Part 2

RAW MATERIAL SPECIFICATION
WATER
Items
Specifications
Methods
Appearance Odor Microbial Content Test (Total Plate Count) (Absence of Psuedomonas species) (Absence of E. Coli)
Match to standard Match to standard
1476468 2846466
<=100cfu/g Must Pass Must Pass
9184535 9413173 9413173
ACACIA SENEGAL GUM EXTRACT
Items
Specifications
Methods
Appearance Odor Microbial Content Test
Match to standard Match to standard <=100 cfu/g
1476468 2846466 9184535
BUTYLENE GLYCOL
Items
Specifications
Methods
Appearance Odor Identification Specific Gravity
Match to standard Match to standard Match to standard 1.004 1.007
1476468 2846466 JSCI methods 2987147
SODIUM BENZOATE
Items
Specifications
Methods
Appearance Odor Identification Assay
Match to standard Match to standard Match to standard 99.0 % minimum
1476468 2846466 JSCI method JSCI method
METHYLPARABEN
Items
Specifications
Methods
Appearance Odor Identification Assay Melting Point
Match to standard Match to standard Match to standard 99.0 100.5 % 125 128 C
1476468 2846466 USP method USP method USP method
PERFUME
Items
Specifications
Methods
Appearance Odor Specific Gravity Microbial Content Test (Total Plate Count)
Match to standard Match to standard 0.94 - 0.98 N/A
1476468 2846466 2987147
CERTIFICATE
The perfume described below complies with the latest IFRA (The International Fragrance Association) guidelines.
Perfume name / code : Rose ver 1 Name of Supplier : Address of supplier: Max Fragrance Co. Ltd.. 35894 Smiling Street, Sydney, NSW, Australia
________________________________________________ M. Jones Senior Scientist Research & Development ASEAN Company
_____________ Date
Part II. A Specifications and test methods of raw material / ingredients

- For fragrance materials, specify the name and code number of the fragrance, name and address of the supplier, declaration of compliance with the latest IFRA guidelines
SCCP/0873/05
EUROPEAN COMMISSION
HEALTH & CONSUMER PROTECTION DIRECTORATE-GENERAL Directorate C - Public Health and Risk Assessment C7 - Risk assessment
SCIENTIFIC COMMITTEE ON CONSUMER PRODUCTS SCCP
Extended Opinion on
the Safety Evaluation of Parabens
Adopted by the SCCP by written procedure on 28 January 2005
SCCP/0873/05 Opinion on the safety evaluation of parabens
TABLE OF CONTENTS 1. 2. 3. 4. 5. 6. 7. BACKGROUND TERMS OF REFERENCE OPINION CONCLUSION MINORITY OPINION REFERENCES ACKNOWLEDGEMENTS 3 3 4 8 10 10 11
1.
BACKGROUND
Parabens (4-Hydroxybenzoic acid, its salts and esters) are regulated by Cosmetic Directive 76/768/EEC, Annex VI, part 1, reference 12 and can therefore be used as a preservative up to a maximum concentration of 0.4 % in the finished product for 1 ester and up to 0.8 % for mixtures of esters. The substances are marketed with the symbol (+) and therefore may also be added to cosmetic products in concentration other than those laid down in Annex VI for other purposes apparent from the presentation of the product. In its opinion of 17 February 1999 (SCCNFP/0125/99) concerning the restrictions on materials listed in Annex VI of Directive 76/768/EEC on cosmetic products, the Scientific Committee on Cosmetic Products and Non-Food Products intended for Consumers (SCCNFP) stated that those substances indicated by (+) in Annex VI, when incorporated into cosmetic formulations for nonpreservative functions, should be subjected to the same restrictions in usage levels and warnings as when used for preservative effects. If a preservative marked with the symbol (+) is added for non-preservative purpose to a cosmetic product in a concentration higher than that laid down in the Annex VI, data to substantiate its safety should be submitted to the SCCNFP.
2. TERMS OF REFERENCE
The SCCP was asked to answer the following questions: 1. Do the data provided justify a concern that parabens when used up to the maximum authorized concentration in cosmetic products might pose a risk to the consumer? 2. If yes, do the data provided justify a change in the maximum concentration for their use in cosmetic products and would this concentration apply to all parabens used (methyl-, ethyl-, propyl- and butylparaben)?
3.
3.1.
OPINION
Recent Official Reports on Parabens
Parabens are the alkyl esters of p-hydroxybenzoic acid and are allowed as antimicrobial preservatives for use in food products, medicinal products and cosmetics. Recently, three important official reports have been issued on the toxicity profile and safety of the use of parabens in consumer products. They were based upon a previous report of the Scientific Committee on Food [SCF 1994]. 3.1.1. The Scientific Committee on Food (SCF), SCF 1994
a) In a document issued 25 February 1994 on p-hydroxybenzoic acid alkyl esters and their sodium salts, the SCF reported that acute toxicity of parabens was only seen at high dosages. All the parabens produced similar symptoms with rapid onset of ataxia, paralysis and central nervous system depression, resembling anaesthesia, suggesting their toxicity is related mainly to the free acid. With non-lethal dosages, recovery is prompt. b) In vitro and in vivo mutagenicity studies provided no evidence of genotoxicity for methyl, propyl and butyl paraben. A carcinogenicity study with butyl paraben in the mouse was reported to be negative, although the study appeared not being performed according to the appropriate guidelines. c) Reproduction and teratogenicity studies in the rat with ethyl paraben (up to 10% in the diet) found no adverse effects on reproductive performance. Foetal anomalies, however, were observed, though without a clear dose-response relationship. For this reason, a new oral teratogenicity study in the rat was requested. d) The absorption, metabolism and excretion of parabens had been studied in rats, rabbits, dogs and humans. The methyl, ethyl and propyl esters of p-hydroxybenzoic acid appeared to be well absorbed and the ester linkage was assumed to be readily hydrolyzed. Urinary excretion of the unchanged esters was very low, usually less than 1% of the administered dose. Butyl paraben was suspected to follow a different metabolite pathway, but studies in dogs had shown no evidence of accumulation of either parent compound or metabolites in the tissues. e) A number of special studies revealed that the parabens (in particular propyl and butyl paraben) were able to induce cell proliferation in the forestomach and glandular stomach of rats. A supplementary study in the rat on propyl paraben, given as a solution instead of a ground powder, was requested. f) Finally, the report stated several subchronic and chronic toxicity tests conducted in rats, dogs and mice, resulting in a NOAEL-value of 1000 mg/kg bw/day. Based on this value, the EC Scientific Committee on Food established a temporary Acceptable Daily Intake (ADI) of up to 10 mg/kg as the sum of methyl, ethyl and propyl paraben and their sodium salts. That ADI was temporary since the Committee asked for some additional information with regard to the reproductive effects and more data on the cell proliferation effect of the compounds in the rat forestomach. 4
3.1.2.
The European Food Safety Authority (EFSA), EFSA 2004
a) Newly available studies on the developmental toxicity of methyl paraben in rats, mice, hamsters and rabbits were evaluated and no evidence of developmental toxicity up to 300 mg/kg bw/day (rabbits) or 550 mg/kg bw/day (rodents) was observed. b) In the re-evaluation of the proliferative effects of parabens on forestomach cells in rats, it was concluded that this effect only occurred above a certain threshold exposure that is not reached in man. c) An evaluation was also undertaken of the estrogenicity of parabens in vitro. However, for methyl, ethyl and propyl paraben, such activity was not detectable in vivo using uterotrophic assays (oral and s.c.) in mice and rats. On the contrary, for butyl and isobutyl paraben (not used in food), a positive effect was seen after s.c. injection. For the major metabolite, phydroxybenzoic acid, no effect was present. d) Dietary administration of methyl and ethyl paraben to juvenile male rats had no effect on sex hormones and reproductive organs at dosage levels up to 1000 mg/kg bw/day. Thus the NOAEL for methyl and ethyl paraben is 1000 mg/kg bw/day. For propyl paraben impaired spermatogenesis, reduced testosterone levels and reduced sperm cell count numbers were observed and a LOAEL of 10 mg/kg bw/day was established. e) The EFSA report came to the conclusion that the ADI of up to 10 mg/kg remains in place for the sum of methyl and ethyl paraben and their sodium salts on the basis of a NOAEL of 1000 mg/kg. For propyl paraben on the other hand, this ADI was not considered appropriate. An ADI for the propyl ester could not be established because of the lack of a clear NOAEL. 3.1.3. The Danish Institute of Food and Veterinary Research, Anonymous 2004
In September 2004, the Danish Institute of Food and Veterinary Research issued a report entitled "Note on Parabens in Food, Cosmetics and Consumer Products". This document refers to the EFSA report for a full overview of the available toxicity data on parabens, and focuses on the problems of endocrine disrupting potential, effects on the male reproductive system, skin penetration of parabens, breast cancer & paraben-containing cosmetics, possible interactions between different xenoestrogens, and possible low doses effects. The authors repeat the conclusions of the EFSA report [EFSA 2004] and do not raise additional concerns with regard to the use of parabens in cosmetics [Anonymous 2004]. 3.1.4. The Norwegian Institute of Public Health (NIPH), Paulsen and Alexander 2003
In 2003, the NIPH published a report briefly summarizing the toxicity of the parabens and studying in particular the alleged endocrine disrupting potential of the molecules. The authors conclude that:
a) Different parabens have varying estrogenic potential in cell cultures and animal studies, but their potency is 1000 to 1,000,000 times lower than the potency of 17-estradiol or testosterone. b) In order to perform a revised and complete risk evaluation, data on reproduction in long-term animal experiments, data from multiple generation experiments and more detailed knowledge on the pharmacokinetics of parabens under use conditions, are required. c) A preliminary risk assessment followed by the calculation of the Margin of Safety (MoS) for the use of parabens as a preservative in cosmetic products, leads to worst case MoS's of 122 and 73 for adults and children, respectively. In these calculations, the following parameters were considered: NOAEL (developmental toxicity of propyl and butyl paraben) 10 mg/kg bw/day total global exposure to all cosmetic products: 17.7 g percutaneous absorption (based on human in vitro studies): 3.5% contribution of dietary parabens: not considered (very small) mean human body weight: 60 kg maximum permitted concentration of paraben mixture: 0.8% larger body surface per body mass of children versus that of adults: factor 1.7 extensive biotransformation of parabens into p-hydroxybenzoic acid (liver, skin): not accounted for
d) Neither interactions, additive or synergistic effects, nor effects at doses below the ones tested, are likely.
3.2. Toxicity Profile of the parabens used in cosmetic products Viewing the availability of the four above-mentioned official reports, the toxicity profile of the parabens will only be briefly summarised in the current report and more detailed sections will be dedicated to the specific potential problem areas.
3.2.1.
General toxicology
Based on acute, subacute and chronic toxicity studies in rats, dogs and mice, parabens have been proven to be practically non-toxic, not carcinogenic, not genotoxic nor co-carcinogenic, and not teratogenic. A NOAEL value of 1000 mg/kg bw/day was accepted for all esters. Parabens are not expected to accumulate in tissues and the ester linkage of the parabens is expected to be readily hydrolyzed [SCF 1994]. 3.2.2. Estrogenic effects of parabens
In a number of in vitro studies, such as the recombinant yeast estrogen screen, parabens have proven being able to bind the estrogen receptor, to activate genes controlled by these receptors, and to stimulate cell growth and increase the level of immune reactive estrogen receptor protein. 6
The estrogenic potency increases with increasing length and branching of the alkyl side chains (methyl < ethyl < propyl < butyl < isobutyl), but remains at all times 1000 to 1,000,000 times below the potency of 17-estradiol. p-Hydroxybenzoic acid, the common metabolite of all parabens, appeared to be inactive in the in vitro assays. The in vivo estrogenic activities of parabens have been tested in uterotrophic assays employing either immature female rodents or adult ovariectomized female rodents after oral, subcutaneous or dermal administration. Again, butyl paraben appeared being more potent than propyl, ethyl and methyl paraben, and again the values remained several magnitudes of order below the potency of 17-estradiol. Conflicting results have been reported for p-hydroxybenzoic acid tested in vivo. One study claims that it has no estrogenic effect; another study gives potency values 1000-fold below the 17-estradiol level [EFSA 2004, Anonymous 2004, Paulsen and Alexander 2003]. 3.2.3. Effects of parabens on the male reproductive system
Methyl, ethyl, propyl and butyl paraben have been examined for effects on the reproductive organs in the male offspring of rats and mice. Male neonatal Wistar rats s.c. injected with butyl paraben at 2 mg/kg bw/day on postnatal days 2 to 18 showed no detectable effects on any reproductive parameter [Fisher et al. 1999]. This study, however, demonstrated only very minor effects for compounds such as genistein, bisphenol A and octylphenol administered at high dosages. On the contrary, 10 mg/kg bw/day administered to post-weaning male Wistar rats for eight weeks through their diet caused a decrease of the cauda epididymal sperm reserve, a decrease in sperm count, in daily sperm production and in serum testosterone [Oishi 2001]. In another study, pregnant Sprague Dawley rats were s.c. injected with daily dosages of 100 or 200 mg butyl paraben/kg bw from gestational day 6 to postnatal day 20, and the offspring were examined. Both tested dosages showed clear effects, amongst which a decrease in sperm count and sperm motile activity in the epididymus [Kang et al. 2002]. Administered to ICR (Cjr:CD-1) mice in the diet for 10 weeks at dosage levels of 14.4, 146 and 1504 mg/kg bw/day, butyl paraben showed some clear effects at the two highest dosage levels, including increased epididymal weights, despite of a decrease in testis spermatid count and in serum testosterone levels. The authors were unable to explain this discrepancy [Oishi 2002a]. In 2002, Darbre et al. published a study on the estrogenic activity of isobutyl paraben in vitro and in vivo (subcutaneous administration). The authors conclude that the studies clearly show that isobutyl paraben is more potent, but the doses used in the in vivo test were not higher than the ones tested for all other parabens (1.2 and 12 mg isobutyl paraben/mouse, equivalent to approximately 24 and 240 mg/kg bw). [Darbre et al. 2002]. As far as propyl paraben is concerned, a four-week administration via the diet (0, 10, 100, 1000 mg/kg bw/day) to the Wistar rat showed similar effects as caused by butyl paraben, though at a dosage of 100 mg/kg bw/day. The propyl ester caused only minor effects at 10 mg/kg bw/day. No dose-response relationship was observed [Oishi 2002b].
Recently, methyl and ethyl paraben have been tested for effects on secretion of sex hormones and the Wistar rat male reproductive system. Dosages of 103 and 1030 mg/kg bw/day failed to induce adverse effects [Oishi 2004]. Taking together the above-mentioned studies, it is clear that butyl paraben shows the highest potency with regard to effects to the male reproductive system. This is in accordance with the results of the estrogenicity tests. It was also concluded that, in order to define an exact NOAEL for propyl paraben, additional studies were necessary [EFSA 2004, Anonymous 2004]. Very recently, a detailed developmental toxicity evaluation of butyl paraben given by oral gavage to Sprague-Dawley rats became available [Daston 2004]. Dosage levels of 0, 10, 100 and 1000 mg/kg bw/day were administered on gestation days 6-19 (sperm positive day being gestation day 0). Foetuses were evaluated on gestation day 20. The highest dosage level caused decreases in maternal weight gain (significant during gestation day 18-20 interval). Maternal food consumption was, however, also decreased in that group for the gestation days 6-20 interval. No differences from the control group could be observed in any of the developmental parameters including embryo/foetal viability, foetal weight, malformations or variations. The maternal NOAEL for butyl paraben was established on 100 mg/kg bw/day. It was further concluded that butyl paraben does not have the potential to cause developmental toxicity in the Sprague-Dawley rat at oral dosages up to 1000 mg/kg bw/day [Daston 2004]. 3.2.4. Breast cancer and the use of paraben-containing cosmetics
The suggested link between the use of (paraben-containing) underarm cosmetics and breast cancer has been discussed and refuted in a separate SCCP opinion on Parabens, underarm cosmetics and breast cancer [SCCP/0874/05]. This issue will therefore not be reconsidered in the present opinion.
4.
CONCLUSION
Is the concern justified that parabens, when used up to the maximum authorized concentration in cosmetic products, might pose a risk to the consumer?
Methyl and ethyl paraben Previous toxicological data have led the EU Scientific Committee on Food to establish an Acceptable Daily Intake (ADI) level of 10 mg/kg bw/day as the sum of methyl, ethyl and propyl p-hydroxybenzoic acid esters and their sodium salts [SCF 1994]. With the most recent findings on the alleged estrogenic effects of the parabens and more importantly with the newly discovered effects on the male reproductive system, as described under point 3.3 of this opinion, the European Food Safety Authority reviewed the safe use of parabens in food. The Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food came to the conclusion that the ADI remained unchanged for methyl, ethyl paraben and their sodium salts, but that for propyl paraben no ADI could be established, by lack of a clear NOAEL value.
Therefore, it is the opinion of the SCCP that methyl and ethyl paraben can be safely used up to the maximum authorized concentration as actually established (0.4%). Propyl, butyl and isobutyl paraben Propyl paraben The developmental rat study provided for propyl paraben failed to indicate a clear NOAEL value, but it suggested that the potency of propyl paraben is clearly lower than the potency of butyl paraben [Oishi 2002b]. For the latter, a NOAEL value of 2 mg/kg bw/day was proposed. This value was obtained in a study where the compound was orally administered to male Wistar rats for 17 days and the investigated reproductive parameters included testicular weight, aquaporin-1 immunoexpression, rete testis distention and efferent duct epithelial cell height [Fisher 1999]. The LOAEL-value for propyl paraben in Wistar rats was shown to be 10 mg/kg bw/day [Oishi 2002a]. The major adverse effects of concern caused by propyl paraben involve the male reproductive system. It must not be forgotten, however, that the majority of cosmetic products will be used by females. Especially the cumulative cosmetic exposure value of 17.79 g/day is a clear overestimation for the normal male population.
Butyl and isobutyl paraben For butyl paraben a NOAEL value in Cjr:CD-1 mice (oral study) of 2 mg/kg bw/day has been proposed [Oishi 2002b]. Very recently, a developmental study on butyl paraben became available. In that study, it was shown that the maternal NOAEL of butyl paraben was 100 mg/kg bw/day and that the compound did not have the potential to cause developmental toxicity in the SpragueDawley rat. It is known that potent estrogens interfere with the development of the reproductive system, placental function, embryonic growth, embryo viability and maintenance of pregnancy [Daston et al. 1997]. Although indirectly, these parameters could be responsive indicators of estrogenicity. This leads to the suggestion that butyl paraben did not have a strong estrogenic potential during the developmental study.
It is the opinion of the SCCP that the available data do not enable a decisive response to the question of whether propyl, butyl and isobutyl paraben can be safely used in cosmetic products at individual concentrations up to 0.4%. Therefore industry is requested to provide the complete developmental toxicity dossier of these three esters of p-hydroxybenzoic acid. The reason for this request is that the current opinion is based upon extended literature data and there is a significant possibility that additional in vivo data have been generated within industry without having been submitted to the SCCP.
If yes, do the available data justify a change in the maximum concentration for their use in cosmetic products and would this concentration apply to all parabens used (methyl-, ethyl-, propyl- and butylparaben)?
Methyl and ethyl paraben For the methyl and ethyl p-hydroxybenzoic acid esters, the maximum authorized concentrations remain unchanged. Propyl, isopropyl, butyl and isobutyl paraben As the present discussion is based solely upon data in the literature, it is the SCCP's opinion that more information is needed in order to formulate a final statement on the maximum concentration of propyl, isopropyl, butyl and isobutyl paraben allowed in cosmetic products. More specifically, the following data are requested before end of March 2005: full descriptions of available in vitro percutaneous absorption studies; a complete dossier with regard to the reproductive and developmental toxicity of propyl, isopropyl, butyl and isobutyl paraben, with special focus on the male reproductive system.
5.
MINORITY OPINION
Not applicable
6.
REFERENCES
Anonymous, Note on Parabens in Food, Cosmetics and Consumer Products. Danish Institute of Food and Veterinary Research, Department of Toxicology and Risk Assessment, September 2004. Darbre P.D., Byford J.R., Shaw L.E., Horton R.A., Pope G.S., Sauer M.J., Oestrogenic activity of isobutylparaben in vitro and in vivo. J Appl Toxicol. 22(4), 219-26 (2002). Daston G.P., Gooch J.W., Breslin W.J., Shuey D.L., Nikiforov A.I., Fico T.A., Gorsuch J.W. Environmental estrogens and reproductive health: a discussion of the human and environmental data. Reprod Toxicol. 11(4), 465-481 (1997). Daston G.P. Developmental toxicity evaluation of butylparaben in Sprague-Dawley rats. Birth Defects Res Part B Dev Reprod Toxicol. 71(4), 296-302 (2004). EFSA, Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food on a Request from the Commission related to para hydroxybenzoates (E214-219), Question number EFAS-Q-2004-063. adopted on 13 July 2004 The EFSA Journal 83, 1-26 (2004).
10
Fisher J.S., Turner K.J., Brown D., Sharpe R.M. Effect of neonatal exposure to estrogenic compounds on development of the excurrent ducts of the rat testis through puberty to adulthood Environ Health Perspect. 107(5), 397-405 (1999). Kang KS, Che JH, Ryu DY, Kim TW, Li GX, Lee YS. Decreased sperm number and motile activity on the F1 offspring maternally exposed to butyl p-hydroxybenzoic acid (butyl paraben). J Vet Med Sci. 64(3), 227-235 (2002). Oishi S. Effects of butylparaben on the male reproductive system in rats. Toxicol Ind Health. 17(1), 31-9 (2001). Oishi S. Effects of propyl paraben on the male reproductive system. Food Chem Toxicol. 40(12), 1807-1813 (2002a). Oishi S. Effects of butyl paraben on the male reproductive system in mice. Arch Toxicol. 76(7), 423-429 (2002b). Oishi S. Lack of spermatotoxic effects of methyl and ethyl esters of p-hydroxybenzoic acid in rats. Food Chem Toxicol. 42(11), 1845-1849 (2004). Paulsen J.E. and Alexander J. Evaluation of parabens in cosmetic products. Norwegian Institute of Public Health (2003). SCCP/0874/05 - Opinion of the Scientific Committee on Consumer Products on Parabens, Underarm Cosmetics and Breast Cancer, adopted by written procedure on 28 January 2005 SCF. Opinion on p-hydroxybenzoic acid alkyl esters and their sodium salts expressed on 25 February 1994. European Commission, Reports of the Scientific Committee for Food (Thirtyfifth series), http://europa.eu.int/comm/food/fs/sc/scf/reports/scf_reports_35.pdf (consulted Nov 2004), p.9-12.
7.
ACKNOWLEDGEMENTS
Members of the working group are acknowledged for their valuable contribution to this opinion. The members of the working group are: Dr. C. Chambers Prof. R. Dubakiene Dr. R. Grimalt Dr. B. Jazwiec-Kanyion Prof. V. Kapoulas Prof. J. Krutmann Prof. C. Lidn Prof. J.-P. Marty Dr. S.C. Rastogi Prof. J. Revuz Prof. V. Rogiers Prof. T. Sanner Prof. G. Speit Dr. I.R. White
(Rapporteur) (Chairman)
11
SCCP/0891/05
EUROPEAN COMMISSION
HEALTH & CONSUMER PROTECTION DIRECTORATE-GENERAL Directorate C - Public Health and Risk Assessment C7 - Risk assessment
SCIENTIFIC COMMITTEE ON CONSUMER PRODUCTS SCCP
OPINION ON Benzoic Acid and Sodium Benzoate
Adopted by the SCCP during the 4th plenary of 21 June 2005
SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate
TABLE OF CONTENTS 1. BACKGROUND 3
2.
OPINION
3.
CONCLUSION
25
4.
MINORITY OPINION
25
5.
REFERENCES
25
6.
ACKNOWLEDGEMENTS
............................................................................
29
1.
BACKGROUND
1.1. Background The Scientific Committee on Cosmetic Products and Non-Food Products intended for Consumers (SCCNFP) was requested to review the data submitted to support the safety of benzoic acid, its salts and esters (COLIPA1 No. P 2), when used at concentrations other than those laid down in Annex VI to Directive 76/768/EEC as preservatives, for other specific nonpreservative purposes apparent from the presentation of the products. The SCCNFP adopted an opinion on 4 June 2002 on Benzoic acid and Sodium benzoate (SCCNFP/0532/01, final). In its opinion the SCCNFP stated, that the SCCNFP can only assess the safety of substances for which appropriate data has been submitted for evaluation. Safety assessment is specific and not generic. Only toxicological data for benzoic acid and its salt sodium benzoate have been made available for review. Therefore, there is no review of other salts of benzoic acid or any of its esters. These will require separate evaluation when the necessary data have been made available. It was stated furthermore, that the SCCNFP does not find the submission appropriate for a safety evaluation of benzoic acid and sodium benzoate for the applied other uses in cosmetic products. Recently, the European Commission received Submission II on Benzoic acid, its salt and esters.
2. TERMS OF REFERENCE
1. On the basis of provided data the SCCP is asked to assess the risk to consumers when Benzoic acid, its salts and esters are used for non-preservative purposes in cosmetic rinse-off products at a maximum concentration of 2.5 % and in cosmetic oral-care products at a maximum concentration of 1.7 %, and in leave-on products up to 0.5%. 2. Does the SCCP recommend any further restrictions with regard to the use of Benzoic acid, its salts and esters safe when used for non-preservative purposes in cosmetic products?
COLIPA European Cosmetics Toiletry and Perfumery Association
3.
OPINION
3.1. Chemical and Physical Specifications 3.1.1. 3.1.1.1. Chemical identity Primary name and/or INCI name
Benzoic acid (INCI name) Sodium benzoate (INCI name) 3.1.1.2. Chemical names Benzene carboxylic acid; benzene formic acid; carboxybenzene; benzene carboxylic acid; phenylcarboxyl acid; phenylformic acid, E210 E211
Benzoic acid Sodium benzoate 3.1.1.3. / 3.1.1.4.
Trade names and abbreviations
CAS / EINECS / ELINECS number CAS 65-85-0 532-32-1 EINECS 200-618-2 208-534-8
Benzoic acid : Sodium benzoate : 3.1.1.5.
Structural formula Benzoic acid Sodium benzoate
3.1.1.6.
Empirical formula C7H6O2 C7H5O2Na
Benzoic acid : Sodium benzoate : 3.1.2.
Physical form solid solid
Benzoic acid : Sodium benzoate :
3.1.3.
Molecular weight 122.13 144.11
Benzoic acid : Sodium benzoate : 3.1.4. No data 3.1.5. No data 3.1.6. Solubility
Purity, composition and substance codes
Impurities / accompanying contaminants
2.91 g/l in water at 20oC 556 g/l in water at 20oC, hygroscopic
Partition coefficient (Log Pow) 1.88 -2.269
Additional physical and chemical specifications
Benzoic acid Organoleptic properties Melting point Boiling point Flash point Vapour pressure Density Viscosity pKa Refractive index Stability Sodium benzoate Organoleptic properties Melting point Boiling point Flash point Vapour pressure Density Viscosity pKa Refractive index Stability
: : : : : : : : : : : : : : : : : : : :
/ 122 C 249.2C / 0.0011hPa 1.321 g/cm3 at 20C / -2.269 / /
>300.0 C 464.9C / 0.0011hPa / -2.269 / / 5
3.2. Function and uses Benzoic acid is a natural ingredient occurring in many foodstuffs and in plant extracts. Benzoic acid, its salts and esters are used as preservatives in cosmetic products, with a maximum concentration of 0.5 %, (calculated as acid), as regulated by the EU Cosmetics directives 76/768/EEC. This request is for use for non-preservative purposes in cosmetic rinse-off products, at a maximum concentration of 2.5 %, and in cosmetic oral-care products, at a maximum concentration of 1.7 %, and in leave-on products, up to 0.5%. However these purposes are not specified. Other uses for benzoic acid and its salts include regulated use as food preservatives, most suitable for foods, fruit juices, and soft drinks in an acidic pH range. In the EU, there are regulations controlling the maximum levels of benzoic acid and its salts for use in foodstuffs ready for consumption and the specific purity criteria of food additives. The levels are expressed as the free acid. Non alcoholic drinks Alcoholic drinks Jams & jellies Aspic 150 mg/l 200 mg/l 500 mg/kg 500 mg/kg Ref.: AR 1, AR 2 In the United States, benzoic acid and sodium benzoate are on the FDA list of substances that are generally recognized as safe (GRAS). Both may be used as antimicrobial agents, flavouring agents and as adjuvants with a current maximum level of 0.1% in food. The FDA has not determined whether significantly different conditions of use would be GRAS. The FDA has sought fully up-to-date toxicology information. Ref.: AR 3 Benzoic acid is used in oral medicines up to 0.15%, in parenteral medicines up to 0.17% and in topical drugs up to 0.2%. Benzoic acid is used as an active ingredient in anti-fungal cream with salicylic acid (3.0%) up to 6%. Sodium Benzoate, expressed as benzoic acid, is permitted in oral medicines up to 0.5%, in parenterally administered up to 0.5%. Ref.: AR 4, AR 5 Benzoic acid is also an intermediate in the synthesis of phenol and caprolactam. Other end products include sodium and other benzoates, benzoyl chloride, and diethylene and dipropylene glycol dibenzoate plasticizers. Sodium benzoate is primarily a preservative and corrosion inhibitor (e.g., in technical systems as an additive to automotive engine antifreeze coolants).
3.3. 3.3.1. 3.3.1.1.
Toxicological Evaluation Acute toxicity Acute oral toxicity
Acute oral toxicity information is based on summary information, no dossiers were provided. The indication is that the substances can be considered to possess low acute oral toxicity. The calculated LD50 values taken from the available experiments on the acute oral toxicity of Benzoic Acid and Sodium Benzoate are listed in the following tables: Benzoic Acid Species LD50 [mg/kg] Rats Mice 1700 2530 1940 2370 Reference 4 5 6 Reference 7 8 9 8 10
Sodium Benzoate Species LD50 [mg/kg] Rats 1714 2100 fasting 3140 3450 not fasted 4070
3.3.1.2.
Acute dermal toxicity
Benzoic acid Rabbit
LD50 > 5 000 mg/kg LD50 > 10 000 mg/kg Ref.: 14, citation only
3.3.1.3.
Acute inhalation toxicity
No data submitted with Submission II (2004) Benzoic acid Rats LC50 > 0.026 mg/l/h Ref.: 14, citation only
3.3.2 3.3.2.1.
Irritation and corrosivity Skin irritation
Animal studies Benzoic Acid Guideline : Species/strain Group size Test substance Batch Purity GLP : : : : : :
OECD 404 (1981), EEC test method B.4, Annex V of EEC Directive 84/449/EEC (September 1984) New Zealand albino rabbit 3 females 0.5 g of benzoic acid moistened with 0.25 ml Milli-RO water / 99.5% in compliance
A paste, (0.5 g benzoic acid and 0.25 ml water), was applied evenly to 6 cm2 Metalline on a permeable tape (Micropore). This was applied to the right flank of the rabbit. A control patch without the test substance was applied to the left flank. These were left in place for 4 hours. The test site was cleaned first with a dry tissue and then by swabbed with a dampened tissue. The skin was examined for erythema, eschar formation and oedema at 1, 24, 48 and 72 hours after removal of the patches. Results Two animals showed slight erythema initially. 1 of these also showed slight oedema up to 24 h. This was resolved by 48 h. There was no indication of a systemic effect. The results of this study indicate that the test item, benzoic acid, was minimally irritating (modified primary irritation index (PII) of 0.5) when applied to the intact rabbit skin under semiocclusive patch conditions. The test substance does not need to be labelled as a skin irritant. Ref.: 12 In submission II, three additional animal tests confirmed the low irritation potential of Benzoic Acid were summarized in a table. These were also provided in Submission I, but are only citations or summary information. Species rabbits rabbits rabbits Exposure neat Benzoic acid/occluded / 24 h 500 mg dry powder/ 24 and 72h 500 mg dry powder/ semiocclusive / 24 h Skin irritation mild PII = 1.66/8.00 not irritating Reference 13 14 15
Sodium Benzoate Guideline : Species/strain : Group size : Test substance : Batch : Purity :
OECD 404 (1981) New Zealand albino rabbit 3 females 0.5 g sodium benzoate moistened with 0.25 ml Milli-RO water / > 99.5% 8
GLP
in compliance
Approximately 24 hours prior to the treatment, the dorsal fur was shaved. A paste, (0.5 g sodium benzoate and 0.25 ml water), was applied evenly to 6 cm Metalline on a permeable tape (Micropore). The 6 cm patch was removed four hours after semi-occlusive contact. The skin reactions were assessed approx. 1 hour, 24, 48 and 72 hours after termination of the exposure. Under the conditions of the study, sodium benzoate was neither corrosive nor irritating (PII 0) when applied to the intact rabbit skin under semi-occlusive patch conditions for four hours. The test substance does not need to be labelled as a skin irritant. The animals did not show any symptoms of systemic intoxication. Ref.: 16 Application of 500 mg sodium benzoate as a dry powder to rabbit for 24 h; responses were scored at end of treatment and after 48 h. It was considered not irritating. There are no details of study. Ref.: 17 Human Studies Benzoic Acid The results, presented only in scientific papers, are from studies both on volunteers and patients from dermatological clinics. 2% benzoic acid in petrolatum over 46h did not irritate intact skin of healthy volunteers. 24h application of 30% benzoic acid in ethanol was found to be the lowest irritating concentration. Ref. : Gad et al, 1986, Kligman, 1977, Frosch & Kligman, 1976 cited in 13 Chamber test (72 h/occlusive): 0.1 ml of 7.5 % and 15 % benzoic acid in ethanol on scarified skin, 30 % benzoic acid in ethanol on normal skin (6 volunteers). Results Scarified skin 15.0 % in ethanol Normal skin : 7.5 % in ethanol, moderate irritant : marked irritant with erosions : 30 % in ethanol, lowest irritant concentration Ref.: 19, 21 Chamber test (20 min/occlusive), open test (30 min): 15 l of 5 % benzoic acid in petrolatum, 15 atopic and 16 non-atopic patients. The atopics showed redness in both the chamber test, (73 %) and the open test, (80 %). Non-atopics showed 80% redness in both the chamber test and in the open test. There was no statistical difference between atopics and non-atopics. Ref.: 20 8 out of 627 patients (1.3%) from dermatological clinics showed positive reactions to 5 % benzoic acid, in petrolatum under an occlusive dressing for 24 or 48 h. At this concentration, the authors suggest that these results could be interpreted as marginally irritating, rather than allergic. Ref.: 18 9
Non-immunologic contact urticaria Benzoic acid (5.0 % in petrolatum) was tested in an open test on 29 atopic and 74 non-atopic persons. Results Contact urticarial reactions to benzoic acid were seen in 27/29 (93 %) of the atopics and in 64/74 (87 %) of the non-atopics. In the chamber test, 20 min occlusion (recorded 10 min later) 0.1 % benzoic acid in petrolatum and 0.05 % benzoic acid in water elicited reactions. When water was the vehicle, the reactions were oedematous. Ref.: AR6 Urticaria occurred in 1/10 and 5/12 healthy volunteers with 0.1 and 1.0% benzoic acid, following 20 min covered contact. It was not clear if this was an irritant or immune response. Ref.: Clemmensen &Hjorth, 1982 cited in 13 Non-immune immediate contact reactions (NIICR), erythema and oedema, have been produced in 78/80 women tested with 2% benzoic acid petrolatum but there was no correlation between the susceptibility to NIICR and age, atopic status or tanning ability. In another study, it was demonstrated that benzoic acid induced non-immune immediate contact reactions in the majority of 200 volunteers with no specific skin condition. Approximately 10% of the volunteers appeared particularly sensitive, reacting fairly strongly. The response, erythema or oedema, was specific to an individual with no significant correlation with age or sex on the degree of NIICR. Ref.: 54 The Concise International Chemical Assessment Document (CICAD) No. 26 conclusion on benzoic acid and sodium benzoate was: However, both substances are known to cause nonimmunologic immediate contact reactions. This effect is scarce in healthy subjects, while in patients with frequent urticaria or asthma, symptoms or exacerbation of the symptoms were observed. Ref.: 55 3.3.2.2. Mucous membrane irritation : : : : : : : : EEC test method B.5, Annex V of EEC Directive 84/449/EEC New Zealand albino rabbit 3 females Benzoic acid > 99.5% / 77 mg as a fine powder in compliance
Guideline Species/strain Group size Test substance Purity Batch no Dose GLP
The test substance was instilled in a single application. The product was poured into the right conjunctival sac. After application, the lids of the treated eye were held closed for approximately two seconds. The untreated left eye was used as a control. The degree of eye irritation was 10
evaluated at immediately after dosing, 1, 24, 48 and 72 hours and 7, 14 and 21 days after treatment. After 60 min, Animal 1 showed no reaction to light, with translucent corneal opacity and iridial injection. The other 2 also had slight corneal opacity. All 3 had moderate chemosis and slight conjunctival redness. The corneal opacity noted in the first animal increased to nacreous areas. This persisted for 72 h. The translucent areas of opacity persisted up to Day 21. In Animal 2, the slight corneal opacity also persisted up to Day 21, but was resolved in Animal 3 by Day 7. By Day 14, in Animal 1, the iridial injection was resolved but no reaction to light. Animal 2 showed iridial injection on Day 2. The slight conjunctival redness in all animals increased to severe with a white/grey discolouration. It persisted in Animals 1 and 2 up to Day 21 and in Animal 3 to Day 7. The chemosis decreased slowly. In Animals 1 and 2, it was not completely resolved by Day 21 but it was resolved in Animal 3 by Day 14. The animals did not show any symptoms of systemic intoxication. The estimated Draize score of 35 (60 min) is classed as severely irritating according to Kay and Calandra. Under the EU criteria, it should be labelled as an eye irritant. Comment This experiment was conducted in 1988, but the information was not provided in Submission 1. Ref.: 22 Guideline Species/strain Group size Test substance Batch no Dose GLP : : : : : : : OECD 405 New Zealand albino rabbit 3 males Benzoic acid DAB 8 / / /
The test substance was instilled in a single application. The product was poured into the right conjunctival sac. After application, the lids of the treated eye were held closed for approximately two seconds. The untreated left eye was used as a control. The degree of eye irritation was evaluated at immediately after dosing, 1, 24, 48 and 72 hours and 7, 14 and 21 days after treatment. The authors considered benzoic acid was considered as a mild irritant, but the data provided is inadequate. Ref.: 23, cited in BUA (14) Instillation of 50 mg benzoic acid into the conjunctival sac of 2 rabbits. Results Moderate irritation. This is just a summary. Ref.: 15, cited in BUA (14) Additional information that was not mentioned but quoted in the BUA reference, was a citation of a single application of 100 mg dry powder to the rabbit eye. The irritation score was 65.0/110. It was scored at 24, 48, and 72 h. 11
Ref.: cited in BUA (14) Comment The data provided is inadequate. Sodium benzoate Guideline Species/strain Group size Test substance Purity Batch no Dose GLP : : : : : : : : OECD 405 New Zealand albino rabbit 3 females Sodium Benzoate 99.5% / 60 mg ground as a fine powder in compliance
The test substance was instilled in a single application. The product was poured into the right conjunctival sac. After application, the lids of the treated eye were held closed for approximately two seconds. The untreated left eye was used as a control. The degree of eye irritation was evaluated at immediately after dosing, 1, 24, 48 and 72 hours and 7, 14 and 21 days after treatment. Under the conditions of this study, sodium benzoate produced irritation of the conjunctiva that was reversed within 14 days. There was no effect on the cornea or iris. It was considered mildly irritating (Kay and Calendra score 9.3) and in the EC classification. Ref.: 24 Application of 50 mg sodium benzoate/rabbit for 24 h; responses were scored at 24 h, 48 h and 72 h; post-exposure observation time: 7 d. Results: not irritating. Ref.: 17 3.3.3. Skin sensitisation
Benzoic acid Animal tests The results of two in vivo guinea pig assays, a Magnusson-Kligman test and a Buehler test were reported. These were in-house tests with no further details. Benzoic Acid did not induce sensitization in either test and was thus considered to have low skin sensitization potential. Ref.: 25
12
Human volunteer studies Benzoic Acid at 2 % and 5 % in petrolatum did not induce sensitization in two maximization tests. 25 human volunteers were given five 48 h patch tests (over a 10 d period) with 2 % benzoic acid in petrolatum. None gave positive reactions when challenged 10-14 d after the induction phase with a final 48 h closed patch test with 2 % benzoic acid in petrolatum. This information is as a summary only. Ref.: 26 and cited in BUA (14) 10 persons allergic to benzoyl peroxide were tested by a 48 h patch test with 5 % benzoic acid in a hydrophilic petrolatum. No reactions at 48, 72 and 96 h. Ref.: 27 In a cosmetic intolerance assay, 5202 patients with suspected allergic contact dermatitis were patch tested (537 of the patients had a history of intolerance or allergy). Patch test conditions were not specified, but allergic reactions was noted in 34 patients (0.7% incidence) to benzoic acid. Ref.: 28 The OECD SIDS report found both benzoic acid and sodium benzoate were non-sensitizing in animal test but showed a very low incidence in humans (patients) tested by the patch test. This report included 2 additional human patch test references that were not in the submissions. The results showed that benzoic acid was an occasional or positive sensitizer (Rademaker & Forsyth, 1989; Forsbeck & Skog, 1977) Ref.: 56 Sodium benzoate Human There were 2 additional human patch test references that were not included with any of the submissions. The first was a large cohort of 2045 patients, 5 gave positive results. These gave occasional positive results (Brasch, J. et al., 1993). In the second test, patch tests gave positive nonimmunologic contact urticaria (Nethercott, J.R., 1984). Ref.: 56 3.3.4.
14
Dermal / percutaneous absorption
C-labelled benzoic acid (4 - 40 g/cm2 dissolved in acetone) was applied to excised human skin in a static diffusion chamber. Samples of penetrated amounts were measured in 1- 2 hr interval over the first 24 hrs and 3-6 hrs interval over the remaining days. No occlusion or washing were applied and the investigation was determined at least in duplicate. A median of 45% of the applied benzoic acid was found in the receptor phase 48 hrs after application. Ref.: 40
Percutaneous absorption of benzoic acid was studied in the Mexican hairless dog and in man. C-labelled benzoic acid was injected subcutaneously and applied dermally to the neck skin of dogs. Human data were obtained from earlier investigations. Excretion of benzoic acid in man
14
13
was rapid, almost complete by day 3. In the dog, excretion was less extensive and greatly prolonged. This was accounted for by the persistence of benzoic acid in the skin. Maximum absorption rate in man was 3.0 %/h, total absorption was 42.6 % of applied dose. This in vivo result is comparable with in vitro test results obtained. The total penetration of radio-labelled benzoic acid was found to be approximately 43 % in a 5-day period. In this human study, 6 test subjects received a dose of 4 g/cm Benzoic Acid dissolved in acetone. They were allowed to wash their skin 24 hours after application of Benzoic Acid. It should be noted that the exposure of the in vitro and in vivo studies were extremely long (2 days and 5 days, respectively). Ref.: 41 3.3.5. 3.3.5.1. Repeated dose toxicity Repeated Dose (28 days) oral / dermal / inhalation toxicity
Oral Benzoic Acid and sodium benzoate show a low toxic potential in rodents in repeat dose studies. Benzoic Acid Guideline Species/strain Group size Test substance Purity Batch no Dose Vehicle GLP : : : : : : : : : Directive 84/449/EEC, B.1 "Acute toxicity (oral) 50 Spartan rat 5 male/ female technical grade benzoic acid / / 500, 1250, 1984, 3150, and 5000 mg/kg. corn oil /
The test compound was suspended in corn oil and administered orally. Volumes of 10 ml/kg bw were administered at all dosage levels. All surviving rats, males and females, exhibited normal body weight gains during the 14 day observation period. The acute oral LD50 of benzoic acid in male albino rats was calculated to be 2742 mg/kg (2279-3299 mg/kg). The acute oral LD50 of benzoic acid in female albino rats was calculated to be 2360 mg/kg (2042-2726 mg/kg). A combined acute oral LD50 for benzoic acid in male and female albino rats was calculated to be 2565 mg/kg (2292-2870 mg/kg). Ref : IUCLID, Unpublished study (IRDC#163-282). Acute Toxicity Studies in Rats and Rabbits. (1974) Comment: This study is available on IUCLID but was not submitted. In rats, 648 mg/kg bw/d in feed for 28 days, has no effects. Ref.: 14
14
Sodium benzoate 0.5, 1, 2, 4, and 8 % sodium benzoate in drinking water were administered for 35 days to groups of four female and four male Swiss albino mice. In the 8 % dose level (approx. 24 g/kg bw/d) all mice died within 3 weeks. In the 4 % dose level (approx. 12 g/kg bw/d) 3 male and 3 female mice died within the 35-day observation period. The bodyweight of the surviving mice was substantially reduced. The 2 % dose level was chosen for a chronic toxicity (carcinogenicity) study. Ref.: 42 In another study the body weight was slightly decreased at 2200 mg/kg bw/d. Groups of 6 male and 6 female Sherman rats were given 2 % (approx. 2.0 to 2.4 g/kg bw) or 5 % (5.7 g/kg bw for females and 7.8 g/kg bw for males) sodium benzoate in the diet for 28 days. In the 5 % dose group, all female rats died by day 11 and males by day 13. In the 2 % dose group a slight significant body weight depression was observed in male rats. Ref.: 43 Dose levels from 16 to 1090 mg sodium benzoate/kg bw were given to groups of 10 rats (5 male and 5 female) for 30 days with the diet. No dose related adverse effects were observed. Ref.: 10 Inhalation Guideline Species/strain Group size Test substance Batch no Purity Dose Exposure GLP
: : : : : : : : :
similar to OECD guideline 403 Rat, Sprague-Dawley (Charles River CD). 10 males + 10 females per dose benzoic acid 59230350 / 0, 0.025, 0.25 and 1.2 mg/l dust aerosol exposure, (diameter 4.7 ) 6 h/day for 5 days/week in compliance
At 1.2 mg/l two animals (out of 20) died, exhibiting irritation of their upper respiratory tract. These animals did not gain as much weight as controls, exhibited decreased organ weights and multifocal to generalized pulmonary fibrosis and inflammatory cell infiltrate. Exposure to 0.25 mg/l also resulted in an irritation of the upper respiratory tract. All treated animals survived and their body weight gain did not differ from controls. Neither significant effects on organ weights, nor significant effects on hematologic or biochemical parameters in the 0.25, 0.025 or 0 mg/l treatment groups were found. Exposure to the test material at all levels resulted in an increase in the frequency of pulmonary fibrosis and inflammatory cell infiltrate. No compound related gross lesions were seen in any of the rats from the test groups that were terminally sacrificed or died during the study. Compound-related microscopic lesions, consisting of an increase in the intensity and extent of inflammatory cell infiltrate and an increase in the incidence, intensity and extent of interstitial fibrosis in lungs of rats from all test groups, were observed. Ref.: 44
15
3.3.5.2.
Sub-chronic (90 days) oral / dermal / inhalation toxicity
Benzoic acid 50 male and 50 female mice received 80 mg benzoic acid/kg bw/d by gavage for 90 days. 14 surviving mice were subjected to a restricted dietary intake (90 % restriction) for up to 5 days. 10 mice were tested on their tolerance to CCl4 (test on detoxifying capacity of liver) by giving 0.1 ml CCl4 in an single dose by oral intubation at the end of the test. Reduced body weight gain was observed and the mortality was higher in connection with reduced tolerance to CCl4 or food restriction than in the control group. The authors did not mention whether this finding was statistically significant. The relevance of the study will be compared to other long-term and carcinogenicity studies. Data are not sufficient to justify conclusion. Ref.: 45 Sodium benzoate Groups of 4-5 male and 4-5 female rats received 0, 1, 2, 4, and 8 % sodium benzoate equivalent to 640, 1320, 2620, and 6290 mg/kg bw/d in the diet for 90 days. 4/8 animals died (average 13 days to death) in the 8 % dose level group, the average weight gain of the surviving rats was reduced and the relative liver and kidney weight was significantly increased with histopathological changes in liver and kidney (7/16). Data are insufficient to justify a NOAEL of 4 % in the diet (2.6 g/kg bw/d). Ref.: 8 3.3.5.3. Chronic (> 12 months) toxicity
Benzoic acid 25 male and 25 female mice were given 40 mg/kg bw/d for 17 months. Benzoic acid was fed in a paste prior to the main feed. The weight of liver, kidney and testes relative to body weight in mice sacrificed at the end of the test period were lower in the group receiving sorbic acid (40 mg/kg bw/d) than in the group treated with benzoic acid. No further details were given. Ref.: 45 10 male and 10 female rats received 40 mg benzoic acid/kg bw/d for 18 months. Benzoic acid was fed in a paste prior to the main feed. The rats developed some tolerance to a lethal dose of benzoic acid given terminally (25 % mortality after 4000 mg/kg bw compared to 100 % mortality on the control group given one dose of 3600 mg/kg bw). No further details were given. Ref.: 45 3.3.6. Mutagenicity / Genotoxicity
Bacterial Reverse Mutation Test Benzoic acid Benzoic acid (up to 10 mg/plate) was tested in the Salmonella/microsome test using S. typhimurium TA 92, TA 94, TA 98, TA 100, TA 1535 and TA 1537. No significant increases in the numbers of revertant colonies were detected in any S. typhimurium strains at the maximum dose. 16
Ref.: 29 Benzoic acid (up to 10 mg/plate) was tested in the Salmonella/microsome test using S. typhimurium TA 97, TA 98, TA 100, TA 1535, and TA 1537 with and without metabolic activation. Benzoic acid was non-mutagenic in this test. Ref.: 30 Benzoic acid was tested in the Salmonella/microsome test using S. typhimurium TA 98, TA 100, TA 1535, and TA 1537 with and without metabolic activation. Benzoic acid was nonmutagenic in this test (< 0.0099 revertants/nmol). Ref.: 31 Sodium benzoate Sodium benzoate (up to 3.0 mg/plate) was tested in the Salmonella/microsome test using S. typhimurium TA 92, TA 94, TA 98, TA 100, TA 1535 and TA 1537. No significant increases in the numbers of revertant colonies were detected in any S. typhimurium strains at the maximum dose. Ref.: 29 Sodium benzoate was tested in the S. typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 in the presence and absence of S9 mix. Sodium benzoate was non-mutagenic in this test. Ref.: 32 In vitro mammalian chromosome aberration test in human lymphocytes Benzoic acid Chromosome aberration test was carried out on benzoic acid (up to 1.5 mg/ml) using Chinese hamster lung fibroblasts. No metabolic activation system was applied. 8 % of the cells treated with benzoic acid (1.5 mg/ml) showed structural aberrations at 48 hrs after treatment. Ref.: 33 Benzoic acid (1.5 mg/ml in DMSO) gave equivocal results using Chinese hamster lung fibroblasts. 8% chromosome aberration and 1% polypoidy were reported. Ref.: 29 Sodium benzoate Human embryonic lung cells (WI-38) were used. Dose levels for sodium benzoate were 0, 2, 20, 200 mg/ml. 200 mg/l, previously established as the lowest toxic level. The positive control was 0.1 mg/ml triethylene melamin. The test compound was added to three culture bottles for each dose level, 24 hours after plating. When sufficient mitoses were observed, usually after 24-48 hours, the cells were harvested and prepared for the analysis. 100 anaphases per dose were analysed. For the mitotic index at least 500 cells were counted. Sodium benzoate produced no significant chromosomal aberrations in human tissue culture cells when tested at any dose level tested. No substance related effects were observed. The chromosome abnormalities as well as the mitotic indices were within normal values. Ref.: 34 Chromosome aberration test was carried out on sodium benzoate (up to 2.0 mg/ml) using a Chinese hamster fibroblast cell line. No metabolic activation system was applied. 38 % of the cells treated with sodium benzoate showed chromosome aberrations at 48 h. 17
Ref.: 29, 35, Chromosome aberration test was carried out on sodium benzoate using a pseudodiploid Chinese hamster cell line (DON). No metabolic activation system was applied. Concentration above 0.002 mol/l showed twofold background effects of chromosome aberrations; but no increase in the frequency of sister chromatid exchange was observed. Ref.: 36 Chromosome aberration test was carried out on sodium benzoate using human embryonic lung culture cells. Sodium benzoate produced no significant increase in the aberration frequency in the anaphase chromosomes when tested at the dosage levels 0, 2.0 g/ml, 20 g/ml and 200 g/ml. Ref.: 33 In vitro Sister Chromatid Exchange (SCE) Benzoic acid Benzoic acid, without metabolic activation, was reported to be negative for SCEs in vitro using 3 different cell lines. These were literature citations with no other information. Ref.: 37, 38, 39 In vivo Host-Mediated Assay 0, 50, 500 and 5000 mg sodium benzoate/kg bw was given orally to mice (single dose or once a day for 5 days) in an Host-Mediated Assay. Elevated mutant frequencies were seen with Salmonella TA 1530 in the acute intermediate dose level. The subacute and the other acute dose levels showed no increase in mutant frequencies. Tests with Salmonella G 46 were negative while giving slightly elevated mutant frequencies. Tests with Saccharomyces D 3 produced no increases in recombinant frequencies. Ref.: 33 In vivo chromosome aberration test Chromosome aberration of sodium benzoate was investigated in vivo in rats. Five rats per group were dosed with 0, 50, 500 and 5000 mg/kg bw by gavage in an single dose or once a day for 5 days. The animals were killed at 6, 24 and 48 h after dosing in the acute study and 6 h after dosing in the subacute study. Bone marrow metaphase chromosomes were checked for aberrations. A low incidence of treatment related breaks was observed in the acute study but within the control range. In the subacute study, only the mid dose showed breaks (1%) but were not considered to be significant. The mitotic indices were not different from controls. Sodium benzoate did not induce chromosomal aberrations in this test system. Ref.: 34 In vivo dominant lethal assay A dominant lethal assay was conducted in rats. Following dosing with sodium benzoate by gavage (0, 50, 500, 5000 mg/kg bw, single dose or once a day for 5 days) treated male rats, 5 per group, were mated with two females per week for 8 weeks (acute study) or 7 weeks (subacute study). Fertility Index, number of implantations, corpora lutea, pre-implantation losses, resorptions/pregnant female and proportions of females with one or more dead, and two and more and overall dead implants were monitored. 18
In the acute study all three doses showed at week 8 significant, dose-related decreases in corpora lutea, at week 7 significant dose-related increases of average pre-implantation losses. Average resorptions were significant, dose-related increased at the low and high doses of week 2 and the low and intermediate doses of week 7 were significantly increased over the control group. Overall dead implants were significant increased at week 7 for the low and intermediate doses and week 2 for the low dose. In the subacute study significant increases of average pre-implantation losses were observed at a number of weeks but no significant increases of average resorptions were observed. Overall dead implants were not increased. The authors considered sodium benzoate to be non-mutagenic in rats in this test system although positive results were obtained. Ref.: Submission 1, 33 Remark IPCS CICAD 26 (2000) mentioned this dominant lethal assay as a positive result, however evaluation of the raw data in the original report (by experts of the industry consortium and a recent independent review by Prof. R. Kroes) gives no support for this. In addition the authors of the study clearly conclude negative. FDA also evaluated this study as negative. In addition sodium benzoate doesnt contain a structural alert for genotoxicity. Ref.: 55 Other recent Evaluations of Genotoxicity OECD SIDS Initial Assessment Report on Benzoates: Benzoic acid, Sodium benzoate, Potassium benzoate, Benzyl alcohol They concluded that Benzoic acid and Sodium benzoate, (also Potassium benzoate and benzyl alcohol) showed no mutagenic activity in in vitro Ames tests. Various results were obtained with other in vitro genotoxicity assays. Sodium benzoate (and benzyl alcohol) showed no genotoxicity in vivo. While some mixed and/or equivocal in vitro chromosomal/chromatid responses have been observed, no genotoxicity was observed in the in vivo cytogenetic, micronucleus, or other assays. The weight of the evidence of the in vitro and in vivo genotoxicity data indicates that these chemicals are not mutagenic or clastogenic. They also are not carcinogenic in long-term carcinogenicity studies. They also remarked since the sodium salt of benzoic acid instantaneously dissociates to the benzoic acid, the studies with sodium benzoate are also representative for benzoic acid and potassium benzoate. Ref.: 56 JECFA report, 1998 In addition data from in vivo genotoxicity studies on benzyl acetate and benzaldehyde are supportive evidence for the non-genotoxicity of benzoic acid and sodium benzoate. Ref.: 52 Scientific Committee on Food Opinion: Re-evaluation of genotoxicity In view of the additional genotoxicity data now available, the Committee has compiled its own summary of the studies (Annex 2). The Committee agrees that since benzylacetate, 19
benzylalcohol and benzylaldehyde are all metabolised to benzoic acid, the results of in vivo tests performed with these compounds as well as with sodium benzoate may be applied also to benzoic acid itself. Considering the database as a whole, weak genotoxic effects have been reported mainly at chromosome level in some in vitro systems. However, all the in vivo genotoxicity tests were negative at somatic or germ cell level. The essentially negative results obtained in three carcinogenicity studies (one in mice, two in rats) on sodium benzoate, nothwithstanding some limitations, give further reassurance. On this basis, it is very unlikely that benzoic acid would interfere with chromosomes in vivo. Ref.: 3 3.3.7. Carcinogenicity
Benzoic Acid: 20 male and 20 female rats were fed 1 % Benzoic Acid (approx. 700 mg/kg bw/d) in diet for a maximum of 1000 days. No evidence of carcinogenicity was seen upon microscopic examination of all analysed tissues. Ref.: 48 Sodium benzoate Sodium benzoate was given in 2 % in drinking water to 50 female and 50 male Swiss albino mice from weeks 5 on for lifespan. The average daily intake of sodium benzoate was 119.2 mg for a female and 124.0 mg for a male (approx. 5.95 - 6.2 g/kg bw/d). There was no effect of the survival of the treated mice when compared with the untreated control. There were no significant differences between the tumour distribution in sodium benzoate-treated and untreated control mice. Ref.: 42 Groups of 50 males and 52 female Fischer 344 rats were fed sodium benzoate at 1 or 2 % in the diet (approx. 0.5 or 1.0 g/kg bw/d) for 18 to 24 months. The control group consisted of 25 males and 43 females. No clinical signs directly attributed to sodium benzoate were observed in treated animals. Differences in the average body weight between the treated and control groups were negligible. 40 rats died during the first 16 months, except for myeloproliferative disorder developed in one female control rat, all other dead animals showed pneumonia with abscess. Around 100 rats including those of the control group died after 16 months of hemorrhagic pneumonia with oedema. The poor survival in all groups does limit the value of this study, although the type of tumours was similar between test and control rats of each sex. Ref.: 42
20
3.3.8. 3.3.8.1
Reproductive toxicity 4-Generation reproductive toxicity
Benzoic acid A four generation study with benzoic acid was conducted in rats. Males and females of the first and second generation were fed 0.5 or 1.0 % benzoic acid in the diet (approximately 0.25 or 0.5 g/kg bw d). The third generation was treated for 16 weeks and generation 4 was treated until breeding. There were no unfavourable side-effects on growth, food utilisation, duration of life, procreation, feeding of the offspring, weight of organs and histological pattern of organs in the 1 % dose group. In the 0.5 % group there was a significant prolongation of lifetime. NOAEL: 500 mg/kg bw. Ref.: 41 3.3.8.2. Teratogenicity
Benzoic acid In a study to determine the teratologic effects, benzoic acid was administered in a single dose of 510 mg/kg bw to 7 on pregnant Wistar albino rats at day 9 of gestation. The malformations and resorption rates were comparable to those in control animals. The data was considered inadequate, since only a single dose was used. Ref.: 46 Sodium benzoate Sodium benzoate at doses of 0, 1.75, 8, 38 and 175 mg/kg bw was administered by gavage to groups of at least 20 pregnant albino CD outbred mice and White albino rats on gestation day 6 to 15. Groups of 21 to 22 pregnant hamsters were dosed with 0, 3, 14, 65 or 300 mg/kg bw on gestation days 6 to 10. Groups of 10 Dutch-belted rabbits were artificially inseminated and then dosed by oral intubation with 0, 2.5, 12, 54 or 250 mg/kg bw on gestation days 6 to 18. Caesareans were performed on mice, rats, hamsters and rabbits on days 17, 20, 14 and 29, respectively. There was no clearly discernible effect on nidation or on maternal or foetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls. The NOEL in these studies was in all species identical with the highest dose tested: mice and rats hamsters rabbits NOEL : 175 mg/kg bw NOEL : 300 mg/kg bw NOEL : 250 mg/kg bw Ref.: 47
21
3.3.9.
Toxicokinetics
Benzoic acid and its sodium and potassium salt are considered with benzylacetate, benzylalcohol, benzaldehyde as a single category from the human health view by JECFA, as they are all rapidly metabolized and excreted via a common pathway within 24hrs.
Sodium benzoate is expected to immediately dissociate and form benzoic acid in an aqueous environment. Ref.: 52 3.3.10. Photo-induced toxicity
No data was submitted. In the JECFA report, there was a summary of an in vitro test by Eberlein-Konig et al, 1993. Suspensions of human erythrocytes were incubated with Benzoic Acid and Sodium Benzoate. Each material was tested at 10-5, 10-4 and 10-3 mol/l. Erythrocyte-free samples were also incubated with the test material and used as controls. Following incubation, suspensions and samples were exposed to varying amounts of UVA Iight from one of three sources. Hemolysis was measured as a function of absorbance of 550 nm light. The substances did not produce significant photohaemolysis. Ref.: 52 3.3.11. Human data
Included in the appropriate sections
22
3.3.12. 3.3.13.
Special investigations Safety evaluation (including calculation of the MoS)
100% skin absorption was assumed since the dermal absorption studies were old and not to modern standards. CALCULATION OF THE MARGIN OF SAFETY Rinse off-products (ro): Maximum content of active ingredient (a. I.) [%] Exposure to rinse-off-products E [g/day] Maximum amount of a. I. applied Iro [mg/day] Oral hygiene-products (oh): Maximum content of active ingredient (a. I.) [%] E [g/day] Exposure to oral hygiene-products Maximum amount of a. I. applied Ioh [mg/day] Eye-products (ep): Maximum content of active ingredient (a. I.) [%] Exposure to eye-products E [g/day] Maximum amount of a. I. applied Iep [mg/day] Non rinse off-products (nro): Maximum content of active ingredient (a. I.) [%] Exposure to non rinse-off-products E [g/day] Maximum amount of a. I. applied Inro [mg/day] Typical body weight (human) TBW [kg] 2.5 0.72 18.00 1.7 3.52 59.84 0.5 0.05 0.25 0.5 13.50 67.50 60 kg
Exposure from all product groups: Systemic exposure dose SED [mg/kg bw/d] = [Ioh + Iro + Iep + Inro x A]/TBW = 2.43 No observed adverse effect level (NOAEL) from a 4-generation study 500 mg/kg bw/d (selected by SCF) MARGIN OF SAFETY (MOS): MOS (NOAEL/SED) 500 mg/kg bw/d / 2.43 mg/kg bw/d = 206
23
3.3.14.
Discussion
Since the adoption of the previous opinion of the SCCNFP on 4 June 2002 on Benzoic acid and Sodium benzoate (SCCNFP/0532/01, final), there have been 2 major re-evaluations of the data on Benzoic acid and sodium benzoate. The SIDS report agrees that many toxicological studies on benzoic acid and its salts are old and do not always fulfil for 100% present-day guidelines. They did appear to be acceptable studies for evaluation, since well-known research groups and/or test laboratories ran the studies according to scientific standards and or accepted protocols at that time. Also, all were peerreviewed and published in high quality scientific literature. Most of them have been reviewed and accepted by other fora like FDA, JECFA, and IPCS as acceptable studies. In addition, there is good consistency in the individual data for a substance in the group as well as between members of the group (benzyl acetate and benzaldehyde data inclusive). Therefore, taken as a whole, the available studies give a robust database for hazard assessment and hazard evaluation of these compounds and further studies are not indicated. The JECFA Committee (1997) concluded that the data reviewed for compounds in this group were sufficient to demonstrate lack of teratogenic, reproductive or carcinogenic potential. Consequently, the Committee concluded that further studies were not required Ref.: 56 The conclusions of the SCF in 2002 were: The database is much more extensive than that considered by the Committee in 1994, both for developmental toxicity and for genotoxicity. There appear to be sufficient studies to conclude absence of teratogenic potential, with an overall NOAEL for developmental toxicity of 500 mg/kg bw/day, based on effects on foetal weight. The fact that this overall NOAEL takes into account gavage as well as dietary studies gives further reassurance. It is therefore concluded that a further teratogenicity study on benzoic acid should no longer be required. Similarly for genotoxicity, while some of the in vitro tests have been positive or equivocal, all the results from in vivo studies have been negative. It is therefore concluded that an in vivo study for clastogenic activity on benzoic acid should no longer be required. On the basis of these data and the other types of study previously evaluated by the Committee, the Committee can establish a full Group ADI of 0 - 5 mg/kg bw for benzoic acid and its salts including benzyl alcohol and related benzyl derivatives used as flavourings. Ref.: 3 This consensus of opinion for teratogenic, reproductive or carcinogenic potential of benzoic acid and sodium benzoate is welcome. Benzoic acid and sodium benzoate rapidly metabolize and excrete via a common pathway within 24hrs. Systemic toxic effects on liver and kidney were observed. Benzoic acid and sodium benzoate have low acute oral and dermal toxicity with LD50 values >2000 mg/kg bw. The 4 hrs inhalation exposure of benzoic acid at 0.026mg/l/h also show low acute inhalation toxicity. Benzoic acid is a mild skin irritant, but sodium benzoate was not a skin irritant. Neither benzoic acid nor benzoate gave indication of a sensitizing effect in animals, but occasionally very low positive reactions were recorded with humans in patch tests with benzoic acid. It has been suggested that these positive reactions are a non-immunologic contact urticaria. 24
In the CICAD report, the conclusion on benzoic acid and sodium benzoate was: However, both substances are known to cause non-immunologic immediate contact reactions. This effect is scarce in healthy subjects, while in patients with frequent urticaria or asthma, symptoms or exacerbation of the symptoms were observed. This was considered to be a possible cholinergic mechanism. This should be borne in mind for products used on children. Benzoic acid should be labelled as an eye irritant under the EU criteria for classification. The percutaneous absorption study of 14C-labelled benzoic acid in vitro with excised human skin was old, not conforming to modern guidelines.. Total absorption was found to be approximately 45 %. These data were comparable to in vivo data in human, in which the total absorption of labelled benzoic acid was approximately 43 %. Data is only given for sodium benzoate, but not the other salts or esters. It is thought that the loss of acidity due to the salt (sodium, potassium) should decrease toxicity. Since the loss of acidity is not uniform, this could be a problem. No data was provided for the esters.
4.
CONCLUSION
Adequate data was provided only for benzoic acid and sodium benzoate, but not the other salts or esters. On the basis of provided data, the SCCP is of the opinion that benzoic acid and sodium benzoate are safe for use for preservative and non-preservative purposes in cosmetic rinse-off products at a maximum concentration of 2.5 % and in cosmetic oral-care products at a maximum concentration of 1.7 %, and in leave-on products up to 0.5%. The possible non-preservative functions have not been stated. However, in the interest of consumer safety, generation of data on irritation and sensitisation of the other salts and esters is required if they are to be used in cosmetic products. Comment: Inclusion of all relevant data should have been made available, particularly if from the grey literature as required by the SCCNFP Notes of Guidance (SCCNFP/0690/03). In the IUCLID database, more modern percutaneous absorption studies were summarised. The study for eye irritation was not provided with the Submission I. These should all have been provided with Submission I.
5.
MINORITY OPINION
Not applicable
6.
1. 2. 3. 4.
REFERENCES
Washkuhn R.J., Patel V.K., Robinson J.R. (1971) J. Pharm. Sci. 60(5), 736-744. Wright J.L. and Carstensen J.T. (1986) J. Pharm. Sci. 75(6), 546-551. SCF/CS/ADD/CONS/48 Final, 17 Sept 2002, expressed on 24 September 2002. Marhold, J.V. Personal communication to the editor of RTECS, VUOS 539-18, Cincinnati (1977). Cited in Henschler, D. (ed) Toxikologisch-arbeitsmedizinische Begrndung von 25
5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37.
MAK-Werten. Benzoesure. VCH VerlagsGmbH, Weinheim (1985). Abe S. et al. (1984), Iyakuhin Kenyuku 15, 359-370. Mc Cormick G.C. and Speaker T.J. (1973) Toxicol Appl Pharmacol 25, 478. Hager G.P. et al. (1942) J. Am. Pharm. Assoc. 31, 253-255. Deuel H.J. Jr et al. (1954) Food Res 19, 1-12. Loeser, E. Bayer AG data. Akute orale Toxizitt (1977). R0300478 Smyth H.F. Jr and Carpenter C.P. (1948) J. Ind. Hyg. Toxicol. 30, 63. Draize J.H. (1959), Appraisal of the safety of chemicals in foods, drugs, and cosmetics, Association of Food and Drug Officials of the US, p. 46-59. RCC NOTOX, Primary skin irritation/corrosion study of Benzoic Acid in the rabbit (study no. 0847/1083). RCC NOTOX B. V., DD s-Hertogenbosch (1988). Moreno O.M. (1977) Report to RIFM, 22 August. Cited in BIBRA Report Toxicity Profile Benzoid Acid, Bibra Toxicology International, 1st ed. (1989), 1-11. Bio-Fax, Benzoid acid, Industrial Bio-Test Laboratories, Inc., Northbrook, Ill., Data Sheet No. 28-4/73 (1973). Cited in BUA-Stoffbericht 145, S. Hirzel, Wissenschaftliche Verlagsgesellschaft, December 1993. Bayer AG, Untersuchung zur Haut- und Schleimhautvertrglichkeit von Benzoesure, Bayer AG Wuppertal (1978). RCC NOTOX, Primary skin irritation/corrosion study with natrium benzoate in rabbits (study no. 014658). RCC NOTOX B. V., DDs-Hertogenbosch, The Netherlands (1989). Loeser E., Bayer AG data, Untersuchungen zur Haut- und Schleimhautvertrglichkeit (1977). De Groot A.C. et al. (1986) Contact Dermatitis 14, 120. Frosch P.J. and Kligman A.M. (1976) Contact Dermatitis 2, 314 Lathi A. (1978) Contact Dermatitis 4, 302-303. Frosch P.J. and Kligman A.M., cited in Drill, V. A. & Lazar, P. (ed.) Cutaneous toxicity, Academic Press Inc., New York, 127-154 (1977). RCC NOTOX, Acute eye irritation/corrosion study with Benzoic Acid in rabbits (study no. 0847/1084). RCC NOTOX B. V., DD s-Hertogenbosch, The Netherlands (1988). Suberg H., Bayer AG data, Benzoesure DAB 8, Prfung auf primr reizende/tzende Wirkung am Kaninchenauge (1986). RCC NOTOX, Acute eye irritation/corrosion study with Sodium Benzoate in rabbits (study no. 014669). RCC NOTOX B. V., DD s-Hertogenbosch, The Netherlands (1989). Gad S.C. et al. (1986) Toxicol Appl Pharm 84, 93-114. Kligman A.M. (1977) Report to RIFM, 24 May. Cited in Food Cosmet Toxicol 17 Special Issue V (1979) Monographs on Fragrance Raw Materials, 695-923. Leyden J.J. and Kligman A.M. (1977) Contact Dermatitis 3, 273-275. Broeckx W. et al. (1987) Contact Dermatitis 16, 189. S Ishidate M. Jr et al. (1984) Food Chem Toxicol 22, 623. Zeiger E. et al. (1988) Environ Mol Mutagen 11 Suppl 12, 1. Mc Cann J. et al. (1975) Proc Nat Acad Sci USA 72, 5135. Prival M.J. et al. (1991) Mutat Res 260, 321. Ishidate M. Jr et al. (1988) Mutat Res 195, 151-213. Litton Bionetics, Inc. (1974) Mutagenic evaluation of compound FDA 71-37, Sodium Benzoate. NTIS Report. Ishidate M. Jr and Odashima S. (1977) Mutat Res 48, 337-354. Abe S. and Sasaki M. (1977) J Nat Cancer Inst 58, 1635-1641. Tohda H., Horaguchi K., Takahashi K., Oikawa A., Matsushima T. (1980), Epstein-Barr virus-transformed human lymphoblastoid cells for study of sister chromatid exchanges. 26
38.
39. 40. 41. 42. 43. 44. 45. 46. 47.
48. 49. 50. 51. 52.
53. 54. 55. 56.
Cancer Research 40: 4775-4780. Jansson T., Curvall M., Hedin A. and Enzell C.R. (1988), In vitro studies of the biological effects of cigarette smoke condensate. Induction of SCE by some phenolic and related constituents derived from cigarette smoke condensate. A study of structure-activity relationship. Mutation Research 206: 17-24. Oikawa A., Tohda H., Kanai M., Miwa M. and Sugimura T. (1980), Inhibitors of poly(adenosine diphosphate ribose)polymerase induce sister chromatid exchanges. Biochemical and Biophysical Research Communications 97: 1311-1316. Franz T.J. (1975) J Invest Derm 64, 190-195. Hunziker N. et al. (1978) Dermatologica 156, 79-88. Toth B. (1984) Fund Appl Toxicol 4, 494-496. Fanelli G.M. and Halliday S.L. (1963) Arch Int Pharmacodyn 144, 120-125. International Research and Development Corporation, Four Week Subacute Inhalation Toxicity Study of Benzoic Acid in Rats (study no. 163-676). International Research and Development Corporation, Mattawan/Michigan USA (1981). Shtenberg A.J. and Ignatev A.D. (1970) Food Cosmet Toxicol 8, 369. Kimmel C.A. et al. (1971) Teratology 4, 15-24. Food and Drug Research Labs., Inc. (1972) Teratologic evaluation of FDA 71-37 (Sodium Benzoate), NTIS Report No. PB-221-777. Cited in: Cosmetic Ingredient Review, Final Report, Safety Assessment of Benzyl Alcohol, Benzoic Acid and Sodium Benzoate, May 19, 1998. Kieckebusch W. and Lang K. (1960) Arzneim-Forsch 10, 1001-1003. Sodemoto Y. and Enomoto M. (1980) J Environ Pathol Toxicol 4, 87-95. SCCNFP Notes of Guidance for Testing of Cosmetic Ingredients for their Safety Evaluation (SCCNFP/0321/00 Final, 2000) Rothschild D.L. Jr. (1990) The Food Chemical News Guide. Washington, D.C., Cited in: Cosmetic Ingredient Review, Final Report, Safety Assessment of Benzyl Alcohol, Benzoic Acid and Sodium Benzoate, May 19, 1998. Food and Agriculture Organization of the United Nations/World Health Organisation (FAO/WHO). 1994, Summary of the Evaluations Performed by the Joint FAO/WHO Expert Committee on Food Additives (JECFA): United States: International Life Sciences Institute. Cited in: Cosmetic Ingredient Review, Final Report, Safety Assessment of Benzyl Alcohol, Benzoic Acid and Sodium Benzoate, May 19, 1998. Williams F.M. (1985) Clinical Significance of Esterases in Man, Clinical Pharmacokinetics 10, 392-403. Cosmetic Ingredient Review (1998) Final report: Safety Assessment of Benzyl Alcohol, Benzoic Acid, and Sodium Benzoate, May 19, 1998, 35 pages. S International Programme on Chemical Safety (2000) Concise International Chemical Assessment Document No. 26, Benzoic Acid and Sodium Benzoate, http://www.inchem.org/documents/cicads/cicads/cicad26.htm SIDS Initial Assessment Report (2001) Benzoates: Benzoic acid, Sodium Benzoate, Potassium Benzoate, Benzyl Alcohol, final draft under: http://www.oecd.org/document/63/0,2340,en_2649_34379_1897983_1_1_1_1,00.htm
References from Submission 1

* Referred to but no documentation supplied. 1. Marhold JV (1977) Personal communication to the editor of the Registry of Toxic Effects of Chemical Substances, VUOS 539-18, Cincinnati , Ohio, USA, 29 March. Cited in Henschler D (ed) Toxikologischarbeitsmedizinische Begrndung von MAK-Werten. Benzoesure. VCH VerlagsGmbH, Weinheim (1985)
27
2. 3. *4. *5. 6. 7. *8. *9. *10. *11. *12. 13. 14. 15. 16. 17. 18. 19. *20. *21. *22. *23. 24. 25. 26. 27. 28. 29.
Abe S et al. (1984) Studies on the Toxicity of Oxaprozin (1) Acute Toxicity of Oxaprozin, its Metabolites and Contaminants. IYAKUHIN KENKYU 15 359 - 70 (Japanese, only abstract and tables in English) McCormick GC & Speaker TJ (1973) Comparison of the Acute Toxicity, Distribution, Fate and Some Pharmacological Properties of the Non-benzenoid Aromatic Compound Acid with those of Benzoid and Naphtoic Acids. Toxicol Appl Pharmacol 25 478 (only abstract) Fassett DW (1962) in Patty FA (ed): "Industrial Hygiene and Toxicology", 2 nd rev. Ed., Vol. II, p. 1858, Interscience Publishers, New York, USA. Cited in Henschler D (ed) Toxikologisch-arbeitsmedizinische Begrndung von MAK-Werten. Benzoesure. VCH VerlagsGmbH, Weinheim (1985) Loeser E (1977) Bayer AG data. Akute orale Toxizitt. Cited in BUA-Stoffbericht 145, December 1993. S. Hirzel, Wissenschaftliche Verlagsgesellschaft, (1995) Deuel HJ et al. (1954) Sorbic Acid as a Fungistatic Agent for Foods. I. Harmlessness of Sorbic Acid as a Dietary Component. Food Res 19 1 - 12 Smyth HF Jr & Carpenter CP (1948) Further Experience with the Range Finding Test in the Industrial Toxicology Laboratory. J Ind Hyg Toxicol 30 63 - 68 Moreno OM (1977) Report to RIFM, 22 August. Cited in BIBRA Report Toxicity Profile - Benzoic Acid, TNO BIBRA Toxicology International Ltd. (1989) Biofax (1973) Benzoic acid. Industrial Bio-Test laboratories, Inc. Northbrook, Illinois, Data Sheet No. 284/73. Cited in BUA-Stoffbericht 145, December 1993. S. Hirzel, Wissenschaftliche Verlagsgesellschaft, (1995) RCC NOTOX (1988) Primary skin irritation/corrosion study of benzoic acid in the rabbit (study no. 0847/1083). RCC NOTOX BV DD's-Hertogenbosch. Cited in BUA-Stoffbericht 145, December 1993. S. Hirzel, Wissenschaftliche Verlagsgesellschaft, (1995) RCC NOTOX Primary skin irritation/corrosion study of natrium benzoate in rabbits (study no. 014658). RCC NOTOX BV DD's-Hertogenbosch. Cited in BUA-Stoffbericht 145, December 1993. S. Hirzel, Wissenschaftliche Verlagsgesellschaft, (1995) Loeser E (1977) Untersuchungen zur Haut- und Schleimhautvertrglichkeit, Bayer AG data. Cited in BUAStoffbericht 145, December 1993. S. Hirzel, Wissenschaftliche Verlagsgesellschaft, (1995) Gad SC (1986) Development and Validation of an Alternative Dermal Sensitization Test: The Mouse Ear Swelling Test (MEST) Toxicol Appl Pharm 84 93 - 114 De Groot AC et al (1986) Contact allergy to preservatives (I) Contact Derm 14 120 122 Lahti A (1978) Skin reactions to some antimicrobial agents. Contact Derm 4 302 - 303 Frosch PJ & Kligman AM (1977) The Chamber-Scarification Test of Assessing Irritancy of Topically Applied Substances. In Drill VA & Lazar P (Ed.) Cutaneous Toxicity, Ac. Press Inc. New York, 127 - 154 Frosch PJ & Kligman AM (1976) The chamber-scarification test for irritancy. Contact Derm 2 314 - 324 Kremer (1999) Gebrauchstest, COLIPA: Pril 2 in 1 Splmittel & antibakterielle Handseife. (Prfbericht (9902786-0) Report Nr. R 9900872) unpublished data. Tronnier H (1999) Anwendungs- und Vertrglichkeitstest des Prfprparates Handschirrgeschirrsplmittel und antibakterielle Handseife 2 in 1 (Berichts-Nr.: R 9901179) unpublished data. Suberg H (1986) Benzoesure DAB 8, Prfung auf primr reizende/tzende Wirkung am Kaninchenauge, Bayer AG data. Cited in BUA-Stoffbericht 145, December 1993. S. Hirzel, Wissenschaftliche Verlagsgesellschaft, (1995) Bayer AG (1978) Untersuchungen zur Haut- und Schleimhautvertrglichkeit, Bayer AG Wuppertal. Cited in BUA-Stoffbericht 145, December 1993. S. Hirzel, Wissenschaftliche Verlagsgesellschaft, (1995) RCC NOTOX Acute eye irritation/corrosion study with natrium benzoate in rabbits (study no. 014669). RCC NOTOX BV DD's-Hertogenbosch. Cited in BUA-Stoffbericht 145, December 1993. S. Hirzel, Wissenschaftliche Verlagsgesellschaft, (1995) Kligman AM (1977) Report to RIFM, 14 May. Cited in BIBRA Report Toxicity Profile - Benzoic Acid (1989) TNO BIBRA Toxicology International Ltd. Leyden JJ & Kligman AM (1977) Contact sensitization to benzoyl peroxide. Contact Derm 3 273 - 275 Broeckx W et al. (1987) Cosmetic intolerance. Contact Derm 16 189 194 Ishidate M JR et al. (1984) Primary mutagenicity screening of food additives currently used in Japan. Fd Chem Toxic 22 623 - 636 Zeiger E et al (1988) Salmonella Mutagenicity Test: IV. Results From the Testing of 300 Chemicals. Environ Mol Mutagen 11 Suppl. 12 1 - 18 McCann J et al (1975) Detection of carcinogens as mutagens in the Salmonella/microsome test: Assay of 300 chemicals. Proc Nat Acad Sci 72 5135 - 5139 Prival MJ et al (1991) Bacterial mutagenicity testing of 49 food ingredients gives very few positive results. Mutat Res 260 321 - 329
28
30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. *43. *44. 45. 46.
Ishidate M JR et al (1988) A comparative analysis of data on the clastogenicity of 951 chemical substances tested in mammalian cell cultures. Mutat Res 195 151 - 213 Ishidate M JR & Odashima S (1977) Chromosome tests with 134 compounds on Chinese hamster cells in vitro - a screening for chemical carcinogens. Mutat Res 48 337 - 354 Abe S & Sasaki M (1977) Chromosome Aberration and Sister Chromatid Exchange in Chinese Hamster Cells Exposed to Various Chemicals. J Natl Cancer Inst 58 1635 - 1641 Fabrizio DBA (1974) Mutagenic Evaluation of Compound FDA 71-27 Sodium Benzoate, Litton Bionetics, Inc. (very bad copy!) Frantz TJ (1975) Percutaneous absorption. On the relevance of in vitro data. J Invest Derm 64 190 - 195 Hunziker et al (1978) Animal Models of Percutaneous Penetration: Comparison between Mexican Hairless Dogs and Man. Dermatologica 156 79 - 88 Toth B (1984) Lack of Tumorigenicity of Sodium benzoate in Mice. Fundam Appl Toxicol 4 494 - 496 Fanelli GM & Halliday SL (1963) Relative toxicity of Chlortetracycline and Sodium benzoate after oral administration to rats. Arch Int Pharmacodyn 144 120 - 125 Shtenberg AJ & Ignat'ev AD (1970) Toxicological Evaluation of some Combinations of Food Preservatives. Fd Cosmet Toxicol 8 369 - 380 Food and Drug Research Labs., Inc. (1972) Teratologic evaluation of FDA 71-37 (sodium benzoate) in mice, rats, hamsters and rabbits. NTIS Report PB-221 777 Kimmel CA et al (1971) Studies on Metabolism and Identification of the Causative Agent in Aspirin Teratogenesis in Rats. Teratology 4 15 - 24 Kieckebusch W & Lang K (1960) Die Vertrglichkeit der Benzoesure im chronischen Ftterungsversuch. Arznei-Forsch 10 1001- 1004 Sodemoto Y & Enomoto M (1980) Report of carcinogenesis bioassay of Sodium benzoate in rats: Absence of carcinogenicity of sodium benzoate in rats. J Environ Pathol Toxicol 4 87 - 95 Not given Not given Beratergremium fr umweltrelevante Altstoffe (BUA) der Gesellschaft Deutscher Chemiker (ed) BUAStoffbericht 145, December 1993. S. Hirzel, Wissenschaftliche Verlagsgesellschaft, (1995) BIBRA Report Toxicity Profile - Benzoic Acid (1989) TNO BIBRA Toxicology International Ltd.
Additional references (provided by SCCNFP): AR 1. European Parliament and Council Directive No 95/2/EC of 20 February 1995 on foodadditives other than colours and sweeteners. Official Journal L 061 , 18/03/1995 p. 0001-0040 AR 2. Commission Directive No 96/77/EC of 2 December 1996 laying down specific purity criteria on food additives other than colours and sweeteners. OJ No L339, 1-6. AR 3. FDA, Code of Federal Regulations, Title 21- Food and Drugs, Volume 3 [Revised as of April 1, 2001], 184. 464-559. AR 4. Handbook of pharmaceutical excipients 3rd ed 2000 editors: Kibbe, I, Arthur H, Pharmaceutical Society of Great Britain; American Pharmaceutical Association AR 5. Martindale : The Complete Drug Reference 32nd ed. 1999 editors: Parfitt K, Sweetman, S C, Blake P S, Parsons, A V. AR 6. Lahti A (1980) Non-immunologic contact urticaria. University of Oulu. AR 7. Final report on the safety assessment of benzyl alcohol, benzoic acid, and sodium benzoate. Cosmetic Ingredient Review, Washington, DC, 20036, USA. Intern. Journal of Toxicology (2001), 20 (Suppl. 3), 2350 AR 8. International Programme On Chemical Safety, (2000) Concise International Chemical Assessment Document No. 26 Benzoic Acid And Sodium Benzoate. http://www.inchem.org/documents/cicads/cicads/cicad26.htm AR9. Feldmann RJ & Maibach HI (1970) Absorbtion of some organic compounds through the skin in man. J Invest Derm 54 399-404). AR10. Edwards RC, Voegeli CJ (1984) Inadvisability of using caffeine and sodium benzoate in neonates. Am J Hosp Pharm 41, 658. AR11. Schiff D et al (1971) Fixed drug combinations and the displacement of bilirubin from albumin. Pediatrics 48, 139 -41.
7.
ACKNOWLEDGEMENTS
29
Members of the working group are acknowledged for their valuable contribution to this opinion. The members of the working group are: Dr. C.M. Chambers (rapporteur) Prof. R. Dubakiene Dr. R. Grimalt Dr. B. Jazwiec-Kanyion Prof. V. Kapoulas Prof. C. Lidn Prof. J.-P. Marty Dr. S.C. Rastogi Prof. J. Revuz Prof. T. Sanner Dr. I.R. White (chairman)
30
JOURNAL OF THE AMERICAN COLLEGE OF TOXICOLOGY Volume 4, Number 5, 1985 vary Ann Liebert, Inc., Publishers
Final Report on the Safety Assessment of Butylene Glycol, Hexylene Glycol, Ethoxydiglycol, Glycol and Dipropylene
Butylene Glycol, Hexylene Glycol, Ethoxydiglycol, and Dipropylene Glycol are viscous liquids used in the cosmetic industry as humectants, emulsifiers, plasticizers, and solvents. The results of acute, subchronic, and chronic oral toxicity studies using a variety of animal species indicate a low order of toxicity for the Glycols. Results of parenteral injection, inhalation, and acute and subchronic cutaneous toxicity studies likewise support a low order of toxicity. Butylene Glycol, Ethoxydiglycol, and Dipropylene Glycol caused minimal to mild irritation of rabbit skin, whereas Hexylene Clycol was moderately irritating. The Glycols produced mild to severe ocular irritation when tested in rabbits, with Hexylene Clycol producing the most severe irritation. Although undiluted Hexylene Glycol produced severe ocular irritation, a 25 percent aqueous solution produced no signs of irritation. Undiluted Butyiene Glycol was not an eye irritant to rabbits but was to humans. Human skin patch tests on undiluted Butylene Glycol and undiluted Hexylene Glycol produced a very low order of primary skin irritation. A repeated insult patch test on Butylene Glycol produced no evidence of skin sensitization. Based on the available data it is concluded the Butylene Glycol, Hexylene Glycol, Ethoxydiglycol, and Dipropylene Glycol are safe as presently used in cosmetics.
INTRODUCTION utylene Glycol, Hexylene Glycol, Ethoxydiglycol, and Dipropylene Glycol are viscous liquids used in the cosmetic industry as humectants, emulsifiers, plasticizers, and solvents.
223
224
COSMETIC
INGREDIENT
REVIEW
CHEMICAL
AND
PHYSICAL
PROPERTIES
Structure/Composition 1. Butylene Glycol is an aliphatic diol. It conforms HOCHzCH,CHCH, to the formula:
CAS Number:
107-88-o and 1,3-Butylene Glycol.() to the formula:
Other names include 1,3-Butanediol 2. Hexylene
Glycol is the aliphatic alcohol that conforms
CHa-C-CHz-CHCHS I OH CAS Number: 107-41-5 and 2,4-Pentanediol,2-Methyl-.() to the formula: I OH
CH, I
Other names are 2-Methyl-2,4-Pentanediol 3. Ethoxydiglycol
is the ether alcohol that conforms
CAS Number:
11 l-90-0 Ether; Ethanol, 2-(2-Eth-
Other names include Diethylene Glycol Monoethyl oxyethoxy)-; 2-(2-Ethoxyethoxy)EthanoI.() 4. Dipropylene formula: Glycol is a mixture
of diols that conforms
generally to the
CHLHCHz-0-CHLHCt+ I OH I OH
The material of commerce is primarily a mixture of 3 isomers, with the majority being disecondary (85 to 90 percent). Primary-secondary and diprimary isomers, along with up to 5 percent unidentified material, make up the remainder. CAS Number: 110-98-5 Glycol; 1,l -Oxybis-2-Propanol; 2-Propa-
Other names are: Di-1,2-Propylene nol, 1,l -Oxybis-. (L.2)
FINAL
REPORT:
SAFETY
ASSESSMENT
OF THE
GLYCOLS
225
Properties Butylene Glycol is a clear, practically colorless, viscous, hygroscopic liquid. It is odorless and has a slightly sweet, characteristic taste, Butylene Glycol is miscible in all proportions with water, acetone, and alcohol. It is immiscible with fixed oils and insoluble in aliphatic hydrocarbons, benzene, toluene, and carbon tetrachloride. This glycol does dissolve most essential oils and synthetic flavoring substances.(3-7) Hexylene Glycol is a clear hygroscopic liquid with a mild, sweet odor. It exhibits exceptional solvency for a variety of materials and is miscible with aliphatic and aromatic hydrocarbons as well as with such polar substances as water, fatty acids, and alcohols. It is combustible.(5*6*s) Ethoxydiglycol is a colorless hygroscopic liquid, soluble in water and most organic solvents.(4vg) Dipropylene Glycol is a colorless, slightly viscous liquid that is soluble in water, ethanol, and acetone.(5) Other physical and chemical properties of the glycols are shown in Table 1. Production Butylene Glycol is produced by the catalytic hydrogenation of acetaldehyde using as catalysts Raney nickel, copper, or platinum oxide. It is purified by distillation. (6.7.lO)
TABLE
1.
Properties
of Glycols Butylene Hexylene Glycol 188.18 1g7vmmm) 197.1(7f3hm) 0.9254': 0.9233:: 1.4250 1.4276 41.7 (209C) 0.26 -105 0.9881': 0.988:: 1.4300 mm Ethoxydiglycol 134.18 195V60mm) Dipropylene Clycol 134.18 229-32 222-38(760mm) Supercools 1.0224:: 1.020-1.030D 1.439 0.01 Soluble Soluble Soluble mm Reference 4 4 2, 7, 8 2, 6, 7, 9 4 2, 7-9 4 2, 7, 8 2, 4, 5, 9 7,8
Property Molecular Boiling weight
Clycol 90.12 208 (0.8 atm) 207.5
point (C)
Freezing
point (T)
-50 1.0053': 1.0053::
Specific gravity (g/ml)
Refractive index r$
1.4418 1.4412
Vapor pressure Viscosity Solubility Water Alcohol Ether Acetone Benzene Carbon tetrachloride Aliphatic hydrocarbons Aromatic hydrocarbons Fatty acids (cps)
0.06 103.9
mm (25C)
Soluble Soluble Insoluble Soluble Insoluble Insoluble Insoluble -
Soluble Soluble Soluble Soluble Soluble Soluble
Soluble Soluble Soluble Soluble Soluble -
3, 4 3, 4 4 2, 4, 7 4, 7 7 7,8 8 8
226
COSMETIC
INGREDIENT
REVIEW
Hexylene Glycol is manufactured by the condensation of 2 molecules of acetone to produce diacetone alcohol, which is further hydrogenated to produce Hexylene Glycol. This is then purified by distillation.* Ethoxydiglycol is prepared from the reaction of ethylene oxide with ethanol followed by purification by distillation.g Dipropylene Glyol is the reaction product of propylene glycol and propylene oxide.(sl)
Analytical
Methods
Chemical and chromatographic methods may be used for the identification and separation of the glycols. Chemical methods involve oxidation of the glycols with subsequent reaction with a reagent. (I*) Gas chromatography may be used for the identification of gIycoIs.3,14
Impurities Butylene Glycol has a minimum gas chromatographic assay of 99.5 percent by weight. It contains a maximum of 0.5 percent water, up to 0.005 percent acetic acid, and trace amounts of branched 1,3-Butylene Glycol.) Hexylene Glycol contains a maximum of 0.1 percent water and 0.005 percent acetic acid. (8) Ethoxydiglycol has a minimum gas chromatographic assay of 99.0 percent and contains water and acetic acid to maximums of 0.1 and 0.01 percent, respectively. Known impurities include diethylene glycol and triethylene glycol.(g) The isomer distribution of Dipropylene Glycol is as specified by the commercial buyer. It contains up to 0.1 percent water, up to 0.01 percent acetic acid, and up to 0.001 percent inorganic chlorides. The maximum combustion residue of Dipropylene Glycol should not exceed 0.005 percent.(*)
USE
Noncosmetic
Use
Butylene Glycol has been tested as a parenteral drug solvent, in the manufacture of polyester plasticizers, and as a humectant for cellophane and tobacCO.(~) It serves as a surfactant, coupling agent, and solvent.) Butylene Glycol has both indirect food additive (IFA) and direct food additive (DFA) status with the Food and Drug Administration when used as a solvent for flavors, as an antioxidant and stabilizer, and as a component of packaging (21 Code of Federal Regulations [CFR] 173.220; 177.1200; 175.105; 177.1680; 177.1210; 178.2010).'16' Hexylene Glycol has IFA status as a defoaming agent (21 CFR 176.210).(6) It is also used in hydraulic brake fluids, printing inks, and textile dye vehicles. Hexylene Glycol serves as a coupling agent, as a fuel and lubricant additive and as an emulsifying agent..)
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Exthoxydiglycol has IFA status for use as a component of paperboard and adhesives (21 CFR 175.105; 176.180). Dipropylene Glycol is an IFA ingredient for use in adhesives, lubricants, and as a defoaming agent (21 CFR 175.105; 178.3910; 1 76.200).6 It is also used as a solvent for nitrocellulose and shellac and as a partial solvent for cellulose acetate. Other applications include solvent mixtures, lacquers, coatings, and printing inks.
Cosmetic
Use
The glycols generally are used as cosmetic emulsifiers, solidifiers, plasticizers, cosolvents, and film producers. (.l*) Butylene Glycol is used as a humectant, especially in hair sprays and setting lotions. (l*-*) It helps retard the loss of aromas from essential oils, preserves against spoilage by microorganisms, and is used as a solvent for benzoates. Special grades of Dipropylene Glycol (based on odor quality) are used as carriers for perfume oils.(*) Cosmetic product formulation data on the use and occurrence of the glycols in finished products are made available by the Food and Drug Administration (FDA) and compiled through voluntary filing of such data in accordance with Title 21 part 720.4 of the Code of Federal Regulations. Ingredients are listed in prescribed concentration ranges under specific product type categories. Since certain cosmetic ingredients are supplied by the manufacturer at less than 100 percent concentration, the value reported by the cosmetic formulator may not necessarily reflect the true concentration found in the finished product; the actual concentration in such a case would be a fraction of that reported to the FDA. Since data are only submitted within the framework of preset concentration ranges, the opportunity exists for a 2- to lo-fold overestimation of the actual concentration of an ingredient in a particular product (Table 2).(*l) Butylene Glycol is used in 165 products at concentrations from less than 0.1 percent to greater than 50 percent. It is used in hair and bath products, eye and facial makeup, fragrances, personal cleanliness products, and shaving and skin care preparations.* Hexylene Glycol is used in 85 cosmetic formulations at concentrations of use ranging from less than 0.1 percent to 25 percent. The types of products in which Hexylene Glycol is used include bath and hair preparations, eye makeup, soaps, and skin care preparations.* Ethoxydiglycol has been reported as an ingredient in 80 product formulations at concentrations from less than 0.1 percent to 50 percent. The types of products include eye makeup, fragrances, hair and nail preparations, and shaving and skin care preparations.* Dipropylene Glycol is reported as an ingredient in 50 cosmetic formulations in concentrations ranging from less than 0.1 percent to 50 percent. It is used in hair care and bath products, perfumes, facial makeup, doedorants, and shaving and skin care preparations.*l The Glycols may contact all parts of the integument to which the products are applied and may remain in contact for several hours daily.*)
228
TABLE 2. Product Formulation Data*)
COSMETIC
INGREDIENT
REVIEW
No. Product Total No. Containing Product Butylene Category* Clycol 1 4 3 13 4 34 1 Ingredient >50 > JO-25 >5-70 Within
Formulation5 Range I%) >O.l-l 50. I
Each Concentration >J-5
Bath oils, tablets, and salts Other bath preparations Eyeliner Eye shadow Eye makeup remover Mascara Other eye makeup preparations Colognes Perfumes Other fragrance preparations Hair conditioners Hair shampoos in@ Tonics, Blushers (noncolorand other aids and toilet waters
1 -
12 1 1 3 1 1 2 16 1 1 1 1 1 3 1 2
3 4 29 1 2 1 1 3 1 1 2 10
2 1 2 -
dressings, (all types)
1 7 1 19 1 2 2
1 -
hair grooming Face powders
Makeup foundations Makeup bases Rouges Other makeup preparations (not eye) Cuticle softeners Bath soaps and detergents Deodorants products Aftershave lotions (underarm) Other personal cleanliness
4 13
Skin cleansing preparations (cold creams, lotions, liquids, and pads) Face, body, and hand skin care preparations Moisturizing arations Night skin care preparations Paste masks (mudpacks) Skin fresheners Wrinkle smoothers (removers) Other skin care preparations Suntan gels, creams, and liquids 1981 TOTALS (excluding shaving preparations) skin care prep
11
3 -
2 1 2 -
1 4 1 3 1
1 1 1 -
7 1
165
23
46
76
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(Continued) No. Product Formulations Total No. Containing Each Concentration >10-25 >5-10 >l-5 Within
Range (%) >o. I-I 50.1
Product Category* Hexylene Clycol
Ingredient
Bath oils, tablets, and salts Bubble baths Eye makeup remover Hair conditioners Permanent Hair rinses waves (noncoloring) (noncoloring) (all types requiring
4 3 7 1 29 20 -
1 -
2 -
1 1 2 4 5 2 3 1 1 3 1 3
1 1 1 10 -
Hair shampoos
Hair dyes and colors Hair bleaches
17
13
caution statement and patch test)
3 2 (cold and pads) 1 4 -
Bath soaps and detergents Deodorants (underarm) liquids, Skin cleansing preparations creams, lotions, rations tions) Moisturizing skin care preparations
Face, body, and hand skin care prepa(excluding shaving prepara-
1 15 -
3 3
2 1 1 32 -
1 2
Paste masks (mudpacks) Skin fresheners Other skin care preparations 1981 TOTALS 85
20
17
No. Product Formulations Total No. Containing Product Category* fthoxydiglycol Mascara Colognes and toilet waters Hair conditioners Hair shampoos ing) Wave sets Hair dyes and colors (all types requiring Hair tints Hair bleaches Other hair coloring rations Nail polish and enamel remover Aftershave lotions 2 14 prepacaution 13 5 statement and patch test) 14 (noncolorIngredient >25-50 >lO-25 >5-10 >l-5 >0.7-l 50. I Within Each Concentration Range (%I
1 1 2 1 1 -
10
2 3
Skin cleansing preparations (cold creams, lotions, liquids, and pads)
230
COSMETIC
2. (Continued)
INGREDIENT
REVIEW
TABLE
No. Product Formulations Total No. Containing Product Category* Jngredient 3 >25-50 > IO-25 >5-10 >l-5 1 >O.T-I 1 50.1 1 Within Each Concentration Range f%)
Face, body, and hand skin care preparations Moisturizing arations Night skin care preparations Paste masks (mudpacks) Skin lighteners Skin fresheners Other skin care preparations 1981 TOTALS (excluding shaving preparations) skin care prep
1 -
1 1 1 1 2
1 1
80 1
No. Product Total No. Containing Product Category* Clycol 1 2 12 1 6 1 1 4 1 Ingredient >50 > IO-25 >5-JO Within
Formulations Range I%) >o. I-I so. 1
Each Concentration >l-5
Dipfopylene
Bath oils, tablets, and salts Colognes Perfumes Sachets Other fragrance preparations Hair sprays (aerosol fixatives) Hair shampoos ing) Tonics, (noncolorand other aids and toilet waters
1 -
1 1 1 1 -
dressings,
hair grooming Wave sets Lipstick Makeup bases Deodorants Aftershave
(underarm) lotions
4 1 -
Skin cleansing preparations (cold creams, lotions, liquids, and pads) 3 Face, body, and hand skin care preparations (excluding shaving preparations) Foot powders and sprays Moisturizing arations Skin fresheners Wrinkle smoothers (re1 50 9 6 movers) Other skin care preparations 1981 TOTALS *Preset 720.4). 2 skin care prep3
1 -
1 1 10
2 1 .14 -
4 regulations (21 CFR
product categories and concentration
ranges in accordance with federal filing
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BIOLOGICAL Absorption,
PROPERTIES and Excretion
Metabolism,
Romsos and associates(**) investigated the effects of Butylene Glycol on lipid metabolism in rats, pigs, and chicks. The animals were fed a basal high carbohydrate diet that contained approximately 20 percent protein and 5 percent fat. In the test diets, Butylene Glycol was substituted isocalorically for the carbohydrate. The diets were offered ad lib except for 1 experiment in which pigs were fed to satiety twice daily. Controls received the basal diet. Addition of up to 20 percent Butylene Glycol to the diet did not affect body weight gain of the 3 species. Blood fi-hydroxybutyrate content increased in all 3 species. Plasma triglyceride concentrations decreased in the rat, increased in pigs, and remained the same in chicks. Plasma glucose decreased in the rat and remained stable in pigs and chicks. Dietary Butylene Glycol decreased the rate of fatty acid synthesis in the liver of rats, but there was no such effect in pigs or chicks. Mehlman et al.(23) studied the metabolic fate of Butylene Glycol in the rat. Two groups of 14 rats each were fed for up to 7 weeks either a control diet of 70 percent carbohydrate and 30 percent fat or 45 percent carbohydrate, 30 percent fat, and 25 percent Butylene Glycol. Body weight gain and epididymal fat pad weight decreased in test animals receiving the test diet. Blood acetoacetate and fl-hydroxybutyrate concentrations were increased significantly. Blood pyruvate concentration was decreased significantly in animals fed this glycol for 7 weeks. The metabolism of glucose and Butylene Glycol to ketones by hepatic tissue taken from test animals was also studied. The conversion of glucose to lactate and pyruvate was decreased, as was the concentration of ketones. In liver slices, Butylene Glycol was metabolized to acetoacetate and P-hydroxybutyrate. Butylene Glycol, therefore, is metabolized in the cytosol and converted by the liver to ketones; it is then oxidized in the tricarboxylic acid cycle. Tate et al.(24) also studied the metabolic fate of Butylene Glycol in rats. They found that the conversion of the glycol to /3-hydroxybutyrate in the liver was dependent on NAD and inhibited by pyrazole. They found that hepatic alcohol dehydrogenase was the catalyst in the catabolism of the glycol to an intermediate aldol and then to /3-hydroxybutyrate. Mehlman et al.(25) also reported that hepatic alcohol dehydrogenase was the enzyme responsible for the initial oxidation of Butylene Glycol. The metabolites of Butylene Glycol in the brain of rats were determined by Morris et al.(26) The animals were fed diets containing 1 of the following: 47 percent dietary calories as glucose, 47 percent calories as Butylene Glycol, or 47 percent calories as ethanol for 62 days. The animals were killed and metabolites in the brain were determined. Butylene Glycol significantly decreased glutamate, lactate, and pyruvate concentrations. Glucose concentrations and the NADPl NADPHIDH ratios were also decreased. Rats and mice excreted up to 40 percent of a 200 mg daily oral dose of Hexylene Glycol in the urine. (*) An oral 1 mmol/kg dose of Hexylene Glycol administered to rabbits was excreted as glucuronate (67 percent of original dose).(28) When administered orally or by subcutaneous injection to rabbits, Ethoxydiglycol was oxidized in the body or excreted as glucuronate. Such administration was followed by a marked increase in the urinary content of glucuronic acid.(2g)
232
COSMETIC
INGREDIENT
REVIEW
Reproductive
Physiology
The effect of the ingestion of Butylene Glycol on pregnant rats and on the metabolism of their offspring was studied. r30) Groups of pregnant rats were given water (control) or Butylene Glycol (9 percent w/v) in drinking water. Treatment was continued throughout the period of gestation and lactation. The length of gestation was not affected by the glycol. The investigators found that rats that ingested Butylene Glycol through gestation bore offspring with a slight increase in RNA content in neurones taken from the cerebral cortex at 18 days. In 8- and 18-day-old pups, protein synthesis in the liver was significantly reduced. In amino acid incorporation studies, neuronal perikarya from 8-day-old pups incorporated 45 percent more amino acids into acid-insoluble polypeptides than did controls. However, protein synthesis in neurons from 18-day-old pups was severely inhibited by maternal ingestion of the glycol. Therefore, maternal treatment with the glycol exerted opposite effects on neuronal protein synthesis at different stages of postnatal development of progeny. Amino acid incorporation by free and membrane-bound ribosomes from liver of 8- and 18-day-old pups was increased by Butylene Glycol.
Neuropharmacology
and Behavior
Ayers and lsgrig (31) studied the effect of Butylene Glycol on the behavior of rats in several experiments. To study its effect on voluntary activity (running), the compound was administered intragastrically in a 3.5 g/kg dose, once a week for 3 weeks. Glycerol, water, sucrose, or a sham was administered on 4 other days in the week. Butylene Glycol depressed voluntary running activity; this finding might be due to the glycols interference with hunger motivation, since intubation of the compound depressed food and water intake. These investigators also studied the dose-effect of Butylene Glycol on food and water intake and urine output in several different experiments. In one study, groups of 8 male Charles River Sprague-Dawley rats were fed Butylene Glycol in doses of 0, 1.75, 3.5, 5.25, or 7.0 g/kg. Corn oil was added to the last 4 dosages to produce a constant caloric value. Distilled water and lecithin (emulsifier) were also added to produce a constant dose volume of 11.4 ml/kg. Each dose was administered to each animal daily over a 5-day period. Ingestion of the glycol produced a dose-related depression of activity and food and water intake. In another experiment, 10 male Charles River Sprague-Dawley rats were trained to balance on a rotating dowel. Butylene Glycol (7.0 g/kg) was administered once a week for 3 weeks. Other animals received glycerol, sucrose, or ethanol. The glycol produced more falls than any of the other test compounds. The glycol-treated rats were barely able to stand, and Butylene Glycol apparently acted as a CNS depressant or a muscle relaxant. The effects of Butylene Glycol on neuropharmacology, behavior, and CNS function were studied in male and female Sprague-Dawley rats, which were given IP doses of 0.2 g/ml of Butylene Glycol in sterile 0.15 M saline.32 Control animals were given equal volumes of saline. Another group of rats was fed a liquid diet containing Butylene Glycol in increasing concentrations (0.07 g/ml for 2 days; 0.08 g/ml for 2 days; 0.09 g/ml for 3 days; then 0.1 g/ml for 5 days). The IP administration of the glycol caused a dose-related impairment of motor coordina-
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tion 1 hour after treatment as measured by aerial righting reflex. Administration of the compound depressed cGMP content in the cerebellum but did not alter plasma-leuteinizing hormone. Conflict behavior, as measured by the number of electrical shocks accepted by rats, was attenuated after treatment with glycol, i.e., more shocks were accepted by treated rats than by control rats. Compound treatment also caused a decrease in blood pH and blood pressure. When ethanol-withdrawn rats were acutely treated with Butylene Glycol, a dose-related decrease in tremors was observed. Feeding of rats caused no significant motor coordination impairment, and all rats gained weight. After 12 days, the glycol was removed from the diet. No tremors developed after 1 hour, but 1 of 9 rats developed seizures. After 7.5 hours, tremors increased, and 33 percent of the rats developed seizures; 1 died.
Microbiological
Effects
Butylene Glycol can be used as the sole carbon source by some strains of mycobacteria.) However, other investigators found it to be toxic to some microorganisms and useful as a cosmetic preservative.(lg) Harb and Toama34) reported that Butylene Glycol is the most efficient polyol as an antimicrobial agent. It inhibits both gram-positive and gram-negative microorganisms, as well as molds and yeast. However, it is not sporicidal. Those microbes against which Butylene Glycol is effective include Escherichia co/i, Pseudomonas aeroginosa, Staphylococcus aureus, Corynebacterium hofmanii, Aspergillus niger, Aspergillus fumigatus, Pityrosporum oxalicurn, Fusarium sp., and Candida albicans.
Animal Oral Toxicity Acute Studies
Toxicology
The acute oral LDSO of Butylene Glycol was 23 g/kg in rats(6.35) and 11 g/kg in guinea pigs.(35 A nail lotion containing 5.0 percent Butylene Glycol had an LDso of > 5 g/kg in rats, (36) and a product containing 21.35 percent Butylene Glycol produced no deaths when fed to rats at 15 g/kg.(37) Windholz(6 reported the acute oral LDso of Hexylene Glycol in rats was 4.70 g/kg. Other sources reported an oral LDSO of 4000 mg/kg for rats,(35) 3290 mg/kg for rabbits,38 2800 mg/kg for guinea pigs,38 and 3900 mg/kg for mice.(35) A skin care product formulation containing 1.6 percent Hexylene Glycol was found to be slightly toxic or practically nontoxic when administered orally to groups of 10 rats in 4 separate assays. (3g)An eye makeup remover containing 1 .O percent Hexylene Glycol caused no deaths when administered orally to 10 mice at 15 ml/kg. c40) The acute oral LDso values for Ethoxydiglycol are: in rats, 5.54 g/kg; in mice, 6.58 g/kg; and in guinea pigs, 3.87 g/kg. (41) A paste mask product formulation containing 2 percent Ethoxydiglycol caused no signs of toxicity when administered orally to 10 rats at 13 ml/kg. (42) A body lotion containing 1 .O percent Ethoxydiglycol caused no deaths when 15 ml/kg oral doses were administered to 10 mice. (43)
234
COSMETIC
INGREDIENT
REVIEW
The acute oral LDso of Dipropylene Glycol in rats was 15 g/kg.35 A shaving preparation containing 7.2 percent Dipropylene Glycol had an oral LDso of >5 g/kg. (44) Subchronic Studies
For subchronic effects of Butylene Glycol, see also the Metabolism section of this report. Larsen(*) reported that Hexylene Glycol fed to mice daily at 5, 10, or 20 mg Hexylene Glycol for 57 to 81 days produced no effect on growth curves. Also, rats receiving up to 150 mg of this glycol in the diet daily for 4 months had no abnormality in growth, behavior, or fertility; some changes were present in renal tissue of rats of the 200 mg/day group.(*) No effect was caused by the daily consumption of 0.49 g/kg Ethoxydiglycol by each of 5 rats for 30 days. However, 0.87 g/kg caused reduced feed consumption. (45) Four groups of Charles River Wistar rats, each consisting of 12 males and 12 females, were fed diets containing 0 (control), 0.25, 1 .O, or 5.0 percent Ethoxydiglycol for periods up to 90 days. Observations were made of body weight, food intake, hematological parameters at 6 and 12 weeks, kidney function, blood urea concentration, and urine composition. Organs examined were the liver, kidneys, brain, spleen, heart, adrenals, and gonads. The investigators found that throughout the 90 days, the general conditions remained good. One male rat in the 5 percent group died on Day 23; there was weight loss and degeneration of renal tubules and liver. Growth rates of male and female rats were reduced when fed the 5 percent diet, and this was associated with a decrease in food consumption. No hematological changes were produced by any diet. However, activity of urinary glutamic-oxaloacetic transaminase was increased in both sexes fed the 5 percent diet, which was indicative of impaired renal function. An increase in weight of the kidneys occurred in both sexes fed the 5 percent diet. No other important changes were found.(46) The effect of subchronic ingestion of Ethoxydiglycol was studied in rats, mice, and pigs. The glycol was fed for 90 days to groups of 15 male and 15 female rats at dietary concentrations of 0 (control), 0.5, or 5 percent and to groups of 20 male and 20 female mice at dietary concentrations of 0 (control), 0.2, 0.6, 1.8,or 5.4 percent. Three groups of 4 male and 4 female pigs were fed daily oral doses of 0 (control), 167, 500, or 1500 mg/kg. There was a reduction of growth in rats and mice at the highest concentrations. All 3 species had reduced hemoglobin concentration at the highest doses administered. Oxaluria occurred in rats and mice at highest concentrations. Three pigs given 1500 mg/kg per day for up to 21 days died with signs of uremia. For the surviving pigs, the dose was then reduced to 1000 mg/kg per day. Six of the 20 male mice fed the 5.4 percent diet died of renal damage. The relative weights of the kidneys was increased in all 3 species fed the highest concentration of glycol and in mice fed the 1.8 percent diet. Microscopic changes were hydropic degeneration of the proximal renal tubules in all 3 species fed the highest dosage and in pigs receiving 500 mg/kg per day. Hydropic degeneration of the hepatocytes was observed in those pigs above a dose of 500 mg/kg. Hepatic cell enlargement was found in those mice fed the 1.8 and 5.4 percent diets. The no effect level for Ethoxydiglycol in rats was 0.5 percent of the
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diet. In mice it was 0.6 percent of the diet, and in pigs it was 167 mg/kg per day.(47)
Chronic
Studies
Butylene Glycol was fed to Sprague-Dawley weanling rats and beagle dogs for 2 years. In the rat study, 60 male and 60 female control rats were fed a basal diet and water ad lib. Three test groups of 30 male and 30 female rats each were fed diets containing 1 .O, 3.0, or 10.0 percent Butylene Glycol for 2 years. Observations were made on body weight, food consumption, compound consumption, pharmacological effects, urinalysis, and gross appearance. Erythrocyte and leukocyte counts, packed cell volume, and hemoglobin values were determined. At 1 year, 10 animals from each group were killed, and all survivors were killed at the end of 2 years. Representative organs were weighed and examined microscopically. These tests were negative for deleterious or toxic effects due to the ingestion of Butylene Glycol at any dietary concentration.48) In the study using beagle dogs, a control group of 4 males and 4 females were fed a basal diet, and 3 similar groups received diets containing 0.5, 1 .O, or 3.0 percent Butylene Glycol. Daily or weekly observations were made of feed intake, elimination, clinical appearance, pharmacological effects, and feed and compound consumption. The blood, urine, and representative organs were examined as with the rat portion of the study described above. Two animals from each group were killed after 1 year and the remainder after 2 years. As with the rats, no toxic effects were produced by the ingestion of Butylene Glycol at any dietary concentration.(48) Ethoxydiglycol was fed to rats at 1 .O g/kg per day for 2 years. The rats had slight hepatic damage, some interstitial edema in the testes, and in 1 animal, oxalate crystals in the kidney.(26)
Parenteral
Toxicity
The subcutaneous LDso of Butylene Glycol in mice and rats was 16.5 ml/kg and 20.1 ml/kg, respectively. (I) No deaths were caused by intraperitoneal injection of 1 .O g/kg Butylene Glycol into 5 mice. (4g) Butylene Glycol was evaluated for tissue irritation using chicken pectoral muscle. Injections of 0.5 ml of the glycol, 1.3 cm deep into the right and left pectoral muscle of each of 6 chickens, caused only minimal tissue irritation.(50) Hexylene Glycol had a subcutaneous LD50 of 13 g/kg in rabbits and rodents (38) The intraperitoneal LDso of Hexylene Glycol in the mouse was 4.5 ml/ kg. (51; N IOSH (35) lists the intraperitoneal LDso in mice as 1299 mglkg. The subcutaneous LDso of Ethoxydiglycol in mice was 5500 mg/kg.(38) In rats and rabbits, it was 3.4 ml/kg and 2.0 ml/kg, respectively.52 The intraperitoneal LDso of Ethoxydiglycol in rats was 6310. mglkg. (3*) The intravenous LDso in dogs was 3000 mg/kg and in cats, 5000 mg/kg. (38) Other investigators report intravenous LD,,s in mice, rats, and rabbits as 3.9, 2.9, and 0.9 ml/kg, respectively.(52) The intraperitoneal LD50 of Dipropylene Glycol in rats and mice was 10 g/kg and 4600 mg/kg, respectively. (35)The intravenous LDso in rats and dogs was 5800 mg/kg and 1 1,500 mg/kg, respectively.35)
236
COSMETIC
INGREDIENT
REVIEW
Inhalation
Toxicity
Rats survived an 8-hour exposure to the saturated, room temperature vapors of Hexylene Glyc~l.(~) Cutaneous Toxicity
Acute Studies The cutaneous LDso of Hexylene Glycol in rabbits and rodents was 13.2 g/ kg.(38 A product formulation containing 5.0 percent Butylene Glycol had a cutaneous LD50 of >2 g/kg when tested in rabbits.(361 The cutaneous LDso of Ethoxydiglycol was 6 g/kg in ratst3*) and 10.3 g/kg in rabbits.53 A product formulation containing 7.2 percent Dipropylene Glycol produced a cutaneous LD50 of >2 g/kg when tested in rabbits.t4 Subchronic Studies
A product formulation containing 3 percent Butylene Glycol was applied daily at 500 mg/kg to the clipped intact and abraded skin of each of 8 albino rabbits for 4 weeks. A control group of 8 rabbits remained untreated. All of the animals survived the duration of the study. Clinical observations of compound-related importance were confined to the skin, which had slight erythema with drying and flaking. No systemic effects as evidenced by microscopic tissue examination were attributable to the test material.(54) Skin Irritation Primary irritation
Undiluted Butylene Glycol produced no more than minimal skin irritation when tested under occlusion on the skin of rabbits for 24 hours55 or daily for 4 consecutive days.(56) Undiluted Hexylene Glycol produced moderate irritation when 465 or 500 mg was applied to the skin of rabbits for 24 hours.3s) A 24-hour application of 1.84 g/kg undiluted Hexylene Glycol to the skin of rabbits caused mild edema and erythema.(57) Undiluted Ethoxydiglycol was a mild irritant when applied to rabbit skin (500 mg for 24 hours). (38) According to Rowe, (57) it is a nonirritant to rabbits. Undiluted Dipropylene Glycol caused mild irritation when 500 mg was applied to rabbit skin for 24 hours.(38) Several product formulations containing 5.0 to 21.4 percent Butylene Glycol, 1 .O to 1.6 percent Hexylene Glycol, 1 .O percent Ethoxydiglycol, or 7.2 percent Dipropylene Glycol were tested for 24 hours under occlusion on rabbit skin (Leberco Labs). (36,44.58-64) e products produced no irritation to moderate irritaTh tion, depending upon the particular formulation tested. The degree of irritation did not correlate with the concentration of glycol. Cumulative Irritation
A daily dose of 0.5 ml of a paste mask product formulation containing 2 percent Ethoxydiglycol was applied to the backs of 3 albino rabbits for 14 consecu-
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237
tive days. Each treatment site was rinsed with warm tap water 30 minutes after treatment. There was slight erythema 24 hours after the initial application that had disappeared by 48 hours. There were no other signs of irritation.(42 Ocular irritation
According to NIOSH, (35) 505 mg of undiluted Butylene Glycol applied to the rabbit eye was an irritant. No irritation was observed when 0.1 ml of undiluted Butylene Glyc01~~ or a 40 percent aqueous solution of Butylene Gly~ol(~~) was instilled into 1 eye of each of 6 rabbits. Irritation was severe when 93 mg undiluted Hexylene Glycol was instilled into the eyes of rabbits,381 and Rowe57) reported that this glycol caused cornea1 damage in a rabbit. A 25 percent aqueous solution of Hexylene Glycol caused no ocular irritation when tested in the rabbit.(67 Moderate toxic effects were found in the eyes of rabbits instilled with 500 mg undiluted Ethoxydiglycol. Mild effects were caused by 125 mg.(38) Laillier et al.(68) studied the ocular effects of Ethoxydiglycol and other chemicals using the rabbit. The chemicals were applied to a series of 4 animals at application frequencies of 1, 3, 6, 7, and 13 times over periods of 2, 4, 7, 26, and 58 hours. The chemicals were used either pure or as a 25 percent dilution in distilled water in 0.1 ml volumes. Ocular edema was measured by the following formula: mg dry tissue weight mg wet tissue weight
x 100
In addition, aqueous humor and conjunctival content were assayed for effects 1 hour after Evans blue solution was injected into the rabbits marginal ear vein. Ethoxydiglycol was very irritating to the rabbits eye in this assay system (Table 3). Undiluted Dipropylene Glycol is an irritant in the rabbit eye in an amount of 5 10 mg. (35) Several product formulations containing 5.0 to 21.35 percent Butylene Glycol, 1 .O percent Hexylene Glycol, 1 .O to 2.0 percent Ethoxydiglycol, or 7.2 percent Dipropylene Glycol produced no more than minimal, transient irritation when instilled into the eyes of rabbits.(36.42*44.69-72 Another product formulation containing 1.6 percent Hexylene Glycol produced mild to moderate irritation in the eyes of rabbits. (73)This formulation had also produced mild to moderate irritation when applied to the skin of rabbits.
Clinical Nutritional and Metabolic
Assessment Studies
of Safety
Tobin and associates(74) investigated the nutritional and human metabolic effect of Butylene Glycol. Three studies were conducted. In the first experiment, the effect of Butylene Glycol and urea in the nutrition of 12 men and women was studied. The volunteers went through a 2-day depletion period in which nitrogen intake was 1.23 g/day. Caloric intake was evaluated and adjusted so that during the 4- to 7-day test periods subjects consumed diets with constant caloric content. Dietary variation was randomly distributed during
TABLE
3.
Ocular Irritation
in Rabbits by Measuring
Tissue
Edema: Ethoxydikol(68) Conjunctivae
No. of instillations (4 Rabbits Each) Ethoxydiglycol (undiluted) 1 3 6 7 13 25% Ethoxydiglycol distilled water in 1 3 6 7 13 *Time in hours over which instillations different from controls confidence limits. 95% made. lime* (hours) 2 4 ,7 26 58 2 4 7 -26 58 (% Dry Weight) 13.9 12.7 13.1 16.4 15.9 17.7 20.7 .18.6 20.8 19.4 f f f f * f f f
l
(pg Evans Blue/ g Dry Weight) 439 439 497 906 988 f f f f f aa+ 92+ 168+ 171+ 283+ 28+ 23 34+ 32+ 27
Corneas (% Dry Weight) 24.1 21.2 18.6 17.1 15.8 24.8 25.3 25.5 27.1 f f f f f f * f f 1.2+ 2.0+ 1.9+ 1.5+ 1.4+ 1.3
1.5
Aqueous Humors (pg Evans Blue/ml) 135.1 21.7 9.0 10.9 29.5 3.3 0.8 11.6* 12.8 5.6 f f f f
l
0.8+ 1.3+ 0.6+ 1~9+ 1.0+ 1.1+ 0.8 1.4 0.4 1.4
69.1+ 16.0+
4.9+
f f f f
8.0+ 22.9+ 2.6+ 0.25 8.6+ 11.9+ 3.0+
189 f 91 f 178 & 177 f 139 f
25.9l
1.2 1.5 1.0
+Significantly Mean f
(Students t-test).
FINAL
REPORT:
SAFETY
ASSESSMENTOF
THE
CLYCOLS
239
the 4 experimental periods: 1 in which the glycol (15 g) was substituted isocaloritally for starch in the diet, 1 in which starch without the glycol was ingested, 1 in which urea (4 g of nitrogen/day) was added to the diet, and the fourth and final period in which the glycol and urea were added to the diet. Butylene Glycol, as compared to starch, caused a significant decrease of urinary nitrogen excretion. Subjects fed urea or glycol plus urea had a significant increase in urinary excretion of nitrogen. The glycol did not increase fecal nitrogen excretion, but urea feeding did. Feeding the glycol or urea or the combination caused a less negative nitrogen balance than did the starch feeding. The glycol caused a lowering of blood glucose and no increase in blood ketones. The investigators concluded that Butylene Glycol can be used as a caloric source by human beings. The second study investigated the .effect of Butylene Glycol on endocrine function and its influence on glucose homeostasis. Twenty-seven women volunteered for a 15day experiment in which one half were fed 40 g of Butylene Glycol per day for 5 days or a calorically equivalent quantity of sucrose for 5 days. At the end of 5 days, the diets were switched. Mean blood glucose concentrations and serum insulin concentrations were lower in the second and third weeks of ingestion. The glycol had no effect on triglyceride or cholesterol concentrations. Fasting insulin and growth hormone concentrations were somewhat increased by the glycol. In the third study, 10 adult male and female volunteers were fed for 12 days 6 g of nitrogen per day, starch, and vitamin and mineral supplements. The Butylene Glycol was substituted isocalorically for sucrose to provide 10 percent of the total caloric intake. Glucose tolerance tests were performed on the sixth and twelfth days of the test. Glucose concentrations were normal, as were free fatty acid and growth hormone values. Serum insulin values and blood pyruvate and lactate values were normal, and /3-hydroxybutyrate, acetoacetate and triglyceride values were likewise normal. Butylene Glycol was nontoxic in these tests.74 Skin Irritation/Sensitization A Shelanski and Shelanski repeated insult patch test was conducted on 200 volunteers (80 male, 120 female) to assess the irritation and sensitization potentials of Butylene Glycol. The compound was diluted to 50 percent in water, and 0.9 ml of the mixture was applied under occlusion to sites on the upper arm. After 24 hours of contact, the patches were removed and the sites were graded on a scale of 0 (no reactions) to 4+ (erythema, edema, vesicles, and extensions beyond the site of contact). After 24 hours, the sites were reexamined. If no changes occurred, a second patch was reapplied to the same site. This cycle was repeated each Monday, Wednesday, and Friday. After the fifteenth application, sites were not treated for a 2-week period, and then 24-hour occlusive patches were applied to the same sites. Test areas were graded immediately and then at 24 and 48 hours after patch removal. The investigator reported visible skin change in one subject after applications 4-6 and in another after applications 1315. No reactions were caused by the challenge patch. Butylene Glycol was a mild fatiguing agent in 2 of 200 test subjects. With statistical extrapolation, greater than 98 percent of the general population would not be sensitized to Butylene Glyc~l(~) (Table 4). Undiluted Butylene Glycol was applied to the volar skin of the forearms or
240
COSMETIC
INGREDIENT
REVIEW
TABLE
4.
Clinical Skin
Patch Tests with Butvlene
Clycol and Hexylene No. of Subjects 37
Clycol
Concentration Test Method 24-hour elusive single insult patch Material Tested Butylene Clycol Vd 100
Results Occlusive reactions patch; no
Reference 75
occlusive or semioc39
Semiocclusive patch; 1 subject with mild irritation
Hexylene
Clycol
100
37
Occlusive minimal
patch; irritation max,
76
(primary irritation index 0.11; 4.0) 39 Semiocclusive patch; minimal ritation irritation 0.02; Shelanski and Shelanski patch occluButylene Glycol 50 (in water) 200 (primary index ir-
max, 4.0) irritation no 19
Mild skin
repeated insult test (24-hour
in 2 subjects; sensitization
sive patches 3 days/ week for 15 induction patches; challenge patch after 2week rest)
medial arms of 37 human subjects under occlusion and 39 subjects under semioccluded conditions for 24 hours. One subject in the semioccluded panel had evidence of mild irritation; no other reactions were observed in either panel75 (Table 4). Hexylene Glycol was tested in an identical fashion, producing primary irritation indices of 0.11 (scale 0 to 4) for the occluded patch and 0.02 for the semioccluded patch. These scores are indicative of only minimal irritation(76) (Table 4). Fisher) reported that cross-reactivity (sensitivity) may occur between Butylene Glycol and propylene glycol. A number of product formulations containing 1 of the glycols at concentrations of 0.016 to 21.4 percent have also been tested for skin irritation and sensitization in humans (Table 5). in single insult occlusive patch tests, products con-taining 3.0 to 21.4 percent Butylene Glycol produced no more than minimal irritation.77-so Several multiple insult tests were conducted on products containing a glycol in which no irritation to moderate irritation was found depending upon the particular product tested. There was no correlation between the degree of irritation and the concentration of glycol (Table 5). Results indicative of irritation cannot be interpreted without knowledge of the other ingredients in a formulation. Of the 1087 subjects tested in skin sensitization assays (Schwartz-Peck and Draize-Shelanski tests), there were no reactions indicative of sensitization to any of the glycols (Table 5).
FINAL
REPORT:
SAFETY
ASSESSMENT
OF THE
CLYCOLS
241
Photoreactivity Four studies included exposure to ultraviolet light as a supplement to the Schwartz-Peck prophetic patch tests and Draize-Shelanski repeated insult patch tests on a nail lotion containing 5.0 percent Butylene GIy~ol(~) and on a shaving preparation containing 7.2 percent Dipropylene Glyc01(~*) (Table 5). The ultraviolet light exposure was to a Hanovia Tanette Mark I quartz lamp at a distance of 12 inches for 1 minute. This lamp has a wavelength coverage of 240 to 370 nM, with a peak at 365 nM. None of the subjects in the Schwartz-Peck tests had reactions when a single UV exposure was made after the second insult. The DraizeShelanski tests included UV exposure after induction patches 1,4, 7, and 10 and after the challenge patch; there were no reactions (Table 5). Ocular Irritation
A drop of Butylene Glycol applied to the eyes of humans caused immediate severe stinging similar to that induced by propylene glycol. Irrigation with water brought rapid relief.(83) When human subjects were exposed for 15 minutes to a vapor concentration of 50 ppm of Hexylene Glycol, ocular irritation occurred.57) Inhalation Toxicity
Nasal and respiratory discomfort occurred from a concentration of 100 ppm aerosolized Hexylene Glycol, and at 1000 ppm irritation of the eyes, nose, throat, and respiratory tract were noted. Industry Complaint Experience
A skin care product containing 1.6 percent Hexylene Glycol had 43 safety-related complaints in 4 years with 243 million units distributed.t9) A shaving preparation containing 7.2 percent Dipropylene Glycol had 7 safety-related complaints in 3 years with 2.3 million units sold; 2 of these were listed asrash and 5 as irritated skin.(98)
SUMMARY Butylene Glycol, Hexylene Glycol, Ethoxydiglycol, and Dipropylene Glycol are viscous liquids used in the cosmetic industry as humectants, emulsifiers, plasticizers, and solvents. They are added to various types of cosmetic products at concentrations up to 50 percent. The Glycols also have many noncosmetic uses and have been given Direct and/or Indirect Food Additive status by the FDA. Various animal species and man metabolize Butylene Glycol and use it as a source of calories. The results of acute, subchronic, and chronic oral toxicity studies using a variety of animal species indicate a low order of toxicity for the Glycols. Results of parenteral injection, inhalation, and acute and subchronic cutaneous toxicity studies likewise support a low order of toxicity. Butylene Glycol, Ethoxydiglycol, and Dipropylene Glycol caused minimal to mild irritation of rabbit skin, whereas Hexylene Glycol was moderately irritating. The Glycols produced mild to severe ocular irritation when tested in rabbits, and Hexylene Glycol produced the most severe irritation. Although undiluted Hexylene Glycol
TABLE
5.
Clinical Skin Patch Tests with Product Formulations
Containing
Glycols
No. of Test Method

24-hour patch Foundation makeup 16.0 Butylene Glycol 19 Minimal irritation. Also imcluded patch with minimal 80 77 84 78 semiocclusive irritation Mascara Rouge Soap chamber test: 1 24-hour followed by 4 daily 6-hour applications Cumulative in Duhring test Eye shadow chambers on volar forearm irritancy (daily 23-hour occlusive Paste mask Schwartz-Peck prophetic patch Nail lotion 2.0 Ethoxydiglycol 5.0 Butylene Glycol 12 104 Personal cleanliness product 8.0 Butylene Glycol 3.0 Butylene Glycol 0.13 Hexylene Glycol (8% aqueous dilution of product containing 1 .6%) 21.35 Butylene Glycol 10 Slight irritation; was 70/630 Essentially total composite max total commax UV ex81 86 score 85 20 20 10 Minimal irritation No signs of irritation Moderate irritation single insult occlusive Material Eye shadow
Jested
Concentration 21.35
(%i
Subjects 20 Minimal
Results irritation
Reference 79
Butylene Glycol
patch for 21 days) nonirritating; posite score was 361630 No reactions; supplemental insult Shaving preparation 7.2 Dipropylene Glycol 101 test (open and closed 48 hour patches, repeated after
posure at open patch after second produced no reactions with closed patch in 6 and in 8 82
2 weeks)
Mild irritation subjects at first exposure and supplemental after second insult actions Draize-Shelanski repeated inFoundation makeup 16.0 Butylene Glycol 108 Mild irritation; no sensitization 87 sult patch test (24- or 48. hour patches 3 days/week for 9 or 10 induction patches; challenge patch after 2-week rest)
subjects at second; open patches, UV exposure produced no re-
Nail lotion
5.0 Butylene
Clycol
49
No irritation;
no sensitization.
Sup-
81
plemental UV exposure
after in-
duction patches 1, 4, 7, and TO and after challenge showed no photosensitization Rouge Eye makeup remover Personal cleanliness product 0.048 Hexylene Glycol 52 Mild irritation induction: at original with fatiguing during 4 reactions on challenge site with 2 persisting Reacwith natural 90 (3% aqueous dilution of product containing 1 .6%) 3.0 Butylene 1 .O Hexylene Glycol Clycol 108 103 Slight irritation; Mild irritation; no sensitization no sensitization 88 89
and 3 reactions on challenge at alternate site with 1 persisting. tions at challenge consistent induction sunlight cation irritation sites exposed to 30 minutes
reactions. Test
24 hours after each applino sensitization 90
Personal cleanliness product
0.016
Hexylene
Glycol
52
Mild irritation;
(1% aqueous dilution of product containing 1 .6%) 0.016 Hexylene Clycol 106 No significant tion irritation; no sensitira91 (1% aqueous dilution of product containing 1 .6%)
Paste mask Body lotion Shaving preparation
2.0 Ethoxydiglycol 1 .O Ethoxydiglycol 7.2 Dipropylene Glycol
213 93 50
Minimal Minimal
irritation; irritation;
no sensitization no sensitization Supplemental
92 93 82
Mild irritation UV exposure
with probable fatiguafter induction
ing; no sensitization.
patches 1, 4, 7, and 10 and after challenge showed no photosensitization Controlled Controlled use test: 4 weeks use test: 2 weeks Mascara Shaving preparation Personal cleanliness product 8.0 Butylene 1.6 Hexylene Glycol Glycol Clycol 50 59 80 No reactions No reactions Minimal irritation 94 95 96 7.2 Dipropylene
244
COSMETIC
INGREDIENT
REVIEW
produced severe ocular irritation, a 25 percent aqueous solution produced no signs of irritation. Feeding studies in man indicated that Butylene Glycol was metabolized and nontoxic. Single insult 24hour skin patch tests on undiluted Butylene Glycol and undiluted Hexylene Glycol showed a very low order of primary skin irritation potential for these ingredients. In a repeated insult patch test, Butylene Glycol produced mild skin fatigue in 2 of 200 test subjects but no evidence of skin sensitization. A number of product formulations containing the Glycols at concentrations up to 21.4 percent have been tested in various human skin irritation and sensitization assays (Table 5). The degree of irritation produced depended upon the particular formation. There was no correlation between the degree of irritation and the concentration of the Glycol present in the formulation. There were no reactions indicative of skin sensitization to the Glycols in any of the 1087 subjects tested under skin sensitization assays. Supplemental exposure to ultraviolet light in some of the skin sensitization tests on product formulations produced no reactions suggestive of phototoxicity or photosensitization. Butylene Glycol and Hexylene Glycol were irritating to the human eye. And Hexylene Glycol was irritating to the respiratory tract at concentrations significantly higher than those generally found in cosmetic products.
CONCLUSION Based on the available data, Butylene Glycol, Hexylene Glycol, Ethoxydiglycol, and Dipropylene Glycol are safe as presently used in cosmetics.
ACKNOWLEDGMENT Jeffrey Moore, MD, Scientific Analyst and writer, prepared the technical analysis used by the Expert Panel in developing this report.
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FINAL
66. 67. 68.
REPORT:
SAFETY
ASSESSMENT
OF THE
CLYCOLS
data. CIR safety data test summary. data. CIR safety data test summary. M.J. (1975, Eye irritation Eye irritation
247
CTFA. CTFA.
(Dec. 29, 1977). Submission Glycol.* Glycol.* (May 1, 1973). Submission
test of test of
Butylene Hexylene LAILLIER, ritation 69. CTFA. 70. 71. 72. 73. 74. 75. 76. 77. 78. CTFA.
(CTFA Code 2-17-73). (CTFA Code 2-l 7-94). B., DE DOUAREC, J.C., and GONIN, 1976). Evaluation of ocular irProc. Eur. Sot. ToxiEye irritation Eye irritation test of test of of an objective method of studying eye irritation. of unpublished of unpublished data. CIR safety data test summary. data. CIR safety data test summary. of unpublished of unpublished data by CTFA. data by CTFA.
J., PLAZONNET,
in the rabbit: Development (Jan. 15, 1972). Submission Butylene Butylene (Nov. 17, 1976). Submission LABORATORIES. LABORATORIES.
col. 17, 336-50. product containing product containing LEBERCO LEBERCO CTFA. TOBIN, CTFA. CTFA. CTFA. CTFA. Glycol.* Glycol. (CTFA Code 2-17-80). (CTFA Code 2-17-83). Rabbit eye irritation Rabbit eye irritation Rabbit eye irritation and Hexylene Glycol.* (CTFA Code 2-17-30).
(May 19, 1980). Submission (Dec. 23, 1980). Submission Ethoxydiglycol.* of unpublished Hexylene
test of eye makeup remover containing test of body lotion containing (1978-1979). R.B., Submission M.A.,
(CTFA Code 2-17-26). data. CIR safety data test summary. Glycol.* (CTFA Code 2-17-135). and SOELDNER, J.S. (Nov. 1975). Nutritional 2171-6. Human skin irritaHuman skin irritaHuman Human skin irritaskin irrita-
tests of skin care product containing MEHLMAN, metabolic studies
KIES, C., FOX, H.M., of unpublished of unpublished of unpublished Glycol.* Glycol.* of unpublished of unpublished Glycol.* of unpublished Glycol.* Butylene
in humans with 1,3-butanediol. Glycol.* Glycol.
Fed. Proc. 34(12),
(Aug. 16, 1973). Submission (Aug. 16, 1973). Submission (Feb. 27, 1974). Submission (Nov. 13, 1975). Submission
data. CIR safety data test summary. data. CIR safety data test summary. data. CIR safety data test summary. (CTFA Code 2-17-93). data. CIR safety data test summary. (CTFA Code 2-17-88). data. CIR safety data test summary.
tion test of Butylene tion test of Hexylene
(CTFA Code 2-l 7-78). (CTFA Code 2-l 7-95). Butylene Butylene
tion test of product containing tion test of product containing test of product containing 80. 81. 82. 83. 84. 85. 86. 87. 88. CTFA. CTFA. insult CTFA. GRANT, CTFA. HILL HILL CTFA. HILL (Feb. 12, 1976). (1981).
79. CTFA. (Jan. 15, 1976). Submission Submission
Human skin irritation Human skin irrita-
Butylene
(CTFA Code 2-17-82). data. CIR safety data test summary. (CTFA Code 2-17-85). Prophetic patch and repeat Glycol.* (CTFA Code 2-17-161). Prophetic and repeated insult
tion test of product containing Submission
Butylene
data. CIR safety data test summary. data. CIR safety data test summary. Glycol.*
patch tests of nail lotion containing (1978). Submission W.M. (1974).
patch tests of product containing Toxicology (Feb. 1978). TOP TOP Submission
Dipropylene
(CTFA Code 2-17-167). IL: Charles C Thomas. Human Human skin irritation irri(CTFA Code 2-17-128). data by CTFA. data by CTFA. cumulative
of the Eye, 2nd ed. Springfield, Hexylene Glycol.*
of unpublished
data. CIR safety data test summary. of unpublished of unpublished
test of personal cleanliness RESEARCH. RESEARCH.
product containing Butylene
(Feb. 5, 1980).
Submission Glycol.*
tancy test of product containing irritant properties
(CTFA Code 2-17-68). The study of cumulative test of product con.
(July 16, 1979). Submission of unpublished
of a series of test materials.* Glycol.* (CTFA Code 2-17-70).
(CTFA Code 2-17-6). data. Allergic contact sensitization of unpublished data by CTFA.
(March 4, 1977). Submission TOP RESEARCH. LABORATORIES. of eye makeup
taining Butylene of ten samples. 89. TESTKIT test 90. CTFA.
(Nov. 3, 1976). Submission Butylene
Repeated insult patch test Repeated insult patch
Rouge containing
Glycol.*
(CTFA Code 2-17-72). of unpublished data by CTFA.
(July 31, 1980). Submission
remover containing Hexylene Glycol.* (CTFA Code 2-17-28). (July 1976). Submission of unpublished data. CIR safety data test summary. Repeated insult patch sun exposure of personal cleanliness product containing Hexylene Glycol.* (CTFA Code patch patch
test with 2-17-126). 91. CTFA.
(Jan. 1978). Submission
of unpublished
data. CIR safety data test summary. Hexylene Glycol.* data. CIR safety data test summary. (CTFA Code 2-17-3).
Repeated insult Repeated insult
test of personal cleanliness
product containing
(CTFA Code 2-17-125).
92. CTFA. (July 1979). Submission of unpublished testing of product containing Ethoxydiglycol.* 93.
TESTKIT LABORATORIES. (March 31, 1981). Submission of unpublished data by CTFA. patch test of body lotion containing Ethoxydiglycol. (CTFA Code 2-17-24). (March 29, 1976). Submission of unpublished data, Clinical use test.*
Repeated insult
94. CTFA.
(CTFA Code 2-17-69).
248
95. 96. 97. CTFA. CTFA. CTFA. (1978). Submission of unpublished
COSMETIC
data. CIR safety data test summary. (CTFA Code 2-l 7-l 68).
INGREDIENT
Human
REVIEW
use test of shaving use test of per-
preparation
containing
Dipropylene
Glycol.* Hexylene
(Sept. 1981). Submission
of unpublished
data. CIR safety data test summary. Glycol.* (CTFA Code 2-l 7-124). data. Industry data. Industry
Human
sonal cleanliness uct containing 98. CTFA. tion containing
product containing Glycol.*
(Feb. 26, 1982). Submission Hexylene (June 11, 1982). Submission Dipropylene
complaint experience on skin care prodcomplaint experience on shave prepara-
(CTFA Code 2-17-137). (CTFA Code 2-17-169).
Glycol.

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RAW MATERIAL SPECIFICATION

Match to standard Match to standard

<=100cfu/g Must Pass Must Pass

9184535 9413173 9413173

RAW MATERIAL SPECIFICATION

ACACIA SENEGAL GUM EXTRACT

Appearance Odor Microbial Content Test

Match to standard Match to standard <=100 cfu/g

1476468 2846466 9184535

RAW MATERIAL SPECIFICATION

Appearance Odor Identification Specific Gravity

Match to standard Match to standard Match to standard 1.004 1.007

1476468 2846466 JSCI methods 2987147

RAW MATERIAL SPECIFICATION

Appearance Odor Identification Assay

Match to standard Match to standard Match to standard 99.0 % minimum

1476468 2846466 JSCI method JSCI method

RAW MATERIAL SPECIFICATION

Appearance Odor Identification Assay Melting Point

1476468 2846466 USP method USP method USP method

RAW MATERIAL SPECIFICATION

Match to standard Match to standard 0.94 - 0.98 N/A

1476468 2846466 2987147

________________________________________________ M. Jones Senior Scientist Research & Development ASEAN Company

Part II. A Specifications and test methods of raw material / ingredients

SCIENTIFIC COMMITTEE ON CONSUMER PRODUCTS SCCP

the Safety Evaluation of Parabens

Adopted by the SCCP by written procedure on 28 January 2005

SCCP/0873/05 Opinion on the safety evaluation of parabens

SCCP/0873/05 Opinion on the safety evaluation of parabens

SCCP/0873/05 Opinion on the safety evaluation of parabens

Recent Official Reports on Parabens

SCCP/0873/05 Opinion on the safety evaluation of parabens

The European Food Safety Authority (EFSA), EFSA 2004

SCCP/0873/05 Opinion on the safety evaluation of parabens

SCCP/0873/05 Opinion on the safety evaluation of parabens

SCCP/0873/05 Opinion on the safety evaluation of parabens

SCCP/0873/05 Opinion on the safety evaluation of parabens

SCCP/0873/05 Opinion on the safety evaluation of parabens

SCCP/0873/05 Opinion on the safety evaluation of parabens

SCIENTIFIC COMMITTEE ON CONSUMER PRODUCTS SCCP

OPINION ON Benzoic Acid and Sodium Benzoate

Adopted by the SCCP during the 4th plenary of 21 June 2005

SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate

TABLE OF CONTENTS 1. BACKGROUND 3

SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate

COLIPA European Cosmetics Toiletry and Perfumery Association

SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate

Benzoic acid Sodium benzoate 3.1.1.3. / 3.1.1.4.

Trade names and abbreviations

Benzoic acid : Sodium benzoate : 3.1.1.5.

Structural formula Benzoic acid Sodium benzoate

Empirical formula C7H6O2 C7H5O2Na

Benzoic acid : Sodium benzoate : 3.1.2.

Physical form solid solid

Benzoic acid : Sodium benzoate :

SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate

Molecular weight 122.13 144.11

Purity, composition and substance codes

Impurities / accompanying contaminants

Benzoic acid : Sodium benzoate : 3.1.7.

2.91 g/l in water at 20oC 556 g/l in water at 20oC, hygroscopic

Partition coefficient (Log Pow) 1.88 -2.269

Benzoic acid : Sodium benzoate : 3.1.8.