25, 250 or 500 mg/kg Rats and Mice NOEL: 125 mg/kg/day Astill et al. (1996a)
(five consecutive days a Decreased body weight gain, gross lesions, serum ALT activities,
week) total protein, albumin concentration, and serum cholesterol
Increased pCoA activity (rats) at 500 mg/kg
18 months Oral 50, 200, or 750 (five Mice Lethargy, unkemptness, reductions in body weight gain, and Astill et al. (1996b)
(gavage) consecutive days a week) increased mortality compared to controls
24 months Oral 50, 150, or 500 (five Rats Astill et al. (1996b)
(gavage) consecutive days a week)
At doses of 100, 330, 1000, or 1500 mg/kg body weight/day 2- 11 days. Toxic effects, such as gross lesions in the forestomach, in-
ethyl-1-hexanol (in propylene glycol) was administered nine times creased relative and absolute stomach and liver weights, or clinical
by gavage to 10 male and 10 female B6C3F1 mice over a period of signs (ataxia, lethargy, piloerection, hypothermy, and loss of
consciousness) were observed in the 330–1500 mg/kg body Male and female rats were given 1000 mg 2-ethyl-1-hexanol/kg
weight/day dosage groups. The authors felt the NOEL was between body weight/day by gavage for 3 weeks. The test substance caused
100 and 330 mg/kg bodyweight/day (EPA, 1992d). a 30% increase in liver-to-body-weight ratio, an increase in the per-
In a preliminary study 2-ethyl-1-hexanol was administered as oxisome cell fraction and peroxisome density in the liver (Barber
an aqueous emulsion by oral gavage for 11 days to 10 male and fe- and Topping, 1995).
male Fischer 344 rats and B6C3F1 mice at 0, 100, 330, 1000, or Ten rats were given 0, 330, 660, 930 mg/kg body weight in sun-
1500 mg/kg/day. Clinical signs in treated animals were ataxia, flower oil by gavage 5 days per week for 22 days. At the highest
lethargy, and lateral/abdominal posturing in rats (at 1000 and dose, 930 mg/kg, one animal died and body weight was decreased
1500 mg/kg/day) and mice (1500 mg/kg/day). One female mouse on day 17 (Schmidt et al., 1973).
from the 1000 mg/kg/day dose group died, and 5/10 died at
1500 mg/kg/day. There were no mortalities in rats. Significant de- 4.7.2. Subchronic (31–90 days) studies
creases in mean rat body weights were observed at 1500 mg/kg on A 90 day subchronic inhalation study was performed on Wistar
day 10. Significant increases were observed in relative liver and rats (10/sex/group) at concentrations of 15, 40, and 120 ppm. The
stomach weights of both male and female rats at 1000 and rats were put into an inhalation chamber of glass/steel construc-
1500 mg/kg/day. Kidney weights were significantly increased in tion (manufactured by BASF AG, Ludwigshafen Germany). Pressure
females at 330 mg/kg/day. Gross lesions in the rats were observed ( 10.2 to 10.1 P) and temperature (23.1–23.8 °C) were measured
in 2/10 males at 1000 mg/kg/day and 4/10 males and 7/10 females continuously. Females of the 40 and 120 ppm exposure group
at 1500 mg/kg/day. The dose level of 500 mg/kg/day was selected had a decreased body weight gain, whereas the males of the
as a tolerable upper dose based on this 11 day study (Astill, 15 ppm group showed an increase. No clinical signs or mortality
1996a). were observed throughout the study. The authors stated that the
Oral toxicity of 2-ethyl-1-hexanol was studied in B6C3F1 mice differences in body weight/body weight gain are incidental, not
after administration by gavage (aqueous emulsion) for 11 days. dose-related and therefore of no toxicological significance. There
In total, nine applications of 0, 100, 330, 1000, or 1500 mg/kg were were no macroscopic findings attributable to the material, or in-
given to 10 male and 10 female mice per group. Some toxic effects crease in the cyanice-insensitive palmitoyl Co A oxidation in any
were observed, such as increases in liver and stomach weights treatment group. Based on the results of this test the NOAEL of in-
(absolute and relative), foci in the forestomach, hyperkeratosis haled 2-ethyl-1-hexanol was 120 ppm (corresponding to
and focal/multifocal acanthosis, or clinical signs (ataxia, lethargy, 638.4 mg/m3) (Klimisch, 1998).
piloerection, abdominal/lateral position, and loss of consciousness)
in the 330–1500 mg/kg dosage groups. The authors reported the 4.7.3. Chronic (90+ days) studies
NOEL was between 100 and 330 mg/kg of 2-ethyl-1-hexanol Male and female F344 rats and B63F1 mice (10/sex/dose) were
(EPA, 1992e). administered 2-ethyl-1-hexanol by oral gavage at doses of 0, 25,
Kieth et al. (1992) studied the dose response for peroxisome 250, or 500 mg/kg/day for 13 weeks. One female mouse at
proliferation due to 2-ethyl-1-hexanol in rats and mice. Rats and 250 mg/kg/day died during treatment, but there were no other
mice, 5/sex/dose, were dosed by oral gavage for 14 days with up mortalities in rats or mice. Decreased body weight gain, 7% in male
to 6.74 mmol/kg (2500 mg/kg/day) diethylhexyl adipate (DEHA) and 6% in female rats, was observed at 500 mg/kg starting at week
or 13.5 mmol/day (1750 mg/kg/day) of 2-ethyl-1-hexanol. 2- 4 (males) and week 11 (females). Decreases in serum ALT activities,
Ethyl-1-hexanol exhibited marked toxicity in male and female rats and serum cholesterol concentrations were observed. Males, at
at doses of 8 mmol/kg/day (1160 mg/kg/day) and higher; the ani- 500 mg/kg, had a decrease in total protein and albumin concentra-
mals were killed in extremis. Such toxicity was not noted for DEHA. tion. Significant differences in the relative organ weights from the
Both compounds resulted in dose-dependent increased liver control rats were moderate and limited to the brain, kidney, liver,
weights and peroxisome proliferation in both rats and mice, with stomach, and testes at 250 and 500 mg/kg/day. Gross lesions in
DEHA being about twice as potent, on a molar basis, as 2-ethyl- both rats and mice were seen at 500 mg/kg/day only. Dose-related
1-hexanol. Since DEHA is metabolized to 2 M equivalents of 2- microscopic findings were limited to the forestomach and liver at
ethyl-1-hexanol. These data suggest that 2-ethyl-1-hexanol is the 500 mg/kg/day in rats and mice. No increases in palmitoyl Coen-
proximate peroxisome proliferator of DEHA. zyme A activity were seen in the livers of any mice. Increased activ-
Rhodes et al. (1984) reported that in contrast to results from ity was observed in rats of the 500 mg/kg/day group. A NOEL of
previously reported high dose studies, treatment of male Wistar- 125 mg/kg/day was concluded (Astill, 1996a).
derived rats by oral gavage with 1 mmol/kg/day (130 mg/kg/day) 2-Ethyl-1-hexanol was given by oral gavage to B6C3F1 mice and
2-ethyl-1-hexanol for 14 days resulted in no hepatomegaly, perox- Fischer 344 rats (50/sex) as an emulsion with Cremophor in dou-
isome proliferation, hypolipidemia, or testicular atrophy. In con- ble-distilled water. Mice received 50, 200, or 750 mg/kg/day for
trast, diethylhexylphthalte at 1 mmol/kg/day (390 mg/kg/day) 18 months in a volume of 10 ml/kg body weight. Rats received
produced hepatic effects. 50, 150, or 500 mg/kg/day for 24 months in a volume of 10 ml/kg
It was reported that serum cholesterol and triglyceride levels body weight. Mortality in male rats (38%) was not dose related,
were significantly decreased in male F-344 rats fed ground rat however female mortality in the 500 mg/kg/day amounted to
chow diet containing 2% v/w (20 mg/kg body weight/day) 2- 52% of the animals in the group. Mice showed a marked increase
ethyl-1-hexanol for three weeks (Moody and Reddy, 1982). in male and female mortality at 750 mg/kg/day, so dosing stopped
The subacute toxicity was tested in 2-ethyl-1-hexanol for three at week 78. Weight gains were significantly different from controls
weeks by oral administration. Five rats were dosed at 1 ml/kg to treated rats at 50, 150, and 500 mg/kg/day (males), as well as
(833 mg/kg) and a statistical increase (p < 0.05) in liver weight 150, and 500 mg/kg/day (females). Weight gains were significantly
was observed (no further details given) (Yamada, 1974). different from control to treated mice at 200, and 750 mg/kg/day
Fischer 344 rats were given doses of 2-ethyl-1-hexanol at 100, (males), as well as 750 mg/kg/day (females). Male and female rats
320, and 950 mg/kg/day in a 21-day gavage study. There was no did not show any differences in food consumption, but mice had a
apparent treatment affect on food intake, although there was a sig- significant decrease at 750 mg/kg/day. Clinical observations re-
nificant decrease in body weight gain in the 950 mg/kg/day group. vealed poor general condition, lethargy, poor grooming, and la-
A dose-related increase in cyanide-insensitive pamitoyl CoA oxida- bored breathing in rats. There were no instances of poor general
tion was observed at 320 and 950 mg/kg/day (Hodgson, 1987). condition or labored breathing in mice. Moderate increase in focal
lesions and discolorations of the lung were observed in rats of the The maternal and the fetal NOAEL in this study were 130 mg/kg/
high dose. In the rat only the 50 mg/kg/day group was associated day (Hellwig and Jackh, 1997).
with small statistically significant increases in relative female In a study of the effects of DEHP and its major metabolites on
stomach weight. The mice showed no changes, besides a slight in- Sertoli cells and gonocytes of 3-day old CD Sprague Dawley rats
crease in testes weight, in relative organ weights at 50 and 200 mg/ (4/group), it was reported that 2-ethyl-1-hexanol administered
kg/day (Astill, 1996b). by oral gavage at 1.28 mmol/kg (167 mg/kg) had no effects, while
DEHP and MEHP at equimolar doses resulted in large, multinucle-
4.8. Reproductive and developmental toxicity (see Table 7) ated gonocytes and a decrease in the number of BrdU labeled Ser-
toli cells. (Li et al., 2000).
In a study of potential teratogenic effects of DEHP and its In a study of the effects of DEHP and its metabolites on rat testis
metabolites, 2-ethyl-1-hexanol was administered to pregnant in vivo and in vitro, it was reported that oral gavage doses daily for
Wistar rats by oral gavage on gestation day 12, and fetuses were five days of 2.7 mmol/kg (350 mg/kg) of 2-ethyl-1-hexanol did
examined on day 20. A dose of 6.25 mmol/kg (1 ml/kg; 833 mg/ not induce testicular damage in 35 day old male Sprague Dawley
kg) 2-ethyl-1-hexanol resulted in 2.0% fetuses with malformations, rats and in vitro administration of 2-ethyl-1-hexanol did not en-
compared to 22.2% at 12.5 mmol/kg (2 ml/kg; 1666 mg/kg) and 0% hance germ-cell detachment from mixed primary cultures of Ser-
for controls. At 1666 mg/kg, the percent survivors with hydrone- toli and germ cells from 35-day old male Sprague Dawley rats,
phrosis or malformations of the cardiovascular system, tail, limbs, while MEHP had effects on these parameters. 2-Ethyl-1-hexanol
or other were 7.8, 0, 4.9, 9.7, and 1.0, respectively (Ritter et al., (200 lM for 24 or 48 h) did not result in an increase of germ-cell
1987). detachment in rat testicular-cell cultures (Gray, 1986; Gray and
In a preliminary developmental toxicity test of 60 chemicals in Beamand, 1984; Sjöberg et al., 1986).
female CD-1 mice, it was reported that 2-ethyl-1-hexanol adminis- Groups of 28 CD-1 Swiss mice were given >99% pure 2-ethyl-1-
tered by oral gavage at 1525 mg/kg/day on gestation days 6–15 re- hexanol microencapsulated in their diet at concentrations of 0,
sulted in 17/49 maternal deaths, and values significantly lower 0.009, 0.03, and 0.09% from days 0–17 of pregnancy. This corre-
than control values for maternal weight gain, viable litters, live sponded to calculated doses of 0.13, 43, and 129 mg/kg body
births per litter, and fetal percent survival, birth weight and weight weight/day. No maternal toxicity was observed and the birth rate
gain (Hardin et al., 1987). was 93–96% in all groups. All of the litters survived and all gesta-
In a study of differential prenatal toxicity of a series of alcohols, tional parameters were normal. There were no external, visceral,
2-ethyl-1-hexanol was administered by oral gavage to Wistar rats or skeletal malformations and no increase in variations occurred.
on gestation days 6 to 19 at doses of 0, 1, 5, and 10 mmol/kg/day, The authors concluded that 2-ethyl-1-hexanol plays essentially
equivalent to 0, 130, 650, and 1300 mg/kg/day. Maternal toxicity no role in the expression of DEHP-induced maternal and develop-
was evident at 650 and 1300 mg/kg/day, with significant differ- mental toxicity (NTP, 1991; Price et al., 1991).
ences from control in maternal body weight on days 15 and 20. 2-Ethyl-1-hexanol was given to female Sprague Dawley rats (6/
There was one death at 650 mg/kg/day attributed to gavage error. group) by gavage so that developmental toxicity could be evalu-
In the 1300 mg/kg/day group there were six deaths attributed to ated. On gestation day (GD) 11.5 dosed administration of 0, 6.25,
treatment, on days 9, 10, and 13. Fetuses were also affected at 9.38, or 12.5 mmol in corn oil (0, 813, 1219, 1625 mg/kg body
the maternally toxic doses, with significant differences from con- weight) was followed by an 8 h intubation with 32 lCi 65Zn.
trol in post-implantation loss, resorptions, fetal weight, number Maternal food intake decreased, and the 65Zn was retained in the
and percent fetuses and litters with malformations and variations, liver. The percentage of resorptions was not affected. The authors
and number and percent fetuses with developmental retardations. concluded that 2-ethyl-1-hexanol did not elicit a profile of
Table 7
Summary of reproductive and developmental toxicity studies.
Method Dose mg/kg body weight/day Species Results References

Oral 833, and 1666 Rat 2% malformations (833 mg/kg) Ritter et al. (1987)
22.2% malformations (1666 mg/kg)
Oral 1525 Mouse 17/49 maternal deaths Hardin et al. (1987)
Significantly lower maternal weight gain, viable litters, live births/
litter, fetal survival, and fetal weight
Oral 0, 130, 650, and 1300 Rat Maternal toxicity at 650 and 1300 mg/kg/day. Hellwig and Jackh (1997)
Maternal and fetal NOAEL 130 mg/kg/day
Oral 167 Rat No effects Li et al. (2000)
Oral 350 Rat Did not induce testicular damage Sjöberg et al. (1986)
Gray et al. (1984)
Gray (1986)
Oral 0.13, 43 and 129 CD-1 Swiss mice NOAEL maternal and developmental toxicity: 129 mg/kg body weight/ NTP (1991), Price et al.
(28 f/group) day but no toxic dose tested (1991)
no maternal toxicity; all of the litters survived and all gestational
parameters were normal.
Oral 0, 813, 1219, 1625 Rat P1219 mg/kg body weight: maternal food intake decreased; 1625 mg/ Bui et al. (1998),
kg body weight: percentage of 65Zn retained in maternal liver increase Taubeneck (1996)
The percentage of resorptions was not affected; 1625 mg/kg body
weight: percentage of 65Zn retained in the embryos decreased
Whole 850 mg/m3 Rat No effects Nelson et al. (1989)
body
Dermal 0, 420, 840, 1680, 2520 Rat NOAEL was 2520 mg/kg/day Fisher et al. (1989)
Tyl et al. (1992)
In vitro 200 uM Rat No effect Moss et al. (1988)
In vitro 200 uM Rat Did not induce dissociation of germinal cells from Sertoli Cells Gangolli (1982)
maternal or developmental toxicity compared to that of its parent 2-Ethyl-1-hexanol was found to be non-mutagenic in
compound, DEHP (Bui et al., 1998; Taubeneck, 1996). S. typhimurium strains TA98, TA100, TA1535, TA1537, TA 1538,
When pregnant Sprague Dawley rats were exposed by whole and TA2637 with and without metabolic activation (Agarwal et
body exposure 7 h per day on gestation days 1–19 to 850 mg/m3 al., 1985).
2-ethyl-1-hexanol, the maximum vapor concentration that could Salmonella typhimurium (strains not specified), 2-ethyl-1-hexa-
be achieved without increasing exposure chamber temperature nol was found to be non-mutagenic with and without addition of
above 80° F, overall mean food consumption was decreased com- rat liver microsomes (Barber et al., 1985).
pared to control, but there were no significant differences in 2-Ethyl-1-hexanol was not mutagenic in S. typhimurium (strains
maternal weight, water intake, corpora lutea per ovary, resorptions TA98, TA100, TA1535, TA1537, and TA1538) tested with and with-
per litter, numbers of females or males per litter, or fetal weight of out addition of microsomes from Aroclor induced rats (Kirby et al.,
females or males, and no external, visceral, or skeletal malforma- 1983).
tions were observed (Nelson et al., 1989). 2-Ethyl-1-hexanol was found to be non-mutagenic in
There were no developmental effects when 2-ethyl-1-hexanol S. typhimurium strains TA98 and TA100 with and without addition
was administered by occluded cutaneous application to Fischer of rat liver microsomes (Warren et al., 1982).
344 rats 6 h per day on gestation days 6–15 at doses of 0, 0.5, At 500 ug/disk, 2-ethyl-1-hexanol was found to be non-muta-
1.0, 2.0, and 3.0 ml/kg/d (0, 420, 840, 1680, or 2520 mg/kg/day) genic in the Rec-assay with Bacillus subtilis strains H17 and M45
in a range-finding study (8/group) or at 0, 0.3, 1.0, and 3.0 ml/kg/ (Tomita et al., 1982).
day (0, 252, 840, or 2520 mg/kg/day) in the main study (25/group). Urine from Sprague–Dawley rats dosed by oral gavage for
Maternal weight gain was reduced at 1680 mg/kg and 2520 mg/kg/ 15 days with 1000 mg/kg 2-ethyl-1-hexanol was found to be
day. Persistent exfoliation and crusting and erythema were seen in non-mutagenic in S. typhimurium strains TA98, TA100, TA1535,
both studies at 840, 1680, and 2520 mg/kg/day. Maternal liver, kid- TA1537, and TA1538 with and without addition of rat liver micro-
ney, thymus, spleen, adrenal, and uterine weights and gestational somes or beta-glucuronidase/arylsulfatase (DiVincenzo et al., 1983,
and fetal parameters were unaffected by treatment. There were 1985).
no treatment related increases in incidence of individual or pooled 2-Ethyl-1-hexanol was found to be mutagenic S. typhimurium
external, visceral, or skeletal malformations or variations. The strain TA 100 in an 8-azaguanine resistance assay (Seed, 1982).
NOAELs for maternal toxicity were 252 mg/kg/day based on skin In a study of the thermal decomposition products of phthalates
irritation and 840 mg/kg/day based on systemic toxicity. The and poly(vinyl) chloride, 2-ethyl-1-hexanol was reported to cause
developmental NOAEL was at least 2520 mg/kg/day, with no tera- DNA damage in the Rec-assay with B. subtilis strains HA101(rec+)
togenicity (Fisher et al., 1989; Tyl et al., 1992). and Rec-4 (rec ) (Saido et al., 2003).
It was reported that 2-ethyl-1-hexanol had no effect in vitro on
lactate and pyruvate production by Sertoli cell enriched cultures
4.9.1.2. Studies in mammalian cells (see Table 9). 2-Ethyl-1-hexanol
derived from 28 day old Sprague Dawley rats, whereas phthalate
was found to be non-mutagenic in the L5178Y TK ± mouse lym-
monoesters known to cause testicular atrophy in vivo increased
phoma cell mutagenicity assay. Doses of 0.01, 0.05, 0.25, 0.5, and
Sertoli cell lactate production and lactate/pyruvate ratio (Moss
1.0 ul/plate representing nontoxic, toxic, and/or maximum toler-
et al., 1988).
ated doses were selected based on preliminary toxicity studies
It was reported that 200 lM 2-ethyl-1-hexanol in vitro did not
(Kirby et al., 1983).
induce dissociation of germinal cells from Sertoli cells in cultures
of rat seminiferous tubules (Gangolli, 1982).
Table 9
4.9. Genotoxicity Summary of mammalian cell studies.
4.9.1. In vitro studies Method Species Results References
4.9.1.1. Bacterial test systems (see Table 8). In Salmonella typhimuri- Mouse lymphoma cell Mouse Non-mutagenic Kirby et al.
um (strains TA98, TA100, TA1535, TA1537, and TA1538 and mutagenicity assay (1983)
Cytogenetic assay Rat Did not induce Hodgson
Eschericia coli (strain WP2uvrA) 2-ethyl-1-hexanol was found to unscheduled DNA et al.
be non-mutagenic with and without addition of the S9 mix from synthesis (1982)
the livers of male Sprague–Dawley rats (Shimizu et al., 1985). Balb 3T3 Rat Did not induce EPA (1983)
In a study of 34 phthalates and related chemicals, 2-ethyl-1- transformation transformation
assay
hexanol was found to be non-mutagenic in S. typhimurium strains
Chromosomal Hamster Did not increase frequency Phillips
TA98, TA100, TA1535, and TA1537 with and without addition of aberration assay of chromosomal et al.
microsomes from Aroclor induced rats and Syrian hamsters (Zeiger aberrations (1982)
et al., 1982).
Table 8
Summary of bacterial studies.
Method Bacterial strains Results References

Ames test S. typhimurium TA 98, 100, 1535, 1537, 1538 and E. coli WP2uvrA Non-mutagenic Shimizu et al. (1985)
Ames test S. typhimurium TA 98, 100, 1535, 1537 Non-mutagenic Zeiger et al. (1982)
Ames test S. typhimurium TA 98, 100, 1535, 1537, 1538, 2637 Non-mutagenic Agarwal et al. (1985)
Ames test S. typhimurium (unspecified) Non-mutagenic Barber et al. (1985)
Ames test S. typhimurium TA 98, 100, 1535, 1537, 1538 Non-mutagenic Kirby et al. (1983)
Ames test S. typhimurium TA 98, 100, Non-mutagenic Warren et al. (1982)
Rec-assay B. subtilis H17 and M45 Non-mutagenic Tomita et al. (1982)
Ames test S. typhimurium TA 98, 100, 1535, 1537, 1538 Non-mutagenic DiVincenzo et al. (1983), (1985)
Resistance assay S. typhimurium TA 100 Mutagenic Seed (1982)
Rec-assay B. subtilis HA101 (rec+) and Rec-4 (rec-) Mutagenic Saido et al. (2003)
2-Ethyl-1-hexanol was evaluated for its ability to induce in vitro promotion potential study with mouse epidermis-derived
unscheduled DNA synthesis (UDS) in primary rat hepatocytes JB6 cells. 2-Ethyl-1-hexanol did not promote JB6 cells to anchorage
cultures prepared from Fischer 344 rats. Cells were treated simul- independence (Ward et al., 1986).
taneously with test compound and tritiated thymidine for 1 h. A cell transformation assay with BALB 3T3 cells did not induce a
2-ethyl-1-hexanol did not induce UDS in this assay (Hodgson significant number of transformed foci (Barber et al., 1985).
et al., 1982, abstract).
2-Ethyl-1-hexanol was tested and found to not induce transfor- 4.10.2. In vivo studies
mation in an assay for in vitro transformation of Balb 3T3 cells with 2-Ethyl-1-hexanol was given to male and female rats and mice
metabolic activation by primary rat hepatocytes obtained from by gavage five times a week in 0.005% aqueous Cremophor EL (rats:
Fischer 344 rats. The compound was tested over the concentration 0 (water), 0 (vehicle), 50, 150, 500 mg/kg body weight/day,
range of 96–180 nl/ml. This concentration range corresponded to 24 months; mice: 0 (water), 0 (vehicle), 50, 200, 750 mg/kg body
approximately 31.7–72% survival in the concomitant cytotoxicity weight/day, 18 months). The incidences of carcinomas and baso-
test. The positive control treatments of cyclophosphamide induced philic foci in the liver increased in female mice with the dose
a total of 26 foci among 18 flasks; therefore, the sensitivity of the and attained statistical significance in the highest dose group com-
assay appeared normal (EPA, 1983). pared with the vehicle control group but not with the water con-
2-Ethyl-1-hexanol over a 1.5–2.8 mM concentration range did trol group. The time-adjusted incidence of hepatocellular
not cause a statistically significant increase in frequency of chro- carcinomas in female mice (13.1%) was outside the normal range
mosomal aberrations compared to control in Chinese Hamster (0–2%), but in male mice (18.8%) was within the historical control
ovary cells (Phillips et al., 1982). range at the testing facility (0–22%). No adenomas were observed.
The number of basophilic liver foci was increased in male mice in
the mid dose group only (Table 5). The authors considered the liver
4.9.2. In vivo studies (see Table 10)
tumors in the mouse to be inconclusive because the incidence of
In the in vivo mouse micronucleus assay using the B6C3F1
hepatocarcinoma precursors did not significantly increase with
mouse and in the Balb 3T3 transformation assay, 2-ethyl-1-hexa-
the dose. Nevertheless, they concluded that 2-ethylhexanol is
nol was found to be non-mutagenic in the presence and absence
weakly or questionably carcinogenic for the female mouse. Under
of a co-cultivated rat hepatocyte activation system (Barber et al.,
the conditions of this study 2-ethyl-1-hexanol was not oncogenic
1985; Astill et al., 1986).
to rats. Doses of 150 and 500 mg/kg body weight/day led to re-
Male Fischer 344 rats were dosed by oral gavage for five consec-
duced body weight gains and in some animals to lethargy and poor
utive days with 0.02, 0.07, and 0.21 ml/kg/day of 2-ethyl-1-hexa-
grooming which proves that the maximum tolerated dose was
nol. When compared to controls, there was no increase in
reached. At the end of the study the mortality was about 52% in
chromatid and chromosome breaks. The mitotic index was also
the high dose group females and about 28% in the other groups
not affected in bone marrow cells (Putman et al., 1983).
(Table 11; Astill et al., 1996b).
A dominant lethal study was conducted in ICR/SIM mice treated
orally with 2-ethyl-1-hexanol. Dose levels of 250, 500, and
4.11. Miscellaneous studies (see Table 12)
1000 mg/kg/day representing the MTD, were selected based on a
preliminary acute toxicity study. The animals were treated by oral
In studies in perfused livers from starved female Sprague–Daw-
gavage daily for five consecutive days. After treatment, each male
ley rats, 2-ethyl-1-hexanol (3 mM or 0.39 g) in the perfusion
was housed with two virgin females per week for eight consecutive
media (Krebs–Henseleit buffer pH 7.4, 37 °C saturated with 95%
weeks to span the spermatogenic cycle. Females were sacrificed on
O2: 5% CO2) inhibited oxygen uptake in periportal, but not centri-
day 14–17 of caging with males and scored for pregnancy, living
lobular regions, and caused damage primarily in the periportal re-
fetuses, and early and late fetal deaths. Fertility indices and aver-
gions, as reflected by trypan blue staining. 2-Ethyl-1-hexanol
age numbers of dead and total implants per pregnancy were within
perfusion also resulted in lactate dehydrogenase release into the
the normal range. It was concluded that 2-ethyl-1-hexanol did not
perfusion effluent. In isolated mitochondria from the treated livers,
induce dominant lethal mutations after oral administration
oxygen uptake was inhibited in the presence of succinate with ADP
(Rushbrook et al., 1982).
and stimulated in the presence of succinate without ADP, indicat-
ing an uncoupling of oxidative phosphorylation. It was proposed
4.10. Carcinogenicity that peroxisome proliferators accumulate in the liver due to their
lipophilicity where they inhibit actively respiring mitochondria
4.10.1. In vitro studies in periportal regions of the liver lobule and cause local toxicity
In a tumor initiation/promotion study of diethylhexyl phthalate (Keller et al., 1990, 1992).
and its hydrolysis products, 2-ethyl-1-hexanol was evaluated in an In an investigation of the effect of 2-ethyl-1-hexanol on fatty
acid metabolism, it was reported that rates of ketone body pro-
duction by perfused livers from starved female Sprague–Dawley
rats were decreased about 60% by 200 uM (0.026 g) 2-ethyl-1-
Table 10
Summary of in vivo studies.
hexanol in the perfusion media (Krebs–Henseleit buffer pH 7.4,
37 °C saturated with 95% O2: 5% CO2). Studies were conducted
Method Species Results References to determine the site of inhibition of fatty acid oxidation. Rates
Mouse B6C3F1 Non-mutagenic Barber et al. of ketone body production in the presence of oleate, which re-
micronucleus mouse (1985) quires transport of the corresponding CoA compound into the
assay Astill et al.
mitochondria, were reduced by 2-ethyl-1-hexanol. In contrast, ke-
Balb 3T3 Rat Non-mutagenic (1986)
transformation tone body production from hexanoate, which is activated in the
assay mitochondria, was not affected by 2-ethyl-1-hexanol. Basal and
Cytogenetic assay Rat No effects Putman et al. oleate-stimulated H2O2 productions were not affected by 2-
(1983)
ethyl-1-hexanol, indicating that beta-oxidation was not altered
Dominant lethal Mouse Did not induce dominant Rushbrook
study lethal mutations et al. (1982)
by the compound. Based on these data, it was concluded that
2-ethyl-1-hexanol inhibits beta-oxidation of fatty acids in
Table 11
Study of the carcinogenicity of 2-ethyl-1-hexanol administered to B6C3F1 mice by oral gavage for 18 months (Astill et al., 1996b) – liver findings.
Dose (mg/kg body weight/day) Water control Vehicle control 50 mg/kg 200 mg/kg 750 mg/kg
Congestion m 1/50 0/50 0/50 0/50 7/502
f 1/50 0/50 0/50 3/50 2/50
Peripheral fatty infiltration m 0/50 0/50 0/50 1/50 31/503
f 0/50 1/50 0/50 3/50 22/503
Basophilic foci m 4/50 4/50 5/50 12/501 6/50
f 2/50 1/50 2/50 4/50 6/501
Focal hyperplasia m 2/50 7/50 4/50 9/50 10/50
f 1/50 0/50 3/50 4/501 1/50
Adenomas m 0/50 0/50 0/50 0/50 1/50
Carcinomas m 4/50 6/50 6/50 7/50 9/50
f 1/50 0/50 1/50 3/50 5/501
Compared with the vehicle control (Fisher’s exact test).

1
p < 0.05,
2
p < 0.01,
3
p < 0.001, f, female; m, male.
Table 12
studies on the mechanism of hepatotoxicity of 2-ethyl-1-hexanol.
Test system Concentration Results References

Isolation of mitochondria from 70 lM, 3 mM in the 2-Ethyl-1-hexanol in the perfusion media: inhibition of the oxygen uptake in Keller et al.
perfused rat livers perfusion medium periportal, but not centrilobular regions; damage primarily in the periportal regions, (1990, 1991,
as reflected by trypan blue staining; lactate dehydrogenase release into the perfusion 1992)
effluent.
Isolated mitochondria from the perfused livers: inhibition of the oxygen uptake in the
presence of succinate with ADP and stimulation in the presence of succinate without
ADP, indicating an uncoupling of oxidative phosphorylation.
It was proposed that peroxisome proliferators accumulate in the liver due to their
lipophilicity where they inhibit actively respiring mitochondria in periportal regions
of the liver lobule and cause local toxicity.
Perfused livers 200 lM in the 2-Ethyl-1-hexanol in the perfusion media: rates of ketone body production were Badr et al.
perfusion medium decreased about 60%; rates of ketone body production in the presence of oleate, which (1990)
requires transport of the corresponding CoA compound into the mitochondria, were
reduced by 2-ethyl-1-hexanol; in contrast, ketone body production from hexanoate,
which is activated in the mitochondria, was not affected by 2-ethyl-1-hexanol; basal
and oleate-stimulated H2O2 productions were not affected by 2-ethyl-1-hexanol,
indicating that beta-oxidation was not altered by the compound;Based on these data,
it was concluded that 2-ethyl-1-hexanol inhibits beta-oxidation of fatty acids in
mitochondria but not in peroxisomes.
Isolated cylinders of periportal and 0.1–3 mM: Incubation of plugs with 0.1 to 3 mM 2-ethyl-1-hexanol: extensive cell damage Liang et al.
pericentral regions of the liver incubation of plugs assessed from LDH leakage in incubations at 800 lM O2 but significantly less injury at (1991)
lobule 200 lM O2; Concomitantly, inhibition of urea synthesis by over 80% at 800 lM O2, but
less than 50% at 200 lM O2; Plugs isolated from both regions of the liver were affected
similarly by 2-ethyl-1-hexanol and O2.
The authors concluded that these data indicate that 2-ethyl-1-hexanol toxicity is
dependent on oxygen tension in isolated sublobular regions of the liver lobule, and
therefore it is unlikely that drug delivery can explain the selective injury to periportal
regions in studies with perfused liver.
GST from rats and mice Up to 15 mM Cytosolic GST activity (substrates: 1,2-dichloro-4-nitrobenzene- or 1,2-epoxy-3-(p- Law and Moody
nitrophenoxy)-propane) was only weakly inhibited in rats (IC50 70 mM or no (1989, 1991)
inhibition up to 10 mM) and mice (IC50 23 mM or 15 mM), in contrast to the effects of
other peroxisome proliferators (e.g. DEHP, MEHP)
Rat liver homogenates 2.5 to 15 mM Concentration-dependent reduction in the activities of aniline hydroxylase and Agarwal et al.
aminopyrine-N-demethylase (1982) Seth
(1982)
Kupffer cells in culture Up to 0.9 mM No effect on the Kupffer cell superoxide production Rose et al.
(1999)
Kupffer cells in culture Up to 3 mM No effect on the cytosolic free calcium concentrations in Kupffer cells up to 2 mM Hijioka et al.
(Wy-16,643 had an effect at 1,25 mM), only at 3 mM increase of the free calcium (1991)
concentration
Mitochondrial fraction from rat liver 1% Little inhibitory effect on mitochondrial respiration at a concentration of 1% Takahashi
(1977)
Cultured hepatocytes 10, 100, 500 lM Inhibition of GJIC was observed, no cytotoxicity in the tested concentration range, a Lington et al.
NOEL for GJIC was observed, n.f.i. (1994)
ADP, adenosine diphosphate; CoA, Coenzyme A; DEHP, di(2-ethylhexyl) phthalate; GJIC, gap junctional intercellular communication; GST, glutathione-S-transferase; MEHP,
mono-(2-ethylhexyl) phthalate; n.f.i., no further information; LDH, lactate dehydrogenase.
mitochondria but not in peroxisomes. Treatment of rats ip with containing fragrances. The authors are all employees of the Re-
0.32 g/kg 2-ethyl-1-hexanol deceased plasma ketone bodies, in- search Institute for Fragrance Materials.
creased hepatic triglycerides, and increased lipid predominantly
in periportal regions of the liver lobule. It was concluded, data
indicates that alterations in hepatic fatty acid metabolism in per- References
iportal regions of the liver lobule may be early events in peroxi-
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of phthalic acid esters and metabolites in Salmonella typhimurium cultures.
Sprague–Dawley rats, pretreated with phenobarbital 1 mg/l for at
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Albro, P.W., Corbett, J.T., Schroeder, J.L., Jordan, S., Matthews, H.B., 1982.
lobule were collected with a micropunch following brief perfusion
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FOOD AND CHEMICAL TOXICOLOGY (Contents continued from outside back cover)
Founding Editor
The late Leon Golberg
Editors D. McGinty, J. Scognamiglio, S97–S101 Fragrance material review on 2-methylbutanol
JOSEPH F. BORZELLECA AL A N R. BO O B I S C. S. Letizia and A. M. Api
Department of Pharmacology and Section of Experimental Medicine and Toxicology, D. McGinty, A. Lapczynski, S102–S109 Fragrance materials review on isoamyl alcohol
Toxicology, Medical College of Virginia, Division of Medicine, Imperial College, Hammersmith Campus, J. Scognamiglio, C. S. Letizia and
Richmond, VA 23298-0613, USA Ducane Road, London W12 0NN, UK
A. M. Api
Review Editor D. McGinty, J. Scognamiglio, S110–S114 Fragrance material review on 2,6-dimethyl-2-heptanol
SU S A N M. BA R L O W C. S. Letizia and A. M. Api
Harrington House, 8 Harrington Road, D. McGinty, J. Scognamiglio, S115–S129 Fragrance material review on 2-ethyl-1-hexanol
Brighton, East Sussex BN1 6RE, UK C. S. Letizia and A. M. Api
Associate Editors
JO H N CH R I S T I A N LA R S E N IV O N N E RI E T J E N S
National Food Institute, Technical University of Denmark, AFSG/Division of Toxicology, Wageningen University, PO Box 8000,
19 Mørkhøj Bygade, DK-2860 Søborg, Denmark 6700 EA Wageningen, The Netherlands
B R Y A N DE L A N E Y
DA V I D J. BR U S I C K
Senior Research Scientist – Toxicology, Pioneer Hi-Bred International,
Brusick Consultancy, 123 Moody Creek Road, VA 23024, Bumpass,
2450 SE Oak Tree Court Ankeny, IA 50021-7102, USA
Virginia, USA
GA R Y WI L L I A M S
Department of Pathology, New York Medical College, Basic Science MI C H A E L W. PA R I Z A
Building, Room 413, Valhalla, NY 10595, USA Department of Food Microbiology and Toxicology, University of
SA M U E L M. CO H E N Wisconsin at Madison, 176 Microbial Sciences Building,
Department of Pathology and Microbiology, University of Nebraska 1550 Linden Drive Madison, WI 53706, USA
Medical Center, 983135 Nebraska Medical Center,
Omaha, NE 68198-3135
International Editorial Board
P. BA L D R I C K , UK I. KI M B E R , UK R. C. SH A N K , USA
J. K. CH I P M A N , UK S. KN A S M Ü
U L L E R , Austria M. SM I T H , The Netherlands
T. F. X. CO L L I N S , USA B. LA K E , UK Y.-J. SU R H , South Korea
Y. P. DR A G A N , USA R. W. LA N E , USA R. G. TA R D I F F , USA
L. O. DR A G S T E D , Denmark M. I. LU S T E R , USA S. L. TA Y L O R , USA
L. FE R G U S O N , New Zealand D. McGR E G O R , France J. A. TH O M A S , USA
S. J. S. FL O R A , India P. MA G E E , UK E. VA V A S O U R , Canada
H. R. GL A T T , Germany H. I. MA I B A C H , USA H. VE R H A G E N , The Netherlands
W. H. GL I N S M A N N , USA K. MO R G A N , UK A. VI S C O N T I , Italy
Y. HA S H I M O T O , Japan R. J. NI C O L O S I , USA X. WA N G , People’s Republic of China
A. W. HA Y E S , USA D. RA Y , UK S. YA N N A I , Israel
Y. HU A , China K. RO Z M A N , USA
S. KA C E W , Canada W. H. M. SA R I S , The Netherlands
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Volume 48, Supplement 4, July 2010 ISSN 0278-6915
48/S4
VOLUME 48 (2010) SUPPLEMENT 4 Editors
Food and
CONTENTS

J F Borzelleca
A Safety Assessment of Saturated Branched Chain Alcohols when used as
Fragrance Ingredients
A R Boobis
D. Belsito, D. Bickers, M. Bruze,

P. Calow, H. Greim, J. M. Hanifin,
A. E. Rogers, J. H. Saurat, I. G. Sipes,
S1–S46 A safety assessment of branched chain saturated alcohols when used as
fragrance ingredients Chemical
Toxicology
H. Tagami, and The RIFM Expert
Panel
D. McGinty, J. Scognamiglio, S47–S50 Fragrance material review on 3,5,5-trimethyl-1-hexanol
D. McGinty, J. Scognamiglio, S51–S54 Fragrance material review on 3,7-dimethyl-7-methoxyoctan-2-ol
Vol. 48/S4 (2010) S1–S130

D. McGinty, J. Scognamiglio, S60–S62 Fragrance material review on 2-methylundecanol
D. McGinty, J. Scognamiglio, S63–S66 Fragrance material review on 3,4,5,6,6-pentamethylheptan-2-ol
C. S. Letizia and A. M. Api A Safety Assessment of Saturated Branched Chain
D. McGinty, J. Scognamiglio, S67–S69 Fragrance material review on isodecyl alcohol
D. McGinty, J. Scognamiglio, S70–S72 Fragrance material review on isooctan-1-ol
D. McGinty, S. P. Bhatia, S73–S78 Fragrance material review on isotridecan-1-ol (isomeric mixture)
J. Scognamiglio, C. S. Letizia and
A. M. Api
D. McGinty, J. Scognamiglio, S79–S81 Fragrance material review on isononyl alcohol
D. McGinty, J. Scognamiglio, S82–S84 Fragrance material review on 6,8-dimethylnonan-2-ol
D. McGinty, C. S. Letizia and S85–S88 Fragrance material review on 2-ethyl-1-butanol
A. M. Api
D. McGinty, J. Scognamiglio, S89–S92 Fragrance material review on 2,6-dimethyl-4-heptanol
(Contents continued on inside back cover)
Available online at www.sciencedirect.com
http://www.elsevier.com/locate/foodchemtox
Fd Chem. Toxic. is indexed/abstracted in Analyt. Abstr., Aqua. Abstr.,
Biosis Data., CAB Inter., CABS (Current Awareness in Biological Sciences),
Cam. Sci. Abstr., Chem. Abstr. Serv., Chem. Haz. in Indus.,
Curr. Cont. ISI/BIOMED Database, Curr. Cont. Sci. Cit. Ind.,
Curr. Cont. SCISEARCH Data., Excerp. Med., Health & Saf. Sci. Abstr.,
Ind. Med., Int. Pack., MEDLINE, Res. Alert, Tox. Abstr.
ELSEVIER
ISSN 0278-6915
48(S4) S1–S130 (2010)
Printed by Polestar Wheatons Ltd, Exeter, UK 237
CYAN MAGENTA YELLOW BLACK

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Volume 48, Supplement 4, July 2010 ISSN 0278-6915

FOOD AND CHEMICAL TOXICOLOGY

D. Belsito, D. Bickers, M. Bruze,

Vol. 48/S4 (2010) S1–S130

Available online at www.sciencedirect.com

Printed by Polestar Wheatons Ltd, Exeter, UK 237

CYAN MAGENTA YELLOW BLACK

Ó 2010 Elsevier Ltd. All rights reserved.

For a full and complete Guide for Authors, please go to http://www.elsevier.com/locate/foodchemtox

Food and Chemical Toxicology has no page charges.

Contents lists available at ScienceDirect

Food and Chemical Toxicology

A safety assessment of branched chain saturated alcohols when used

4.3. Respiratory route of exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S9

1. Introduction shown in Table 1.1 In addition, several noncyclic branched chain

Water solubility: 41,580 mg/l at 25 °C 3-Methylbutan-1-ol

Isononyl alcohol (isomer unspeciﬁed)

(continued on next page)

(continued on next page)

Molecular weight: 158.29

authors calculated an oxidation rate of 5 mg/kg body weight/h

4.3. Respiratory route of exposure

5.1. Acute toxicity 5.2.1. Dermal studies

OECD TG 408, isoamyl alcohol was administered in the drinking

Material Species No./dose LD50 mg/kg body weightb References

n.f.i.: no further information.

Material Species No./dose LD50 mg/kg body weightb References

n.f.i.: no further information.

n.f.i.: no further information.

Material Method Dose Species (No./dose) Results References

Abbreviations see Table 3-3.

Material Method Dose Species (No./dose) Results References

hematology no substance-related changes. No

(continued on next page)

Material Method Dose Species (No./dose) Results References

320 and 1280 mg/kg/day (females): increased prothrombin

GOT, total protein, total cholesterol, total bilirubin, blood

Abbreviations see Table 3-3.

Material Method Concentration Species (No./dose) Results References

Material Test system Concentration Results References

(continued on next page)

Material Test system Concentration Results References

Mouse lymphoma test n.f.i. n.f.i. Equivocal IPCS (1990) as cited in

DMSO: dimethylsulfoxide, n.f.i.: no further information, n.s.: not statistically signiﬁcant.

Material Test system Species (No./dose) Dose/Concentration Results References

n.f.i.: no further information, PCE: polychromatic erythrocytes, NCE: normochromatic erythrocytes.

Material Method Dose Species (No./dose) Results References

Material Method Concentration/dose Species (No./dose) Results References

Material Method Concentration/dose Species (No./dose) Results References

weight decreased, skeletal variations and

(continued on next page)

Material Method Concentration/dose Species (No./dose) Results References S28

indices (fertility and implants) (n.f.i.)

Material Method Concentration/dose Species (No./dose) Results References

Fetal: no litter parameters affected; no gross

5.6. Skin irritation 5.7.1. Sensory irritation

Material Method Concentration Subjects Results References

Material Method Concentration Species Results References

(continued on next page)

the UV spectra and review of phototoxic/photoallergy data, the

To address hepatotoxicity, several miscellaneous studies were

4/10: slight redness, 4/10: moderate redness, 2/10:

very slight edema, 3/6 animals were not entirely