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Appearance Odor Microbial Content Test (Total Plate Count) (Absence of Psuedomonas species) (Absence of E. Coli)
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 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 .
RAW MATERIAL SPECIFICATION METHYLPARABEN Items Specifications Methods Appearance Odor Identification Assay Melting Point Match to standard Match to standard Match to standard 99.5 % 125 – 128 C 1476468 2846466 USP method USP method USP method .0 – 100.
0.RAW MATERIAL SPECIFICATION PERFUME Items Specifications Methods Appearance Odor Specific Gravity Microbial Content Test (Total Plate Count) Match to standard Match to standard 0.98 N/A 1476468 2846466 2987147 .94 .
CERTIFICATE The perfume described below complies with the latest IFRA (The International Fragrance Association) guidelines. Jones Senior Scientist Research & Development ASEAN Company _____________ Date Part II.. 35894 Smiling Street. Australia ________________________________________________ M. Perfume name / code : Rose ver 1 Name of Supplier : Address of supplier: Max Fragrance Co. A Specifications and test methods of raw material / ingredients . Sydney. Ltd. specify the name and code number of the fragrance. name and address of the supplier.For fragrance materials. NSW. declaration of compliance with the latest IFRA guidelines .
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 EUROPEAN COMMISSION HEALTH & CONSUMER PROTECTION DIRECTORATE-GENERAL Directorate C .Public Health and Risk Assessment C7 .
SCCP/0873/05 Opinion on the safety evaluation of parabens TABLE OF CONTENTS 1. 6. 3. 5. BACKGROUND TERMS OF REFERENCE OPINION CONCLUSION MINORITY OPINION REFERENCES ACKNOWLEDGEMENTS 3 3 4 8 10 10 11 2 . 2. 4. 7.
Annex VI. propyl.4 % in the finished product for 1 ester and up to 0. data to substantiate its safety should be submitted to the SCCNFP.8 % for mixtures of esters. ethyl-. 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. part 1. BACKGROUND Parabens (4-Hydroxybenzoic acid. 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-. 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. TERMS OF REFERENCE The SCCP was asked to answer the following questions: 1.SCCP/0873/05 Opinion on the safety evaluation of parabens 1. when incorporated into cosmetic formulations for nonpreservative functions. 2.and butylparaben)? 3 . If yes. 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. 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. the Scientific Committee on Cosmetic Products and Non-Food Products intended for Consumers (SCCNFP) stated that those substances indicated by (+) in Annex VI. its salts and esters) are regulated by Cosmetic Directive 76/768/EEC. reference 12 and can therefore be used as a preservative up to a maximum concentration of 0. should be subjected to the same restrictions in usage levels and warnings as when used for preservative effects.
SCCP/0873/05 Opinion on the safety evaluation of parabens
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
SCCP/0873/05 Opinion on the safety evaluation of parabens
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:
SCCP/0873/05 Opinion on the safety evaluation of parabens
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 17β-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.
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
3. Conflicting results have been reported for p-hydroxybenzoic acid tested in vivo. butyl paraben showed some clear effects at the two highest dosage levels. p-Hydroxybenzoic acid. including increased epididymal weights.c. but the doses used in the in vivo test were not higher than the ones tested for all other parabens (1. In another study. Male neonatal Wistar rats s. 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. This study. One study claims that it has no estrogenic effect. and the offspring were examined. subcutaneous or dermal administration.3. 7 . 146 and 1504 mg/kg bw/day. Paulsen and Alexander 2003]. No dose-response relationship was observed [Oishi 2002b]. and again the values remained several magnitudes of order below the potency of 17β-estradiol. On the contrary. [Darbre et al. but remains at all times 1000 to 1. another study gives potency values 1000-fold below the 17β-estradiol level [EFSA 2004. a four-week administration via the diet (0. Effects of parabens on the male reproductive system Methyl. appeared to be inactive in the in vitro assays. 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. Both tested dosages showed clear effects. ethyl. As far as propyl paraben is concerned.000 times below the potency of 17β-estradiol. 10. equivalent to approximately 24 and 240 mg/kg bw). amongst which a decrease in sperm count and sperm motile activity in the epididymus [Kang et al. propyl and butyl paraben have been examined for effects on the reproductive organs in the male offspring of rats and mice. in daily sperm production and in serum testosterone [Oishi 2001]. injected with daily dosages of 100 or 200 mg butyl paraben/kg bw from gestational day 6 to postnatal day 20. though at a dosage of 100 mg/kg bw/day. bisphenol A and octylphenol administered at high dosages. Darbre et al. 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. butyl paraben appeared being more potent than propyl.4.000. a decrease in sperm count. despite of a decrease in testis spermatid count and in serum testosterone levels. 1000 mg/kg bw/day) to the Wistar rat showed similar effects as caused by butyl paraben. the common metabolite of all parabens.c. The authors conclude that the studies clearly show that isobutyl paraben is more potent. demonstrated only very minor effects for compounds such as genistein. pregnant Sprague Dawley rats were s.2 and 12 mg isobutyl paraben/mouse. published a study on the estrogenic activity of isobutyl paraben in vitro and in vivo (subcutaneous administration). Anonymous 2004. Administered to ICR (Cjr:CD-1) mice in the diet for 10 weeks at dosage levels of 14. 2002].SCCP/0873/05 Opinion on the safety evaluation of parabens The estrogenic potency increases with increasing length and branching of the alkyl side chains (methyl < ethyl < propyl < butyl < isobutyl).2. ethyl and methyl paraben. The propyl ester caused only minor effects at 10 mg/kg bw/day. however. Again. 2002]. The authors were unable to explain this discrepancy [Oishi 2002a]. 100. In 2002. 1999].
Foetuses were evaluated on gestation day 20. Taking together the above-mentioned studies. Dosages of 103 and 1030 mg/kg bw/day failed to induce adverse effects [Oishi 2004]. 4. however. by lack of a clear NOAEL value. when used up to the maximum authorized concentration in cosmetic products.3 of this opinion. foetal weight. Very recently. a detailed developmental toxicity evaluation of butyl paraben given by oral gavage to Sprague-Dawley rats became available [Daston 2004]. in order to define an exact NOAEL for propyl paraben. 3. No differences from the control group could be observed in any of the developmental parameters including embryo/foetal viability.4. also decreased in that group for the gestation days 6-20 interval. 8 . underarm cosmetics and breast cancer [SCCP/0874/05].SCCP/0873/05 Opinion on the safety evaluation of parabens Recently. Flavourings. ethyl and propyl p-hydroxybenzoic acid esters and their sodium salts [SCF 1994]. The Panel on Food Additives. Processing Aids and Materials in Contact with Food came to the conclusion that the ADI remained unchanged for methyl. Maternal food consumption was. 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]. This is in accordance with the results of the estrogenicity tests. 10. 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. the European Food Safety Authority reviewed the safe use of parabens in food. Anonymous 2004].2. 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. It was also concluded that. methyl and ethyl paraben have been tested for effects on secretion of sex hormones and the Wistar rat male reproductive system. • CONCLUSION Is the concern justified that parabens. This issue will therefore not be reconsidered in the present opinion. but that for propyl paraben no ADI could be established. 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. 100 and 1000 mg/kg bw/day were administered on gestation days 6-19 (sperm positive day being gestation day 0). malformations or variations. ethyl paraben and their sodium salts. Dosage levels of 0. it is clear that butyl paraben shows the highest potency with regard to effects to the male reproductive system. The maternal NOAEL for butyl paraben was established on 100 mg/kg bw/day. additional studies were necessary [EFSA 2004. as described under point 3. The highest dosage level caused decreases in maternal weight gain (significant during gestation day 18-20 interval).
79 g/day is a clear overestimation for the normal male population. It must not be forgotten. 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. In that study. however. rete testis distention and efferent duct epithelial cell height [Fisher 1999]. embryo viability and maintenance of pregnancy [Daston et al. 9 .4%. butyl and isobutyl paraben Propyl paraben The developmental rat study provided for propyl paraben failed to indicate a clear NOAEL value. It is known that potent estrogens interfere with the development of the reproductive system. Propyl. 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. but it suggested that the potency of propyl paraben is clearly lower than the potency of butyl paraben [Oishi 2002b]. these parameters could be responsive indicators of estrogenicity. a developmental study on butyl paraben became available.SCCP/0873/05 Opinion on the safety evaluation of parabens Therefore. Although indirectly. This leads to the suggestion that butyl paraben did not have a strong estrogenic potential during the developmental study. - 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]. 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. It is the opinion of the SCCP that the available data do not enable a decisive response to the question of whether propyl. 1997]. The LOAEL-value for propyl paraben in Wistar rats was shown to be 10 mg/kg bw/day [Oishi 2002a]. For the latter. butyl and isobutyl paraben can be safely used in cosmetic products at individual concentrations up to 0. that the majority of cosmetic products will be used by females. 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.4%). Especially the cumulative cosmetic exposure value of 17. Very recently. placental function. aquaporin-1 immunoexpression. The major adverse effects of concern caused by propyl paraben involve the male reproductive system. embryonic growth. Therefore industry is requested to provide the complete developmental toxicity dossier of these three esters of p-hydroxybenzoic acid.
22(4).E. a complete dossier with regard to the reproductive and developmental toxicity of propyl. Breslin W. Byford J.A. REFERENCES Anonymous. butyl and isobutyl paraben. 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-. MINORITY OPINION Not applicable 6. Opinion of the Scientific Panel on Food Additives. adopted on 13 July 2004 The EFSA Journal 83.W. Developmental toxicity evaluation of butylparaben in Sprague-Dawley rats.and butylparaben)? Methyl and ethyl paraben For the methyl and ethyl p-hydroxybenzoic acid esters. Department of Toxicology and Risk Assessment. 296-302 (2004). Reprod Toxicol..R..P. September 2004. it is the SCCP's opinion that more information is needed in order to formulate a final statement on the maximum concentration of propyl. Processing Aids and Materials in Contact with Food on a Request from the Commission related to para hydroxybenzoates (E214-219).L. Nikiforov A. 71(4).. butyl and isobutyl paraben As the present discussion is based solely upon data in the literature. Horton R.. More specifically. Question number EFAS-Q-2004-063. Birth Defects Res Part B Dev Reprod Toxicol. the following data are requested before end of March 2005: full descriptions of available in vitro percutaneous absorption studies. 5. EFSA.SCCP/0873/05 Opinion on the safety evaluation of parabens • If yes. Danish Institute of Food and Veterinary Research. propyl. Sauer M. 11(4). with special focus on the male reproductive system. Fico T. Shuey D. isopropyl. Darbre P..I. 219-26 (2002). the maximum authorized concentrations remain unchanged. Environmental estrogens and reproductive health: a discussion of the human and environmental data.P.. butyl and isobutyl paraben allowed in cosmetic products. Cosmetics and Consumer Products. Gorsuch J.. J Appl Toxicol. Flavourings. Daston G.D.. ethyl-. 10 .W. isopropyl. Pope G. 465-481 (1997)... isopropyl.S. 1-26 (2004). Daston G.J.. Gooch J. Shaw L.A. Propyl.J. Note on Parabens in Food.. Oestrogenic activity of isobutylparaben in vitro and in vivo.
Paulsen J. Norwegian Institute of Public Health (2003). Decreased sperm number and motile activity on the F1 offspring maternally exposed to butyl p-hydroxybenzoic acid (butyl paraben). Rogiers Prof. Che JH.eu. 42(11).. Lack of spermatotoxic effects of methyl and ethyl esters of p-hydroxybenzoic acid in rats. Oishi S. Kang KS. Oishi S. I. ACKNOWLEDGEMENTS Members of the working group are acknowledged for their valuable contribution to this opinion. and Alexander J. 397-405 (1999). J Vet Med Sci. 1845-1849 (2004).J. Turner K. 227-235 (2002). Underarm Cosmetics and Breast Cancer.. Krutmann Prof. 107(5). Oishi S. Chambers Prof. C. V. Arch Toxicol. Sharpe R. 64(3). The members of the working group are: Dr. Kapoulas Prof. Dubakiene Dr. S.9-12. Brown D.C. Oishi S. 76(7). 31-9 (2001). Revuz Prof. Food Chem Toxicol. 40(12). Jazwiec-Kanyion Prof. V.. Toxicol Ind Health. p.pdf (consulted Nov 2004). 1807-1813 (2002a). adopted by written procedure on 28 January 2005 SCF.-P. C. Kim TW. Effects of butylparaben on the male reproductive system in rats. Food Chem Toxicol. Evaluation of parabens in cosmetic products. J.R. Effects of propyl paraben on the male reproductive system. Li GX. Reports of the Scientific Committee for Food (Thirtyfifth series). 17(1).Opinion of the Scientific Committee on Consumer Products on Parabens. J. SCCP/0874/05 .SCCP/0873/05 Opinion on the safety evaluation of parabens Fisher J. Effects of butyl paraben on the male reproductive system in mice. J. Grimalt Dr. http://europa. T. Sanner Prof. Speit Dr. Rastogi Prof. B. G.M.S. White (Rapporteur) (Chairman) 11 . Opinion on p-hydroxybenzoic acid alkyl esters and their sodium salts expressed on 25 February 1994.E. R. Effect of neonatal exposure to estrogenic compounds on development of the excurrent ducts of the rat testis through puberty to adulthood Environ Health Perspect. Lidén Prof.int/comm/food/fs/sc/scf/reports/scf_reports_35. 7. Ryu DY. 423-429 (2002b). European Commission. Marty Dr. Lee YS. R.
Public Health and Risk Assessment C7 .SCCP/0891/05 EUROPEAN COMMISSION HEALTH & CONSUMER PROTECTION DIRECTORATE-GENERAL Directorate C .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 .
......... MINORITY OPINION ………………………………………………… 25 5....... 29 2 .. ACKNOWLEDGEMENTS ............... OPINION ………………………………………………… 4 3.................... REFERENCES ………………………………………………… 25 6..........SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate TABLE OF CONTENTS 1.. CONCLUSION ………………………………………………… 25 4..... BACKGROUND ………………………………………………… 3 2.............
its salts and esters are used for non-preservative purposes in cosmetic rinse-off products at a maximum concentration of 2. there is no review of other salts of benzoic acid or any of its esters. 2. 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”.5%. its salts and esters (COLIPA1 No.1. and in leave-on products up to 0.7 %. its salt and esters. for other specific nonpreservative purposes apparent from the presentation of the products.SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate 1.” It was stated furthermore. BACKGROUND 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. On the basis of provided data the SCCP is asked to assess the risk to consumers when Benzoic acid. that “the SCCNFP can only assess the safety of substances for which appropriate data has been submitted for evaluation. These will require separate evaluation when the necessary data have been made available. The SCCNFP adopted an opinion on 4 June 2002 on Benzoic acid and Sodium benzoate (SCCNFP/0532/01. TERMS OF REFERENCE 1. In its opinion the SCCNFP stated. when used at concentrations other than those laid down in Annex VI to Directive 76/768/EEC as preservatives. Safety assessment is specific and not generic. its salts and esters safe when used for non-preservative purposes in cosmetic products? 1 COLIPA – European Cosmetics Toiletry and Perfumery Association 3 . Therefore.5 % and in cosmetic oral-care products at a maximum concentration of 1. 2. Does the SCCP recommend any further restrictions with regard to the use of Benzoic acid. final). the European Commission received Submission II on Benzoic acid. Only toxicological data for benzoic acid and its salt sodium benzoate have been made available for review. P 2). Recently.
18.104.22.168.1. carboxybenzene. benzene formic acid.SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate 3.5.1. Chemical names Benzene carboxylic acid. phenylcarboxyl acid. Chemical identity Primary name and/or INCI name Benzoic acid (INCI name) Sodium benzoate (INCI name) 3. E210 E211 Benzoic acid Sodium benzoate 22.214.171.124.1. Structural formula Benzoic acid Sodium benzoate 126.96.36.199.1. OPINION 3.4. Physical form solid solid Benzoic acid : Sodium benzoate : 4 . Empirical formula C7H6O2 C7H5O2Na Benzoic acid : Sodium benzoate : 3.1. Chemical and Physical Specifications 3.1. 3. 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. benzene carboxylic acid.1.1. phenylformic acid.1. / 3.1.1.
hygroscopic Partition coefficient (Log Pow) 188.8.131.52 Benzoic acid : Sodium benzoate : 3.321 g/cm3 at 20°C / -2.269 Benzoic acid : Sodium benzoate : 3.SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate 3. composition and substance codes Impurities / accompanying contaminants Benzoic acid : Sodium benzoate : 3.269 / / 5 . Molecular weight 122.13 144.9°C / 0.91 g/l in water at 20oC 556 g/l in water at 20oC.4.1. Solubility Purity.1. 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 249.88 -2.1.0011hPa 1.0 °C 464.7.6. No data 3. 2. No data 3.2°C / 0.269 / / >300.3.1.0011hPa / -2.1.5.
SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate
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).
SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate
3.3. 3.3.1. 184.108.40.206.
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
Acute dermal toxicity
Benzoic acid Rabbit
LD50 > 5 000 mg/kg LD50 > 10 000 mg/kg Ref.: 14, citation only
Acute inhalation toxicity
No data submitted with Submission II (2004) Benzoic acid Rats LC50 > 0.026 mg/l/h Ref.: 14, citation only
SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate
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
24. 24h application of 30% benzoic acid in ethanol was found to be the lowest irritating concentration. sodium benzoate was neither corrosive nor irritating (PII 0) when applied to the intact rabbit skin under semi-occlusive patch conditions for four hours. 2% benzoic acid in petrolatum over 46h did not irritate intact skin of healthy volunteers.: 19. (80 %). are from studies both on volunteers and patients from dermatological clinics. rather than allergic. Ref. Ref.: 16 Application of 500 mg sodium benzoate as a dry powder to rabbit for 24 h.: 20 8 out of 627 patients (1. (73 %) and the open test. It was considered not irritating. in petrolatum under an occlusive dressing for 24 or 48 h.SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate GLP : in compliance Approximately 24 hours prior to the treatment. lowest irritant concentration Ref.5 % and 15 % benzoic acid in ethanol on scarified skin. 1977.0 % in ethanol Normal skin : 7. Frosch & Kligman. 1976 cited in 13 Chamber test (72 h/occlusive): 0. Results Scarified skin 15. A paste. was applied evenly to 6 cm² Metalline on a permeable tape (Micropore). 15 atopic and 16 non-atopic patients.: 17 Human Studies Benzoic Acid The results. 1986. : Gad et al.: 18 9 . the authors suggest that these results could be interpreted as marginally irritating. The test substance does not need to be labelled as a skin irritant. the dorsal fur was shaved.5 % in ethanol. There was no statistical difference between atopics and non-atopics. Non-atopics showed 80% redness in both the chamber test and in the open test. Ref. Under the conditions of the study. The skin reactions were assessed approx. 48 and 72 hours after termination of the exposure. The 6 cm² patch was removed four hours after semi-occlusive contact. There are no details of study.25 ml water). presented only in scientific papers. responses were scored at end of treatment and after 48 h.3%) from dermatological clinics showed positive reactions to 5 % benzoic acid. 21 Chamber test (20 min/occlusive).5 g sodium benzoate and 0. moderate irritant : marked irritant with erosions : 30 % in ethanol. Ref. open test (30 min): 15 µl of 5 % benzoic acid in petrolatum. Kligman. 30 % benzoic acid in ethanol on normal skin (6 volunteers). At this concentration. The atopics showed redness in both the chamber test. (0. Ref. 1 hour.1 ml of 7. The animals did not show any symptoms of systemic intoxication.
Ref.2. Annex V of EEC Directive 84/449/EEC New Zealand albino rabbit 3 females Benzoic acid > 99.1 and 1.2. The untreated left eye was used as a control. it was demonstrated that benzoic acid induced non-immune immediate contact reactions in the majority of 200 volunteers with no specific skin condition. 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. symptoms or exacerbation of the symptoms were observed”. following 20 min covered contact.05 % benzoic acid in water elicited reactions. was specific to an individual with no significant correlation with age or sex on the degree of NIICR. In the chamber test. erythema and oedema.: 54 The Concise International Chemical Assessment Document (CICAD) No. This effect is scarce in healthy subjects. Mucous membrane irritation : : : : : : : : EEC test method B. After application.SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate Non-immunologic contact urticaria Benzoic acid (5. atopic status or tanning ability.: 55 3. The product was poured into the right conjunctival sac.: Clemmensen &Hjorth.3.0% benzoic acid. both substances are known to cause nonimmunologic immediate contact reactions. 26 conclusion on benzoic acid and sodium benzoate was: “However.1 % benzoic acid in petrolatum and 0. The response.0 % in petrolatum) was tested in an open test on 29 atopic and 74 non-atopic persons. Ref.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. 20 min occlusion (recorded 10 min later) 0. Approximately 10% of the volunteers appeared particularly sensitive. The degree of eye irritation was 10 . In another study. When water was the vehicle.: AR6 Urticaria occurred in 1/10 and 5/12 healthy volunteers with 0.5. 1982 cited in 13 Non-immune immediate contact reactions (NIICR). the lids of the treated eye were held closed for approximately two seconds. 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. Ref. while in patients with frequent urticaria or asthma. It was not clear if this was an irritant or immune response. reacting fairly strongly. erythema or oedema. the reactions were oedematous. Ref.
with translucent corneal opacity and iridial injection. The corneal opacity noted in the first animal increased to nacreous areas. it was not completely resolved by Day 21 but it was resolved in Animal 3 by Day 14. Comment This experiment was conducted in 1988. Animal 1 showed no reaction to light. The slight conjunctival redness in all animals increased to severe with a white/grey discolouration.: 15. was a citation of a single application of 100 mg dry powder to the rabbit eye. cited in BUA (14) Instillation of 50 mg benzoic acid into the conjunctival sac of 2 rabbits. 48 and 72 hours and 7. The irritation score was 65. 48 and 72 hours and 7. Animal 2 showed iridial injection on Day 2.SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate evaluated at immediately after dosing. The degree of eye irritation was evaluated at immediately after dosing. but was resolved in Animal 3 by Day 7. the iridial injection was resolved but no reaction to light. but the information was not provided in Submission 1. 1. Results Moderate irritation. The authors considered benzoic acid was considered as a mild irritant. 14 and 21 days after treatment. 48. It persisted in Animals 1 and 2 up to Day 21 and in Animal 3 to Day 7. After application. In Animal 2. After 60 min. 11 . The chemosis decreased slowly. All 3 had moderate chemosis and slight conjunctival redness. 24.: 23. This is just a summary. The translucent areas of opacity persisted up to Day 21. 1. In Animals 1 and 2. The animals did not show any symptoms of systemic intoxication. The untreated left eye was used as a control. It was scored at 24. The estimated Draize score of 35 (60 min) is classed as severely irritating according to Kay and Calandra.: 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. it should be labelled as an eye irritant. Ref. The other 2 also had slight corneal opacity.0/110. Ref. 24. By Day 14. 14 and 21 days after treatment. This persisted for 72 h. the slight corneal opacity also persisted up to Day 21. cited in BUA (14) Additional information that was not mentioned but quoted in the BUA reference. Under the EU criteria. but the data provided is inadequate. in Animal 1. and 72 h. Ref. the lids of the treated eye were held closed for approximately two seconds.
These were in-house tests with no further details.3.5% / 60 mg ground as a fine powder in compliance The test substance was instilled in a single application. a Magnusson-Kligman test and a Buehler test were reported.3) and in the EC classification. the lids of the treated eye were held closed for approximately two seconds. 1.3. 24.SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate Ref. Results: not irritating. responses were scored at 24 h. Benzoic Acid did not induce sensitization in either test and was thus considered to have low skin sensitization potential. Ref. After application. Skin sensitisation Benzoic acid Animal tests The results of two in vivo guinea pig assays.: 24 Application of 50 mg sodium benzoate/rabbit for 24 h. 48 h and 72 h.: 25 12 . 14 and 21 days after treatment. 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. The degree of eye irritation was evaluated at immediately after dosing. Ref. Ref. post-exposure observation time: 7 d.: cited in BUA (14) Comment The data provided is inadequate. Under the conditions of this study. 48 and 72 hours and 7. It was considered mildly irritating (Kay and Calendra score 9. The product was poured into the right conjunctival sac.: 17 3. The untreated left eye was used as a control. sodium benzoate produced irritation of the conjunctiva that was reversed within 14 days. There was no effect on the cornea or iris.
: 56 Sodium benzoate Human There were 2 additional human patch test references that were not included with any of the submissions.4. No reactions at 48. Ref. Ref. et al. The results showed that benzoic acid was an occasional or positive sensitizer (Rademaker & Forsyth. 25 human volunteers were given five 48 h patch tests (over a 10 d period) with 2 % benzoic acid in petrolatum.. 5 gave positive results.SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate Human volunteer studies Benzoic Acid at 2 % and 5 % in petrolatum did not induce sensitization in two maximization tests. J.: 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. C-labelled benzoic acid was injected subcutaneously and applied dermally to the neck skin of dogs. Excretion of benzoic acid in man 14 13 . Ref. Human data were obtained from earlier investigations. Samples of penetrated amounts were measured in 1.: 40 Percutaneous absorption of benzoic acid was studied in the Mexican hairless dog and in man. 1989. patch tests gave positive nonimmunologic contact urticaria (Nethercott.R. The first was a large cohort of 2045 patients. 14 Dermal / percutaneous absorption C-labelled benzoic acid (4 . Forsbeck & Skog.: 56 3. These gave occasional positive results (Brasch.: 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. but allergic reactions was noted in 34 patients (0.: 27 In a cosmetic intolerance assay. In the second test. 1993).2 hr interval over the first 24 hrs and 3-6 hrs interval over the remaining days. 1984). J.. This report included 2 additional human patch test references that were not in the submissions. 1977) Ref. This information is as a summary only.7% incidence) to benzoic acid. A median of 45% of the applied benzoic acid was found in the receptor phase 48 hrs after application. 5202 patients with suspected allergic contact dermatitis were patch tested (537 of the patients had a history of “intolerance” or allergy). 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. Ref.3.40 µg/cm2 dissolved in acetone) was applied to excised human skin in a static diffusion chamber. 72 and 96 h. No occlusion or washing were applied and the investigation was determined at least in duplicate. Ref. Patch test conditions were not specified.
1984. 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. It should be noted that the exposure of the in vitro and in vivo studies were extremely long (2 days and 5 days. (1974) Comment: This study is available on IUCLID but was not submitted. exhibited normal body weight gains during the 14 day observation period. All surviving rats. Ref : IUCLID. corn oil / The test compound was suspended in corn oil and administered orally.5.6 % of applied dose.1.: 14 14 . The total penetration of radio-labelled benzoic acid was found to be approximately 43 % in a 5-day period. 3. 3150.3. total absorption was 42. almost complete by day 3. Volumes of 10 ml/kg bw were administered at all dosage levels. B.3.: 41 3.0 %/h. This in vivo result is comparable with in vitro test results obtained.5. respectively). 6 test subjects received a dose of 4 µg/cm² Benzoic Acid dissolved in acetone. In this human study. Benzoic Acid Guideline Species/strain Group size Test substance Purity Batch no Dose Vehicle GLP : : : : : : : : : Directive 84/449/EEC. has no effects.1 "Acute toxicity (oral)” 50 Spartan rat 5 male/ female technical grade benzoic acid / / 500. In rats. They were allowed to wash their skin 24 hours after application of Benzoic Acid. Unpublished study (IRDC#163-282). The acute oral LD50 of benzoic acid in female albino rats was calculated to be 2360 mg/kg (2042-2726 mg/kg). 1250. Ref.SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate was rapid. and 5000 mg/kg. Ref. excretion was less extensive and greatly prolonged. 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). 648 mg/kg bw/d in feed for 28 days. This was accounted for by the persistence of benzoic acid in the skin. The acute oral LD50 of benzoic acid in male albino rats was calculated to be 2742 mg/kg (2279-3299 mg/kg). Acute Toxicity Studies in Rats and Rabbits. In the dog. males and females. Maximum absorption rate in man was 3.
25. All treated animals survived and their body weight gain did not differ from controls. (diameter 4. In the 2 % dose group a slight significant body weight depression was observed in male rats. 2. Compound-related microscopic lesions. Exposure to the test material at all levels resulted in an increase in the frequency of pulmonary fibrosis and inflammatory cell infiltrate. Ref. 0. Ref.7 µ) 6 h/day for 5 days/week in compliance At 1. 1. exhibiting irritation of their upper respiratory tract. 24 g/kg bw/d) all mice died within 3 weeks.: 42 In another study the body weight was slightly decreased at 2200 mg/kg bw/d.4 g/kg bw) or 5 % (5.25 mg/l also resulted in an irritation of the upper respiratory tract. Groups of 6 male and 6 female Sherman rats were given 2 % (approx. and 8 % sodium benzoate in drinking water were administered for 35 days to groups of four female and four male Swiss albino mice. The bodyweight of the surviving mice was substantially reduced. 4. Ref.0 to 2.2 mg/l dust aerosol exposure. Ref. In the 5 % dose group. 0. Sprague-Dawley (Charles River CD).7 g/kg bw for females and 7. 10 males + 10 females per dose benzoic acid 59230350 / 0.25 and 1. 12 g/kg bw/d) 3 male and 3 female mice died within the 35-day observation period. In the 4 % dose level (approx. all female rats died by day 11 and males by day 13. 2. nor significant effects on hematologic or biochemical parameters in the 0.025 or 0 mg/l treatment groups were found. were observed.8 g/kg bw for males) sodium benzoate in the diet for 28 days. 0.5.2 mg/l two animals (out of 20) died. The 2 % dose level was chosen for a chronic toxicity (carcinogenicity) study. consisting of an increase in the intensity and extent of inflammatory cell infiltrate and an increase in the incidence. exhibited decreased organ weights and multifocal to generalized pulmonary fibrosis and inflammatory cell infiltrate. No dose related adverse effects were observed.: 44 15 .025.: 10 Inhalation Guideline Species/strain Group size Test substance Batch no Purity Dose Exposure GLP : : : : : : : : : similar to OECD guideline 403 Rat. Exposure to 0. In the 8 % dose level (approx.SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate Sodium benzoate 0. 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. intensity and extent of interstitial fibrosis in lungs of rats from all test groups.: 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. Neither significant effects on organ weights. These animals did not gain as much weight as controls.
: 45 3. and 8 % sodium benzoate equivalent to 640.6. TA 1535 and TA 1537.SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate 3.: 8 3.: 45 Sodium benzoate Groups of 4-5 male and 4-5 female rats received 0. typhimurium TA 92. The weight of liver. 2620. Mutagenicity / Genotoxicity Bacterial Reverse Mutation Test Benzoic acid Benzoic acid (up to 10 mg/plate) was tested in the Salmonella/microsome test using S. 10 mice were tested on their tolerance to CCl4 (test on detoxifying capacity of liver) by giving 0. No further details were given. 2. 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). No further details were given.5.2.6 g/kg bw/d). Data are insufficient to justify a NOAEL of 4 % in the diet (2. TA 98. 1. 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. Ref. Benzoic acid was fed in a paste prior to the main feed. 4/8 animals died (average 13 days to death) in the 8 % dose level group.3. Ref. The relevance of the study will be compared to other long-term and carcinogenicity studies. TA 94. 14 surviving mice were subjected to a restricted dietary intake (90 % restriction) for up to 5 days. Chronic (> 12 months) toxicity Benzoic acid 25 male and 25 female mice were given 40 mg/kg bw/d for 17 months. 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. Data are not sufficient to justify conclusion. Ref. 1320. 4.3.3. Ref. 16 .3. 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).: 45 10 male and 10 female rats received 40 mg benzoic acid/kg bw/d for 18 months. 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. typhimurium strains at the maximum dose.5. Benzoic acid was fed in a paste prior to the main feed. The authors did not mention whether this finding was statistically significant.1 ml CCl4 in an single dose by oral intubation at the end of the test. No significant increases in the numbers of revertant colonies were detected in any S. and 6290 mg/kg bw/d in the diet for 90 days. TA 100.
typhimurium strains at the maximum dose. 200 mg/ml. TA 94.: 32 In vitro mammalian chromosome aberration test in human lymphocytes Benzoic acid Chromosome aberration test was carried out on benzoic acid (up to 1. 38 % of the cells treated with sodium benzoate showed chromosome aberrations at 48 h. Ref. previously established as the lowest toxic level. TA 100. TA1537 and TA1538 in the presence and absence of S9 mix. TA 100. Benzoic acid was non-mutagenic in this test.: 31 Sodium benzoate Sodium benzoate (up to 3. For the mitotic index at least 500 cells were counted. TA 1535 and TA 1537. 200 mg/l. typhimurium TA 97. When sufficient mitoses were observed. typhimurium TA 98.: 33 Benzoic acid (1. 8% chromosome aberration and 1% polypoidy were reported. 17 . No significant increases in the numbers of revertant colonies were detected in any S.: 29 Sodium benzoate Human embryonic lung cells (WI-38) were used. Ref. Sodium benzoate was non-mutagenic in this test.: 30 Benzoic acid was tested in the Salmonella/microsome test using S. TA 1535.5 mg/ml in DMSO) gave equivocal results using Chinese hamster lung fibroblasts. 24 hours after plating. 100 anaphases per dose were analysed. and TA 1537 with and without metabolic activation. Ref. and TA 1537 with and without metabolic activation. Benzoic acid was nonmutagenic in this test (< 0. The test compound was added to three culture bottles for each dose level.: 29 Benzoic acid (up to 10 mg/plate) was tested in the Salmonella/microsome test using S.: 29 Sodium benzoate was tested in the S.5 mg/ml) using Chinese hamster lung fibroblasts. No substance related effects were observed. Dose levels for sodium benzoate were 0. TA100. The chromosome abnormalities as well as the mitotic indices were within normal values. usually after 24-48 hours. TA 1535.1 mg/ml triethylene melamin. TA 100.5 mg/ml) showed structural aberrations at 48 hrs after treatment. Ref. Ref. TA 98. Ref. TA 98. No metabolic activation system was applied.SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate Ref. typhimurium strains TA98. TA1535.0 mg/plate) was tested in the Salmonella/microsome test using S.0 mg/ml) using a Chinese hamster fibroblast cell line. the cells were harvested and prepared for the analysis. Ref. 20. typhimurium TA 92. No metabolic activation system was applied.0099 revertants/nmol). 8 % of the cells treated with benzoic acid (1. The positive control was 0. Sodium benzoate produced no significant chromosomal aberrations in human tissue culture cells when tested at any dose level tested.: 34 Chromosome aberration test was carried out on sodium benzoate (up to 2. 2.
Bone marrow metaphase chromosomes were checked for aberrations.SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate Ref. Tests with Saccharomyces D 3 produced no increases in recombinant frequencies. without metabolic activation. Ref. Ref. 20 µg/ml and 200 µg/ml. 24 and 48 h after dosing in the acute study and 6 h after dosing in the subacute study. 38. Tests with Salmonella G 46 were negative while giving slightly elevated mutant frequencies.002 mol/l showed twofold background effects of chromosome aberrations. The subacute and the other acute dose levels showed no increase in mutant frequencies. 50. These were literature citations with no other information. A low incidence of treatment related breaks was observed in the acute study but within the control range. and two and more and overall dead implants were monitored. 39 In vivo Host-Mediated Assay 0. corpora lutea. 5000 mg/kg bw. Ref. In the subacute study. The mitotic indices were not different from controls. Sodium benzoate did not induce chromosomal aberrations in this test system. 18 .: 36 Chromosome aberration test was carried out on sodium benzoate using human embryonic lung culture cells. single dose or once a day for 5 days) treated male rats.: 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. Sodium benzoate produced no significant increase in the aberration frequency in the anaphase chromosomes when tested at the dosage levels 0. number of implantations. Elevated mutant frequencies were seen with Salmonella TA 1530 in the acute intermediate dose level. Ref. 500. resorptions/pregnant female and proportions of females with one or more dead.: 37. 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. 50. Concentration above 0. only the mid dose showed breaks (1%) but were not considered to be significant. but no increase in the frequency of sister chromatid exchange was observed. No metabolic activation system was applied. was reported to be negative for SCEs in vitro using 3 different cell lines. 35.: 34 In vivo dominant lethal assay A dominant lethal assay was conducted in rats. Following dosing with sodium benzoate by gavage (0. 2. Chromosome aberration test was carried out on sodium benzoate using a pseudodiploid Chinese hamster cell line (DON). were mated with two females per week for 8 weeks (acute study) or 7 weeks (subacute study).0 µg/ml.: 33 In vitro Sister Chromatid Exchange (SCE) Benzoic acid Benzoic acid.: 29. 500 and 5000 mg/kg bw by gavage in an single dose or once a day for 5 days. Ref. 50. pre-implantation losses. 5 per group. Fertility Index. The animals were killed at 6.
Sodium benzoate. Average resorptions were significant. The Committee agrees that since benzylacetate.: 56 JECFA report. micronucleus. Overall dead implants were significant increased at week 7 for the low and intermediate doses and week 2 for the low dose. Kroes) gives no support for this. (also Potassium benzoate and benzyl alcohol) showed no mutagenic activity in in vitro Ames tests. R. 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. however evaluation of the raw data in the original report (by experts of the industry consortium and a recent independent review by Prof. In addition sodium benzoate doesn’t contain a structural alert for genotoxicity.: 52 Scientific Committee on Food Opinion: Re-evaluation of genotoxicity In view of the additional genotoxicity data now available. no genotoxicity was observed in the in vivo cytogenetic. The authors considered sodium benzoate to be non-mutagenic in rats in this test system although positive results were obtained. In addition the authors of the study clearly conclude negative. Potassium benzoate. 19 . dose-related decreases in corpora lutea. FDA also evaluated this study as negative. They also remarked since the sodium salt of benzoic acid instantaneously dissociates to the benzoic acid. Ref. Ref.: Submission 1.SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate In the acute study all three doses showed at week 8 significant. The weight of the evidence of the in vitro and in vivo genotoxicity data indicates that these chemicals are not mutagenic or clastogenic. 33 Remark IPCS CICAD 26 (2000) mentioned this dominant lethal assay as a positive result. Overall dead implants were not increased. 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. Ref. the Committee has compiled its own summary of the studies (Annex 2). or other assays. Benzyl alcohol They concluded that Benzoic acid and Sodium benzoate. Sodium benzoate (and benzyl alcohol) showed no genotoxicity in vivo. Various results were obtained with other in vitro genotoxicity assays. the studies with sodium benzoate are also representative for benzoic acid and potassium benzoate. They also are not carcinogenic in long-term carcinogenicity studies. Ref. While some mixed and/or equivocal in vitro chromosomal/chromatid responses have been observed. at week 7 significant dose-related increases of average pre-implantation losses.: 55 Other recent Evaluations of Genotoxicity OECD SIDS Initial Assessment Report on Benzoates: Benzoic acid. 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.
No evidence of carcinogenicity was seen upon microscopic examination of all analysed tissues. Ref.: 3 3.: 42 Groups of 50 males and 52 female Fischer 344 rats were fed sodium benzoate at 1 or 2 % in the diet (approx. There were no significant differences between the tumour distribution in sodium benzoate-treated and untreated control mice. Carcinogenicity Benzoic Acid: 20 male and 20 female rats were fed 1 % Benzoic Acid (approx. The poor survival in all groups does limit the value of this study. Considering the database as a whole. Ref. Ref. the results of in vivo tests performed with these compounds as well as with sodium benzoate may be applied also to benzoic acid itself.7. 0. two in rats) on sodium benzoate.0 g/kg bw/d) for 18 to 24 months. it is very unlikely that benzoic acid would interfere with chromosomes in vivo.: 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. 5. although the type of tumours was similar between test and control rats of each sex. However. weak genotoxic effects have been reported mainly at chromosome level in some in vitro systems. Around 100 rats including those of the control group died after 16 months of hemorrhagic pneumonia with oedema.: 42 20 .2 mg for a female and 124. The essentially negative results obtained in three carcinogenicity studies (one in mice.SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate benzylalcohol and benzylaldehyde are all metabolised to benzoic acid.0 mg for a male (approx. The average daily intake of sodium benzoate was 119. 700 mg/kg bw/d) in diet for a maximum of 1000 days. nothwithstanding some limitations.5 or 1.6. all the in vivo genotoxicity tests were negative at somatic or germ cell level. Ref. give further reassurance. The control group consisted of 25 males and 43 females.3. 40 rats died during the first 16 months.2 g/kg bw/d). There was no effect of the survival of the treated mice when compared with the untreated control. all other dead animals showed pneumonia with abscess.95 . Differences in the average body weight between the treated and control groups were negligible. except for myeloproliferative disorder developed in one female control rat. No clinical signs directly attributed to sodium benzoate were observed in treated animals. On this basis.
5 g/kg bw d). Groups of 10 Dutch-belted rabbits were artificially inseminated and then dosed by oral intubation with 0.2.5 % group there was a significant prolongation of lifetime. Groups of 21 to 22 pregnant hamsters were dosed with 0. 3. 2.75. 14 and 29. 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. Caesareans were performed on mice. NOAEL: 500 mg/kg bw. The data was considered inadequate. The malformations and resorption rates were comparable to those in control animals. In the 0. Ref. 54 or 250 mg/kg bw on gestation days 6 to 18.8. 1.1 Reproductive toxicity 4-Generation reproductive toxicity Benzoic acid A four generation study with benzoic acid was conducted in rats.SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate 3. 12. 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. Ref. respectively. rats. 20. There were no unfavourable side-effects on growth. hamsters and rabbits on days 17. Males and females of the first and second generation were fed 0. 65 or 300 mg/kg bw on gestation days 6 to 10. Teratogenicity Benzoic acid In a study to determine the teratologic effects. 14. 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.8.3. 8. since only a single dose was used. duration of life. 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.: 41 3. food utilisation. The third generation was treated for 16 weeks and generation 4 was treated until breeding.25 or 0.5.3. procreation.8. weight of organs and histological pattern of organs in the 1 % dose group.: 47 21 . feeding of the offspring.0 % benzoic acid in the diet (approximately 0.5 or 1.3. There was no clearly discernible effect on nidation or on maternal or foetal survival.: 46 Sodium benzoate Sodium benzoate at doses of 0. 3.
as they are all rapidly metabolized and excreted via a common pathway within 24hrs. Human data Included in the appropriate sections 22 . Each material was tested at 10-5. benzaldehyde as a single category from the human health view by JECFA. Following incubation. 1993. there was a summary of an in vitro test by Eberlein-Konig et al. In the JECFA report. Hemolysis was measured as a function of absorbance of 550 nm light. benzylalcohol. Ref. The substances did not produce significant photohaemolysis.3.11. Sodium benzoate is expected to immediately dissociate and form benzoic acid in an aqueous environment.SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate 3. 10-4 and 10-3 mol/l.: 52 3.9.: 52 3. Ref.3. Photo-induced toxicity No data was submitted.3. Suspensions of human erythrocytes were incubated with Benzoic Acid and Sodium Benzoate. Toxicokinetics Benzoic acid and its sodium and potassium salt are considered with benzylacetate. Erythrocyte-free samples were also incubated with the test material and used as controls.10. suspensions and samples were exposed to varying amounts of UVA Iight from one of three sources.
I.25 0.50 67. applied Ioh [mg/day] Eye-products (ep): Maximum content of active ingredient (a.5 0. applied Iro [mg/day] Oral hygiene-products (oh): Maximum content of active ingredient (a.13.84 0.72 18. CALCULATION OF THE MARGIN OF SAFETY Rinse off-products (ro): Maximum content of active ingredient (a. applied Inro [mg/day] Typical body weight (human) TBW [kg] 2.3. I.) [%] E [g/day] Exposure to oral hygiene-products Maximum amount of a.12.SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate 3.05 0. I.5 13.3. I.5 0.43 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. 3. applied Iep [mg/day] Non rinse off-products (nro): Maximum content of active ingredient (a.) [%] Exposure to non rinse-off-products E [g/day] Maximum amount of a. I.50 60 kg Exposure from all product groups: Systemic exposure dose SED [mg/kg bw/d] = [Ioh + Iro + Iep + Inro x A]/TBW = 2.) [%] Exposure to eye-products E [g/day] Maximum amount of a.) [%] Exposure to rinse-off-products E [g/day] Maximum amount of a.7 3.43 mg/kg bw/d = 206 23 . 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. I. I. I.00 1.52 59.
24 . In addition. but occasionally very low positive reactions were recorded with humans in patch tests with benzoic acid. Systemic toxic effects on liver and kidney were observed. Neither benzoic acid nor benzoate gave indication of a sensitizing effect in animals. the Committee can establish a full Group ADI of 0 . the available studies give a robust database for hazard assessment and hazard evaluation of these compounds and further studies are not indicated. It is therefore concluded that an in vivo study for clastogenic activity on benzoic acid should no longer be required. all the results from in vivo studies have been negative. Similarly for genotoxicity.026mg/l/h also show low acute inhalation toxicity. Most of them have been reviewed and accepted by other fora like FDA. since ‘well-known’ research groups and/or test laboratories ran the studies according to scientific standards and or accepted protocols at that time. The fact that this overall NOAEL takes into account gavage as well as dietary studies gives further reassurance.14. Benzoic acid and sodium benzoate rapidly metabolize and excrete via a common pathway within 24hrs. Consequently. It has been suggested that these positive reactions are a non-immunologic contact urticaria. Benzoic acid and sodium benzoate have low acute oral and dermal toxicity with LD50 values >2000 mg/kg bw.” Ref. both for developmental toxicity and for genotoxicity. there have been 2 major re-evaluations of the data on Benzoic acid and sodium benzoate. reproductive or carcinogenic potential of benzoic acid and sodium benzoate is welcome. all were peerreviewed and published in high quality scientific literature. Therefore. 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).SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate 3. Discussion Since the adoption of the previous opinion of the SCCNFP on 4 June 2002 on Benzoic acid and Sodium benzoate (SCCNFP/0532/01. the Committee concluded that further studies were not required’ Ref. The 4 hrs inhalation exposure of benzoic acid at 0. On the basis of these data and the other types of study previously evaluated by the Committee. with an overall NOAEL for developmental toxicity of 500 mg/kg bw/day. final).5 mg/kg bw for benzoic acid and its salts including benzyl alcohol and related benzyl derivatives used as flavourings. It is therefore concluded that a further teratogenicity study on benzoic acid should no longer be required.3.: 56 The conclusions of the SCF in 2002 were: ”The database is much more extensive than that considered by the Committee in 1994. Also. They did appear to be acceptable studies for evaluation. reproductive or carcinogenic potential. 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”. There appear to be sufficient studies to conclude absence of teratogenic potential.: 3 This consensus of opinion for teratogenic. The JECFA Committee (1997) concluded that the data reviewed for compounds in this group were sufficient to demonstrate lack of teratogenic. JECFA. but sodium benzoate was not a skin irritant. Benzoic acid is a mild skin irritant. while some of the in vitro tests have been positive or equivocal. and IPCS as acceptable studies. based on effects on foetal weight. taken as a whole.
while in patients with frequent urticaria or asthma. in the interest of consumer safety. in which the total absorption of labelled benzoic acid was approximately 43 %. 736-744.5%. more modern percutaneous absorption studies were summarised.K. (ed) Toxikologisch-arbeitsmedizinische Begründung von 25 . No data was provided for the esters. particularly if from the grey literature as required by the SCCNFP Notes of Guidance (SCCNFP/0690/03). 1. 60(5). but not the other salts or esters. Marhold. 75(6). This effect is scarce in healthy subjects. and in leave-on products up to 0. symptoms or exacerbation of the symptoms were observed”. 5. However.J. but not the other salts or esters. 546-551. Robinson J. Since the loss of acidity is not uniform. 4. J. Total absorption was found to be approximately 45 %. 4. These data were comparable to in vivo data in human. Data is only given for sodium benzoate. not conforming to modern guidelines.. 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. In the IUCLID database. It is thought that the loss of acidity due to the salt (sodium. Benzoic acid should be labelled as an eye irritant under the EU criteria for classification.T. Pharm. Wright J. 3. Cincinnati (1977). both substances are known to cause non-immunologic immediate contact reactions. This was considered to be a possible cholinergic mechanism. 17 Sept 2002. SCF/CS/ADD/CONS/48 Final.. Patel V. generation of data on irritation and sensitisation of the other salts and esters is required if they are to be used in cosmetic products. REFERENCES Washkuhn R. The percutaneous absorption study of 14C-labelled benzoic acid in vitro with excised human skin was old.L. VUOS 539-18.V.. Comment: Inclusion of all relevant data should have been made available. D. 2. expressed on 24 September 2002. the conclusion on benzoic acid and sodium benzoate was: “However. MINORITY OPINION Not applicable 6.5 % and in cosmetic oral-care products at a maximum concentration of 1. On the basis of provided data. this could be a problem.SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate In the CICAD report. Pharm.7 %. (1971) J. Personal communication to the editor of RTECS. (1986) J.R. Cited in Henschler. and Carstensen J. This should be borne in mind for products used on children. Sci. CONCLUSION Adequate data was provided only for benzoic acid and sodium benzoate. These should all have been provided with Submission I. The possible non-preservative functions have not been stated. The study for eye irritation was not provided with the Submission I. potassium) should decrease toxicity. Sci.
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213 Ishidate M JR & Odashima S (1977) Chromosome tests with 134 compounds on Chinese hamster cells in vitro . Additional references (provided by SCCNFP): AR 1.496 Fanelli GM & Halliday SL (1963) Relative toxicity of Chlortetracycline and Sodium benzoate after oral administration to rats.htm AR9. Fd Cosmet Toxicol 8 369 . Hirzel. Litton Bionetics. 464-559. Handbook of pharmaceutical excipients 3rd ed 2000 editors: Kibbe. European Parliament and Council Directive No 95/2/EC of 20 February 1995 on foodadditives other than colours and sweeteners. S. (1972) Teratologic evaluation of FDA 71-37 (sodium benzoate) in mice. FDA.SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate 30. AR 4. rats. On the relevance of in vitro data. Journal of Toxicology (2001). Arch Int Pharmacodyn 144 120 . 32.Food and Drugs.a screening for chemical carcinogens. December 1993. 1999 editors: Parfitt K. Schiff D et al (1971) Fixed drug combinations and the displacement of bilirubin from albumin. Teratology 4 15 . J Invest Derm 54 399-404).. Fundam Appl Toxicol 4 494 . Blake P S. 41. 184. 33. 20 (Suppl.354 Abe S & Sasaki M (1977) Chromosome Aberration and Sister Chromatid Exchange in Chinese Hamster Cells Exposed to Various Chemicals. ACKNOWLEDGEMENTS 29 . Arznei-Forsch 10 1001. 40. Code of Federal Regulations. 38. 26 Benzoic Acid And Sodium Benzoate. and sodium benzoate. Intern. Edwards RC.24 Kieckebusch W & Lang K (1960) Die Verträglichkeit der Benzoesäure im chronischen Fütterungsversuch. International Programme On Chemical Safety. DC. (2000) Concise International Chemical Assessment Document No. Martindale : The Complete Drug Reference 32nd ed. AR 6.org/documents/cicads/cicads/cicad26. 3). 7.380 Food and Drug Research Labs. hamsters and rabbits. Mutat Res 195 151 . 42. 20036. 139 -41.195 Hunziker et al (1978) Animal Models of Percutaneous Penetration: Comparison between Mexican Hairless Dogs and Man. Mutat Res 48 337 . 45. *43. 18/03/1995 p. *44. Volume 3 [Revised as of April 1. Pharmaceutical Society of Great Britain. 31. Final report on the safety assessment of benzyl alcohol. Am J Hosp Pharm 41. J Natl Cancer Inst 58 1635 .1641 Fabrizio DBA (1974) Mutagenic Evaluation of Compound FDA 71-27 Sodium Benzoate. I. Feldmann RJ & Maibach HI (1970) Absorbtion of some organic compounds through the skin in man. Cosmetic Ingredient Review. (very bad copy!) Frantz TJ (1975) Percutaneous absorption. 46.Benzoic Acid (1989) TNO BIBRA Toxicology International Ltd. 36. J Invest Derm 64 190 . Ishidate M JR et al (1988) A comparative analysis of data on the clastogenicity of 951 chemical substances tested in mammalian cell cultures. Dermatologica 156 79 .1004 Sodemoto Y & Enomoto M (1980) Report of carcinogenesis bioassay of Sodium benzoate in rats: Absence of carcinogenicity of sodium benzoate in rats. Official Journal L 061 .125 Shtenberg AJ & Ignat'ev AD (1970) Toxicological Evaluation of some Combinations of Food Preservatives. http://www. (1995) BIBRA Report Toxicity Profile . 1-6. Voegeli CJ (1984) Inadvisability of using caffeine and sodium benzoate in neonates. Parsons. Wissenschaftliche Verlagsgesellschaft. Sweetman. Inc. AR10.inchem. 2350 AR 8. benzoic acid. Arthur H. 37. Washington. 658. Lahti A (1980) Non-immunologic contact urticaria. S C. AR 3. AR11. University of Oulu. OJ No L339. A V. NTIS Report PB-221 777 Kimmel CA et al (1971) Studies on Metabolism and Identification of the Causative Agent in Aspirin Teratogenesis in Rats.95 Not given Not given Beratergremium für umweltrelevante Altstoffe (BUA) der Gesellschaft Deutscher Chemiker (ed) BUAStoffbericht 145. Pediatrics 48. Title 21. Commission Directive No 96/77/EC of 2 December 1996 laying down specific purity criteria on food additives other than colours and sweeteners. 2001]. 39. USA. J Environ Pathol Toxicol 4 87 . 34. 0001-0040 AR 2. 35.88 Toth B (1984) Lack of Tumorigenicity of Sodium benzoate in Mice. American Pharmaceutical Association AR 5. AR 7. Inc.
T.M. Chambers (rapporteur) Prof. V.C. J. Marty Dr. Grimalt Dr. Jazwiec-Kanyion Prof. C. Lidén Prof. C. Kapoulas Prof. Dubakiene Dr. R. Revuz Prof. White (chairman) 30 . Sanner Dr. S. R. The members of the working group are: Dr. B. Rastogi Prof.R. I.SCCP/0891/05 Opinion on Benzoic Acid and Sodium benzoate Members of the working group are acknowledged for their valuable contribution to this opinion.-P. J.
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.
Structure/Composition 1. Butylene Glycol is an aliphatic diol. It conforms HOCHzCH,CHCH, to the formula:
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
Other names are 2-Methyl-2,4-Pentanediol 3. Ethoxydiglycol
is the ether alcohol that conforms
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)
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)
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
-50 1.0053': 1.0053::
Specific gravity (g/ml)
Refractive index r$
Vapor pressure Viscosity Solubility Water Alcohol Ether Acetone Benzene Carbon tetrachloride Aliphatic hydrocarbons Aromatic hydrocarbons Fatty acids (cps)
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
005 percent acetic acid.220. It contains a maximum of 0.0 percent and contains water and acetic acid to maximums of 0. printing inks. and as a component of packaging (21 Code of Federal Regulations [CFR] 173.5 percent by weight.“3.1200. and textile dye vehicles.005 percent. (I*) Gas chromatography may be used for the identification of gIycoIs.“.210).(‘6) It is also used in hydraulic brake fluids. and solvent.001 percent inorganic chlorides.(‘sl’) Analytical Methods Chemical and chromatographic methods may be used for the identification and separation of the glycols. up to 0.‘*’ Ethoxydiglycol is prepared from the reaction of ethylene oxide with ethanol followed by purification by distillation.'16' Hexylene Glycol has IFA status as a defoaming agent (21 CFR 176.2010).3-Butylene Glycol. up to 0. This is then purified by distillation.“” as an antioxidant and stabilizer.‘g’ Dipropylene Glyol is the reaction product of propylene glycol and propylene oxide. which is further hydrogenated to produce Hexylene Glycol. coupling agent.1 percent water and 0. 175. and trace amounts of branched 1. 178.“) Hexylene Glycol contains a maximum of 0. 177. Known impurities include diethylene glycol and triethylene glycol. Chemical methods involve oxidation of the glycols with subsequent reaction with a reagent. The maximum combustion residue of Dipropylene Glycol should not exceed 0.“) 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.(~) It serves as a surfactant. (8) Ethoxydiglycol has a minimum gas chromatographic assay of 99.1680. It contains up to 0.“) . as a fuel and lubricant additive and as an emulsifying agent.1 and 0.226 COSMETIC INGREDIENT REVIEW Hexylene Glycol is manufactured by the condensation of 2 molecules of acetone to produce diacetone alcohol.14’ Impurities Butylene Glycol has a minimum gas chromatographic assay of 99. and as a humectant for cellophane and tobacCO.“” in the manufacture of polyester plasticizers. and up to 0.1210.5 percent water.1 percent water.(*) USE Noncosmetic Use Butylene Glycol has been tested as a parenteral drug solvent.005 percent acetic acid. 177.(g) The isomer distribution of Dipropylene Glycol is as specified by the commercial buyer. respectively. 177.01 percent acetic acid. Hexylene Glycol serves as a coupling agent.105.01 percent.
180).“’ Cosmetic Use The glycols generally are used as cosmetic emulsifiers. 1 76.“6’ It is also used as a solvent for nitrocellulose and shellac and as a partial solvent for cellulose acetate. It is used in hair and bath products.1 percent to 50 percent. Since data are only submitted within the framework of preset concentration ranges. The types of products include eye makeup. 176. the actual concentration in such a case would be a fraction of that reported to the FDA. It is used in hair care and bath products. coatings. hair and nail preparations.105.1 percent to greater than 50 percent. the opportunity exists for a 2.‘*” Dipropylene Glycol is reported as an ingredient in 50 cosmetic formulations in concentrations ranging from less than 0. doedorants.1 percent to 50 percent. (“. and shaving and skin care preparations.l*) Butylene Glycol is used as a humectant. lubricants.(*) 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. Ingredients are listed in prescribed concentration ranges under specific product type categories.‘*‘) . fragrances. the value reported by the cosmetic formulator may not necessarily reflect the true concentration found in the finished product. plasticizers. and shaving and skin care preparations.FINAL REPORT: SAFETY ASSESSMENT OF THE CLYCOLS 227 Exthoxydiglycol has IFA status for use as a component of paperboard and adhesives (21 CFR 175.‘*” Hexylene Glycol is used in 85 cosmetic formulations at concentrations of use ranging from less than 0.200). fragrances. personal cleanliness products. preserves against spoilage by microorganisms.105.to lo-fold overestimation of the actual concentration of an ingredient in a particular product (Table 2). solidifiers.(*l) Butylene Glycol is used in 165 products at concentrations from less than 0. 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. and as a defoaming agent (21 CFR 175. eye and facial makeup. facial makeup. and film producers. cosolvents. and printing inks.3910. Since certain cosmetic ingredients are supplied by the manufacturer at less than 100 percent concentration.““’ Dipropylene Glycol is an IFA ingredient for use in adhesives. Special grades of Dipropylene Glycol (based on odor quality) are used as carriers for perfume oils.4 of the Code of Federal Regulations. soaps. 178. The types of products in which Hexylene Glycol is used include bath and hair preparations. and shaving and skin care preparations. perfumes. especially in hair sprays and setting lotions.1 percent to 25 percent. and is used as a solvent for benzoates.‘*” Ethoxydiglycol has been reported as an ingredient in 80 product formulations at concentrations from less than 0. Other applications include solvent mixtures. lacquers. eye makeup. (l*-*‘) It helps retard the loss of aromas from essential oils.
Containing Product Butylene Category* Clycol 1 4 3 13 4 34 1 Ingredient >50 > JO-25 >5-70 Within Formulation5 Range I%) >O. Product Total No. and liquids 1981 TOTALS (excluding shaving preparations) skin care prep 8 - 1 2 2 1 11 - 3 - 2 1 2 - 6 - 1 4 1 3 1 1 1 1 - 7 1 - 165 2 23 46 76 9 . creams. liquids. I Each Concentration >J-5 Bath oils.228 TABLE 2. 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. body. tablets. 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. 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. and pads) Face.l-l 50. Product Formulation Data’*‘) COSMETIC INGREDIENT REVIEW No.
lotions. 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 50.1 Product Category* Hexylene Clycol Ingredient Bath oils. lotions.FINAL TABLE REPORT: 2. rations tions) Moisturizing skin care preparations Face. I-I 50. Product Formulations Total No. liquids. I Within Each Concentration Range (%I 2 1 1 2 1 1 - - - 4 10 1 - 1 1 8 2 3 Skin cleansing preparations (cold creams. and pads) . body. Skin cleansing preparations creams. 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 - 3 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. tablets. and hand skin care prepa(excluding shaving prepara- - 1 15 - 3 3 - 2 1 1 32 - 1 2 1 Paste masks (mudpacks) Skin fresheners Other skin care preparations 1981 TOTALS 85 20 17 No. Containing Each Concentration >10-25 >5-10 >l-5 Within Range (%) >o. SAFETY ASSESSMENT OF THE CLYCOLS 229 (Continued) No. Product Formulations Total No.
body. lotions. and pads) 3 Face. Containing Product Category* Clycol 1 2 12 1 6 1 1 4 1 Ingredient >50 > IO-25 >5-JO Within Formulations Range I%) >o. and salts Colognes Perfumes Sachets Other fragrance preparations Hair sprays (aerosol fixatives) Hair shampoos ing) Tonics. Product Total No. (noncolorand other aids and toilet waters 2 1 - 1 1 1 1 - dressings.14 - 1 1 4 regulations (21 CFR product categories and concentration ranges in accordance with federal filing .T-I 1 50. 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. Product Formulations Total No. Containing Product Category* Jngredient 3 >25-50 > IO-25 >5-10 >l-5 1 >O. 2 skin care prep3 - 3 - - 1 - 1 1 10 2 1 .1 1 Within Each Concentration Range f%) Face.4).230 COSMETIC 2. 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 3 1 - 2 1 1 1 1 2 1 1 1 80 1 - 3 No. body. I-I so. tablets. - 1 4 hair grooming Wave sets Lipstick Makeup bases Deodorants Aftershave - (underarm) lotions - 1 4 1 - Skin cleansing preparations (cold creams. liquids. 1 Each Concentration >l-5 Dipfopylene Bath oils. (Continued) INGREDIENT REVIEW TABLE No.
pigs.(26) The animals were fed diets containing 1 of the following: 47 percent dietary calories as glucose. The diets were offered ad lib except for 1 experiment in which pigs were fed to satiety twice daily. 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. The animals were killed and metabolites in the brain were determined. and 25 percent Butylene Glycol. Mehlman et al. They found that the conversion of the glycol to /3-hydroxybutyrate in the liver was dependent on NAD’ and inhibited by pyrazole. it is then oxidized in the tricarboxylic acid cycle. Rats and mice excreted up to 40 percent of a 200 mg daily oral dose of Hexylene Glycol in the urine. Body weight gain and epididymal fat pad weight decreased in test animals receiving the test diet. Blood pyruvate concentration was decreased significantly in animals fed this glycol for 7 weeks.(28) When administered orally or by subcutaneous injection to rabbits. Plasma glucose decreased in the rat and remained stable in pigs and chicks. Controls received the basal diet. Dietary Butylene Glycol decreased the rate of fatty acid synthesis in the liver of rats.FINAL REPORT: SAFETY ASSESSMENT OF THE CLYCOLS 231 BIOLOGICAL Absorption. is metabolized in the cytosol and converted by the liver to ketones. and pyruvate concentrations. Butylene Glycol significantly decreased glutamate. Butylene Glycol was substituted isocalorically for the carbohydrate.(24) also studied the metabolic fate of Butylene Glycol in rats. Blood acetoacetate and fl-hydroxybutyrate concentrations were increased significantly.(25) also reported that hepatic alcohol dehydrogenase was the enzyme responsible for the initial oxidation of Butylene Glycol. PROPERTIES and Excretion Metabolism. therefore. Blood fi-hydroxybutyrate content increased in all 3 species. The conversion of glucose to lactate and pyruvate was decreased. Plasma triglyceride concentrations decreased in the rat. Glucose concentrations and the NADPl NADPHIDH ratios were also decreased. but there was no such effect in pigs or chicks.(23) studied the metabolic fate of Butylene Glycol in the rat. Tate et al. In liver slices. lactate. Ethoxydiglycol was oxidized in the body or excreted as glucuronate. and remained the same in chicks. They found that hepatic alcohol dehydrogenase was the catalyst in the catabolism of the glycol to an intermediate aldol and then to /3-hydroxybutyrate. Romsos and associates(**) investigated the effects of Butylene Glycol on lipid metabolism in rats. as was the concentration of ketones. Such administration was followed by a marked increase in the urinary content of glucuronic acid. The metabolites of Butylene Glycol in the brain of rats were determined by Morris et al. Addition of up to 20 percent Butylene Glycol to the diet did not affect body weight gain of the 3 species. The animals were fed a basal high carbohydrate diet that contained approximately 20 percent protein and 5 percent fat. The metabolism of glucose and Butylene Glycol to ketones by hepatic tissue taken from test animals was also studied. Mehlman et al. and chicks. 30 percent fat. Butylene Glycol.(2g) - . Butylene Glycol was metabolized to acetoacetate and P-hydroxybutyrate. In the test diets. or 47 percent calories as ethanol for 62 days. increased in pigs. (*‘) An oral 1 mmol/kg dose of Hexylene Glycol administered to rabbits was excreted as glucuronate (67 percent of original dose). 47 percent calories as Butylene Glycol.
10 male Charles River Sprague-Dawley rats were trained to balance on a rotating dowel. 5. behavior. or a sham was administered on 4 other days in the week. or 7. the compound was administered intragastrically in a 3. 3. maternal treatment with the glycol exerted opposite effects on neuronal protein synthesis at different stages of postnatal development of progeny. protein synthesis in neurons from 18-day-old pups was severely inhibited by maternal ingestion of the glycol. groups of 8 male Charles River Sprague-Dawley rats were fed Butylene Glycol in doses of 0.‘32’ Control animals were given equal volumes of saline.08 g/ml for 2 days. Distilled water and lecithin (emulsifier) were also added to produce a constant dose volume of 11. These investigators also studied the dose-effect of Butylene Glycol on food and water intake and urine output in several different experiments.1 g/ml for 5 days). then 0. The glycol produced more falls than any of the other test compounds. protein synthesis in the liver was significantly reduced.09 g/ml for 3 days. Therefore. Each dose was administered to each animal daily over a 5-day period. The glycol-treated rats were barely able to stand. r30) Groups of pregnant rats were given water (control) or Butylene Glycol (9 percent w/v) in drinking water.07 g/ml for 2 days. Amino acid incorporation by free and membrane-bound ribosomes from liver of 8. water. Other animals received glycerol.15 M saline. once a week for 3 weeks. 1.5.25. However. Ingestion of the glycol produced a dose-related depression of activity and food and water intake. In 8. In amino acid incorporation studies. which were given IP doses of 0. 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.5 g/kg dose. The length of gestation was not affected by the glycol. Treatment was continued throughout the period of gestation and lactation. In one study.4 ml/kg.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.and 18-day-old pups was increased by Butylene Glycol. To study its effect on voluntary activity (running). and Butylene Glycol apparently acted as a CNS depressant or a muscle relaxant.and 18-day-old pups. or ethanol. since intubation of the compound depressed food and water intake. sucrose.2 g/ml of Butylene Glycol in sterile 0. neuronal perikarya from 8-day-old pups incorporated 45 percent more amino acids into acid-insoluble polypeptides than did controls. Glycerol. Neuropharmacology and Behavior Ayers and lsgrig (31) studied the effect of Butylene Glycol on the behavior of rats in several experiments.0 g/kg) was administered once a week for 3 weeks. In another experiment. sucrose. 0. Butylene Glycol depressed voluntary running activity.0 g/kg. Another group of rats was fed a liquid diet containing Butylene Glycol in increasing concentrations (0. Corn oil was added to the last 4 dosages to produce a constant caloric value.75. The IP administration of the glycol caused a dose-related impairment of motor coordina- . The effects of Butylene Glycol on neuropharmacology. 0. Butylene Glycol (7. and CNS function were studied in male and female Sprague-Dawley rats. this finding might be due to the glycol’s interference with hunger motivation.
When ethanol-withdrawn rats were acutely treated with Butylene Glycol.35) and 11 g/kg in guinea pigs. Other sources reported an oral LDSO of 4000 mg/kg for rats. and Candida albicans. a dose-related decrease in tremors was observed.” as measured by the number of electrical shocks accepted by rats. was attenuated after treatment with glycol.5 hours. Those microbes against which Butylene Glycol is effective include Escherichia co/i. After 7. Aspergillus niger. it is not sporicidal.FINAL REPORT: SAFETY ASSESSMENT OF THE GLYCOLS 233 tion 1 hour after treatment as measured by aerial righting reflex. (43) - . Administration of the compound depressed cGMP content in the cerebellum but did not alter plasma-leuteinizing hormone. Compound treatment also caused a decrease in blood pH and blood pressure. other investigators found it to be toxic to some microorganisms and useful as a cosmetic preservative.0 percent Butylene Glycol had an LDso of > 5 g/kg in rats. Pseudomonas aeroginosa.(lg) Harb and Toama’34) reported that Butylene Glycol is the most efficient polyol as an antimicrobial agent.87 g/kg. Feeding of rats caused no significant motor coordination impairment.. but 1 of 9 rats developed seizures. c40) The acute oral LDso values for Ethoxydiglycol are: in rats.‘38’ and 3900 mg/kg for mice. Animal Oral Toxicity Acute Studies Toxicology The acute oral LDSO of Butylene Glycol was 23 g/kg in rats(6.35 percent Butylene Glycol produced no deaths when fed to rats at 15 g/kg.70 g/kg.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.O percent Hexylene Glycol caused no deaths when administered orally to 10 mice at 15 ml/kg. 1 died.(35’ A nail lotion containing 5. tremors increased.(37) Windholz(6’ reported the acute oral LDso of Hexylene Glycol in rats was 4. 5. as well as molds and yeast. 3.e. in mice. (36) and a product containing 21. (42) A body lotion containing 1 . more shocks were accepted by treated rats than by control rats. 6.‘38’ 2800 mg/kg for guinea pigs. Fusarium sp. Staphylococcus aureus. (3g)An eye makeup remover containing 1 .‘““) However. (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. It inhibits both gram-positive and gram-negative microorganisms. and 33 percent of the rats developed seizures. Corynebacterium hofmanii. After 12 days.54 g/kg. the glycol was removed from the diet. No tremors developed after 1 hour. Microbiological Effects Butylene Glycol can be used as the sole carbon source by some strains of mycobacteria. “Conflict behavior. Pityrosporum oxalicurn.. Aspergillus fumigatus.58 g/kg.O percent Ethoxydiglycol caused no deaths when 15 ml/kg oral doses were administered to 10 mice. i.(35) A skin care product formulation containing 1. However. and all rats gained weight.(35) 3290 mg/kg for rabbits. and in guinea pigs.
brain.2. 0.8. 1.‘35’ A shaving preparation containing 7. However. 0. and this was associated with a decrease in food consumption.(*‘) No effect was caused by the daily consumption of 0. or 1500 mg/kg. and urine composition.8 percent diet.25. rats receiving up to 150 mg of this glycol in the diet daily for 4 months had no abnormality in growth. heart.0 percent Ethoxydiglycol for periods up to 90 days. or 20 mg Hexylene Glycol for 57 to 81 days produced no effect on growth curves. The “no effect” level for Ethoxydiglycol in rats was 0.O. the dose was then reduced to 1000 mg/kg per day. One male rat in the 5 percent group died on Day 23. 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.234 COSMETIC INGREDIENT REVIEW The acute oral LDso of Dipropylene Glycol in rats was 15 g/kg.4 percent diet died of renal damage. there was weight loss and degeneration of renal tubules and liver. 0.4 percent diets. Six of the 20 male mice fed the 5.49 g/kg Ethoxydiglycol by each of 5 rats for 30 days. (44) Subchronic Studies For subchronic effects of Butylene Glycol.6.5. hematological parameters at 6 and 12 weeks. and gonads. 167. behavior. or fertility. see also the Metabolism section of this report. kidneys. or 5. (45) Four groups of Charles River Wistar rats. Organs examined were the liver. spleen.or 5. All 3 species had reduced hemoglobin concentration at the highest doses administered. which was indicative of impaired renal function. were fed diets containing 0 (control). No other important changes were found. 500. 0. kidney function. Growth rates of male and female rats were reduced when fed the 5 percent diet. Larsen(*‘) reported that Hexylene Glycol fed to mice daily at 5. the general conditions remained good.2 percent Dipropylene Glycol had an oral LDso of >5 g/kg. activity of urinary glutamic-oxaloacetic transaminase was increased in both sexes fed the 5 percent diet. some changes were present in renal tissue of rats of the 200 mg/day group. 0. There was a reduction of growth in rats and mice at the highest concentrations. The investigators found that throughout the 90 days. each consisting of 12 males and 12 females. An increase in weight of the kidneys occurred in both sexes fed the 5 percent diet. or 5 percent and to groups of 20 male and 20 female mice at dietary concentrations of 0 (control). mice. Observations were made of body weight. However. The glycol was fed for 90 days to groups of 15 male and 15 female rats at dietary concentrations of 0 (control). For the surviving pigs.5 percent of the . Also. Oxaluria occurred in rats and mice at highest concentrations. 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 and 5. No hematological changes were produced by any diet. and pigs.4 percent. 1 . Hepatic cell enlargement was found in those mice fed the 1. Three groups of 4 male and 4 female pigs were fed daily oral doses of 0 (control). 10. Three pigs given 1500 mg/kg per day for up to 21 days died with signs of uremia. blood urea concentration.87 g/kg caused reduced feed consumption. food intake. Hydropic degeneration of the hepatocytes was observed in those pigs above a dose of 500 mg/kg. adrenals.(46) The effect of subchronic ingestion of Ethoxydiglycol was studied in rats.
urinalysis. and rabbits as 3. 60 male and 60 female control rats were fed a basal diet and water ad lib. 10 animals from each group were killed. 5000 mg/kg. (‘I) No deaths were caused by intraperitoneal injection of 1 . The blood.O.. respectively.O g/kg per day for 2 years. (35)The intravenous LDso in rats and dogs was 5800 mg/kg and 1 1. and feed and compound consumption. respectively. elimination. The subcutaneous LDso of Ethoxydiglycol in mice was 5500 mg/kg. The rats had slight hepatic damage. 1 .(52) The intraperitoneal LD50 of Dipropylene Glycol in rats and mice was 10 g/kg and 4600 mg/kg. pharmacological effects. oxalate crystals in the kidney. 2. (4g) Butylene Glycol was evaluated for tissue irritation using chicken pectoral muscle. and hemoglobin values were determined.0 percent Butylene Glycol for 2 years. Representative organs were weighed and examined microscopically.‘35) . respectively. and representative organs were examined as with the rat portion of the study described above. In the rat study. As with the rats.s in mice.(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 4.0. Two animals from each group were killed after 1 year and the remainder after 2 years.5 ml/kg and 20. 1. and in 1 animal.6 percent of the diet.(26) Parenteral Toxicity The subcutaneous LDso of Butylene Glycol in mice and rats was 16.FINAL REPORT: SAFETY ASSESSMENT OF THE GLYCOLS 235 diet. a control group of 4 males and 4 females were fed a basal diet.9 ml/kg. (38) Other investigators report intravenous LD.0 ml/kg.9. and 0. and 3 similar groups received diets containing 0.(47) Chronic Studies Butylene Glycol was fed to Sprague-Dawley weanling rats and beagle dogs for 2 years. and all survivors were killed at the end of 2 years. and in pigs it was 167 mg/kg per day. it was 3. mglkg. or 3. respectively.1 ml/kg. (3*) The intravenous LDso in dogs was 3000 mg/kg and in cats. urine.(38) In rats and rabbits. pharmacological effects. Injections of 0. and gross appearance.3 cm deep into the right and left pectoral muscle of each of 6 chickens. respectively. or 10.O g/kg Butylene Glycol into 5 mice.‘52’ The intraperitoneal LDso of Ethoxydiglycol in rats was 6310. packed cell volume.O. food consumption.4 ml/kg and 2.9.5 ml/ kg.500 mg/kg.(48) Ethoxydiglycol was fed to rats at 1 . Daily or weekly observations were made of feed intake.0 percent Butylene Glycol. At 1 year. clinical appearance. (51. Erythrocyte and leukocyte counts. In mice it was 0. These tests were negative for deleterious or toxic effects due to the ingestion of Butylene Glycol at any dietary concentration. Observations were made on body weight.‘48) In the study using beagle dogs. compound consumption. rats. no toxic effects were produced by the ingestion of Butylene Glycol at any dietary concentration. caused only minimal tissue irritation.5 ml of the glycol. Three test groups of 30 male and 30 female rats each were fed diets containing 1 . N IOSH (35) lists the intraperitoneal LDso in mice as 1299 mglkg.5. 3. some interstitial edema in the testes.
2 percent Dipropylene Glycol were tested for 24 hours under occlusion on rabbit skin (Leberco Labs). Clinical observations of compound-related importance were confined to the skin. A control group of 8 rabbits remained untreated. The degree of irritation did not correlate with the concentration of glycol.0 to 21.(38) Several product formulations containing 5. 1 .‘53’ A product formulation containing 7.4 percent Butylene Glycol. room temperature vapors of Hexylene Glyc~l.6 percent Hexylene Glycol.3 g/kg in rabbits. Undiluted Dipropylene Glycol caused mild irritation when 500 mg was applied to rabbit skin for 24 hours.O to 1. (36.O percent Ethoxydiglycol. All of the animals survived the duration of the study. (38) According to Rowe. (57) it is a nonirritant to rabbits. 1 . No systemic effects as evidenced by microscopic tissue examination were attributable to the test material. Cumulative Irritation A daily dose of 0.2 percent Dipropylene Glycol produced a cutaneous LD50 of >2 g/kg when tested in rabbits.84 g/kg undiluted Hexylene Glycol to the skin of rabbits caused mild edema and erythema. or 7.(38’ A product formulation containing 5. which had slight erythema with drying and flaking.5 ml of a paste mask product formulation containing 2 percent Ethoxydiglycol was applied to the backs of 3 albino rabbits for 14 consecu- .0 percent Butylene Glycol had a cutaneous LD50 of >2 g/kg when tested in rabbits.(“~) Cutaneous Toxicity Acute Studies The cutaneous LDso of Hexylene Glycol in rabbits and rodents was 13.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.2 g/ kg.‘3s) A 24-hour application of 1. depending upon the particular formulation tested.44.(57) Undiluted Ethoxydiglycol was a mild irritant when applied to rabbit skin (500 mg for 24 hours).(361 The cutaneous LDso of Ethoxydiglycol was 6 g/kg in ratst3*) and 10.236 COSMETIC INGREDIENT REVIEW Inhalation Toxicity Rats survived an 8-hour exposure to the saturated.(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 hours’55’ or daily for 4 consecutive days.58-64) e products produced no irritation to moderate irritaTh tion.(56) Undiluted Hexylene Glycol produced moderate irritation when 465 or 500 mg was applied to the skin of rabbits for 24 hours.
There were no other signs of irritation.‘381 and Rowe’57) reported that this glycol caused cornea1 damage in a rabbit.O to 2. In the first experiment. Clinical Nutritional and Metabolic Assessment Studies of Safety Tobin and associates(74) investigated the nutritional and human metabolic effect of Butylene Glycol. The chemicals were applied to a series of 4 animals at application frequencies of 1. Dietary variation was randomly distributed during .69-72’ Another product formulation containing 1.to 7-day test periods subjects consumed diets with constant caloric content. (73)This formulation had also produced mild to moderate irritation when applied to the skin of rabbits. 7. The volunteers went through a 2-day depletion period in which nitrogen intake was 1. Ethoxydiglycol was very irritating to the rabbit’s eye in this assay system (Table 3). Ocular edema was measured by the following formula: mg dry tissue weight mg wet tissue weight x 100 In addition. 3. the effect of Butylene Glycol and urea in the nutrition of 12 men and women was studied.0 percent Ethoxydiglycol.FINAL REPORT: SAFETY ASSESSMENT OF THE CLYCOLS 237 tive days. 4. or 7.(38) Laillier et al.1 ml volumes. (35) 505 mg of undiluted Butylene Glycol applied to the rabbit eye was an irritant.0 to 21. Mild effects were caused by 125 mg. and 58 hours. 1 .23 g/day. A 25 percent aqueous solution of Hexylene Glycol caused no ocular irritation when tested in the rabbit.(36.2 percent Dipropylene Glycol produced no more than minimal. Caloric intake was evaluated and adjusted so that during the 4. (35) Several product formulations containing 5.O percent Hexylene Glycol. 26. 7. Undiluted Dipropylene Glycol is an irritant in the rabbit eye in an amount of 5 10 mg. and 13 times over periods of 2. Three studies were conducted. 1 . The chemicals were used either pure or as a 25 percent dilution in distilled water in 0.35 percent Butylene Glycol.(42’ Ocular irritation According to NIOSH. No irritation was observed when 0.(67’ Moderate toxic effects were found in the eyes of rabbits instilled with 500 mg undiluted Ethoxydiglycol.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. 6.6 percent Hexylene Glycol produced mild to moderate irritation in the eyes of rabbits.(68) studied the ocular effects of Ethoxydiglycol and other chemicals using the rabbit. aqueous humor and conjunctival content were assayed for effects 1 hour after Evans blue solution was injected into the rabbit’s marginal ear vein. Each treatment site was rinsed with warm tap water 30 minutes after treatment.42*44. There was slight erythema 24 hours after the initial application that had disappeared by 48 hours. Irritation was severe when 93 mg undiluted Hexylene Glycol was instilled into the eyes of rabbits. transient irritation when instilled into the eyes of rabbits.
0 10.3 25.4 0.1+ 0.1 21.5 Aqueous Humors (pg Evans Blue/ml) 135.5+ 1.9 12.0+ 189 f 91 f 178 & 177 f 139 f 25.0 k +Significantly Mean f (Student’s t-test).8 25.7 20.0+ 4.9l 1.9+ 3.5 27. Ocular Irritation in Rabbits by Measuring Tissue Edema: Ethoxydikol(68) Conjunctivae No.5 1.3+ 0.8 19.2 1.3 1.6 f f f f l 0.1 f f f f f f * f f 1.1+ 16.4 69.18.4 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) 24.2 18.4 15.9+ f f f f 8.9+ 2.9 29.0+ 22.8 5.9+ 1.5 3.4 1. lime* (hours) 2 4 .7 .6 17.1 15.3 0.8+ 1.6* ’ 12.8 1.9 17.7 13. 95% made.7 9.2+ 2.1 16.0+ 1.0+ 1. 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.6 20.6+ 11.4+ 1.6+ 0.TABLE 3.8 24.25 8. .1 21.7 26 58 2 4 7 -26 58 (% Dry Weight) 13.6+ 1~9+ 1.8 11.
After 24 hours of contact. 120 female) to assess the irritation and sensitization potentials of Butylene Glycol. The investigator reported visible skin change in one subject after applications 4-6 and in another after applications 1315. The Butylene Glycol was substituted isocalorically for sucrose to provide 10 percent of the total caloric intake.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. and the fourth and final period in which the glycol and urea were added to the diet. After 24 hours. This cycle was repeated each Monday. The second study investigated the . caused a significant decrease of urinary nitrogen excretion. Butylene Glycol was nontoxic in these tests. In the third study. If no changes occurred. Serum insulin values and blood pyruvate and lactate values were normal. and then 24-hour occlusive patches were applied to the same sites. acetoacetate and triglyceride values were likewise normal. 1 in which starch without the glycol was ingested. a second patch was reapplied to the same site. as were free fatty acid and growth hormone values. as compared to starch. edema. The glycol caused a lowering of blood glucose and no increase in blood ketones. Glucose concentrations were normal. vesicles. starch. No reactions were caused by the challenge patch. but urea feeding did. the sites were reexamined. Undiluted Butylene Glycol was applied to the volar skin of the forearms or . Fasting insulin and growth hormone concentrations were somewhat increased by the glycol. 1 in which urea (4 g of nitrogen/day) was added to the diet. and vitamin and mineral supplements.9 ml of the mixture was applied under occlusion to sites on the upper arm. At the end of 5 days. greater than 98 percent of the general population would not be sensitized to Butylene Glyc~l(‘~) (Table 4). 10 adult male and female volunteers were fed for 12 days 6 g of nitrogen per day. the diets were switched. and extensions beyond the site of contact). Butylene Glycol. and 0.effect of Butylene Glycol on endocrine function and its influence on glucose homeostasis. sites were not treated for a 2-week period. After the fifteenth application. and /3-hydroxybutyrate. The investigators concluded that Butylene Glycol can be used as a caloric source by human beings. Subjects fed urea or glycol plus urea had a significant increase in urinary excretion of nitrogen. Feeding the glycol or urea or the combination caused a less negative nitrogen balance than did the starch feeding. Wednesday. and Friday. Glucose tolerance tests were performed on the sixth and twelfth days of the test. The compound was diluted to 50 percent in water. Test areas were graded immediately and then at 24 and 48 hours after patch removal. 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. The glycol had no effect on triglyceride or cholesterol concentrations. Mean blood glucose concentrations and serum insulin concentrations were lower in the second and third weeks of ingestion. the patches were removed and the sites were graded on a scale of 0 (no reactions) to 4+ (erythema. Butylene Glycol was a mild fatiguing agent in 2 of 200 test subjects.‘74’ Skin Irritation/Sensitization A Shelanski and Shelanski repeated insult patch test was conducted on 200 volunteers (80 male. The glycol did not increase fecal nitrogen excretion. With statistical extrapolation.
‘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.11 (scale 0 to 4) for the occluded patch and 0.240 COSMETIC INGREDIENT REVIEW TABLE 4. Of the 1087 subjects tested in skin sensitization assays (Schwartz-Peck and Draize-Shelanski tests).02. in single insult occlusive patch tests. Clinical Skin Patch Tests with Butvlene Clycol and Hexylene No. 4. sensitization sive patches 3 days/ week for 15 induction patches.0 to 21. Results indicative of irritation cannot be interpreted without knowledge of the other ingredients in a formulation. There was no correlation between the degree of irritation and the concentration of glycol (Table 5). . Shelanski and Shelanski patch occluButylene Glycol 50 (in water) 200 (primary index ir- max. These scores are indicative of only minimal irritation(76) (Table 4).0) irritation no 19 Mild skin repeated insult test (24-hour in 2 subjects. irritation max. 76 (primary irritation index 0. products con-taining 3.4 percent have also been tested for skin irritation and sensitization in humans (Table 5). no other reactions were observed in either panel’75’ (Table 4). there were no reactions indicative of sensitization to any of the glycols (Table 5). 1 subject with mild irritation Hexylene Clycol 100 37 Occlusive minimal patch.11. Fisher”‘) reported that cross-reactivity (sensitivity) may occur between Butylene Glycol and propylene glycol. no Reference 75 occlusive or semioc39 Semiocclusive patch. challenge patch after 2week rest) medial arms of 37 human subjects under occlusion and 39 subjects under semioccluded conditions for 24 hours.016 to 21.4 percent Butylene Glycol produced no more than minimal irritation. of Subjects 37 Clycol Concentration Test Method 24-hour elusive single insult patch Material Tested Butylene Clycol Vd 100 Results Occlusive reactions patch. Hexylene Glycol was tested in an identical fashion.0) 39 Semiocclusive patch. producing primary irritation indices of 0. One subject in the semioccluded panel had evidence of mild irritation. 4. A number of product formulations containing 1 of the glycols at concentrations of 0. minimal ritation irritation 0.02 for the semioccluded patch.
The DraizeShelanski tests included UV exposure after induction patches 1. Although undiluted Hexylene Glycol . Irrigation with water brought rapid relief. Ethoxydiglycol. there were no reactions (Table 5). Various animal species and man metabolize Butylene Glycol and use it as a source of calories. throat.t9’) A shaving preparation containing 7. Hexylene Glycol. and acute and subchronic cutaneous toxicity studies likewise support a low order of toxicity. Ethoxydiglycol. Results of parenteral injection.2 percent Dipropylene Glycol had 7 safety-related complaints in 3 years with 2. The Glycols produced mild to severe ocular irritation when tested in rabbits.‘57) Inhalation Toxicity Nasal and respiratory discomfort occurred from a concentration of 100 ppm aerosolized Hexylene Glycol. The results of acute. Ocular Irritation A drop of Butylene Glycol applied to the eyes of humans caused immediate severe stinging similar to that induced by propylene glycol.(83) When human subjects were exposed for 15 minutes to a vapor concentration of 50 ppm of Hexylene Glycol.2 percent Dipropylene Glyc01(~*) (Table 5). and Dipropylene Glycol caused minimal to mild irritation of rabbit skin. and chronic oral toxicity studies using a variety of animal species indicate a low order of toxicity for the Glycols. and 10 and after the challenge patch. whereas Hexylene Glycol was moderately irritating.6 percent Hexylene Glycol had 43 safety-related complaints in 4 years with 243 million units distributed. 2 of these were listed as”rash” and 5 as “irritated skin. ocular irritation occurred. 7. None of the subjects in the Schwartz-Peck tests had reactions when a single UV exposure was made after the second insult. The ultraviolet light exposure was to a Hanovia Tanette Mark I quartz lamp at a distance of 12 inches for 1 minute.‘“” Industry Complaint Experience A skin care product containing 1. Butylene Glycol.“(98) SUMMARY Butylene Glycol. They are added to various types of cosmetic products at concentrations up to 50 percent.3 million units sold. inhalation. subchronic.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. and respiratory tract were noted.0 percent Butylene GIy~ol(~‘) and on a shaving preparation containing 7. and at 1000 ppm irritation of the eyes. and Hexylene Glycol produced the most severe irritation.4. nose. with a peak at 365 nM. and Dipropylene Glycol are viscous liquids used in the cosmetic industry as humectants. and solvents. plasticizers. This lamp has a wavelength coverage of 240 to 370 nM. emulsifiers. The Glycols also have many noncosmetic uses and have been given Direct and/or Indirect Food Additive status by the FDA.
challenge patch after 2-week rest) subjects at second. of Test Method 24-hour patch Foundation makeup 16.0 Ethoxydiglycol 5. hour patches 3 days/week for 9 or 10 induction patches.0 Butylene Glycol 108 Mild irritation.35 (%i Subjects 20 Minimal Results irritation Reference 79 Butylene Glycol patch for 21 days) nonirritating.0 Butylene Glycol 0.or 48. no sensitization 87 sult patch test (24.2 Dipropylene Glycol 101 test (open and closed 48 hour patches.6%) 21.13 Hexylene Glycol (8% aqueous dilution of product containing 1 .35 Butylene Glycol 10 Slight irritation. posite score was 361630 No reactions.0 Butylene Glycol 12 104 Personal cleanliness product 8.TABLE 5. open patches. Clinical Skin Patch Tests with Product Formulations Containing Glycols No. supplemental insult Shaving preparation 7. 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. UV exposure produced no re- .0 Butylene Glycol 19 Minimal 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 21.0 Butylene Glycol 3. 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.
O Hexylene Glycol Clycol 108 103 Slight irritation.6 Hexylene Glycol Glycol Clycol 50 59 80 No reactions No reactions Minimal irritation 94 95 96 7. (1% aqueous dilution of product containing 1 . 7. 7. no sensitization no sensitization Supplemental 92 93 82 Mild irritation UV exposure with probable fatiguafter induction ing.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 .016 Hexylene Glycol 52 Mild irritation.0 Ethoxydiglycol 1 .016 Hexylene Clycol 106 No significant tion irritation. and TO and after challenge showed no photosensitization Rouge Eye makeup remover Personal cleanliness product 0. irritation. 4. Mild irritation. 4. Test 24 hours after each applino sensitization 90 Personal cleanliness product 0.6%) Paste mask Body lotion Shaving preparation 2.0 Butylene 1. tions at challenge consistent induction sunlight cation irritation sites exposed to 30 minutes reactions. Sup- 81 plemental UV exposure after in- duction patches 1.6%) 0. 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. no sensitization. no sensitization no sensitization 88 89 and 3 reactions on challenge at alternate site with 1 persisting.0 Butylene 1 . patches 1. no sensitization.6%) 3.O Ethoxydiglycol 7.2 Dipropylene .0 Butylene Clycol 49 No irritation.2 Dipropylene Glycol 213 93 50 Minimal Minimal irritation.Nail lotion 5. no sensitira91 (1% aqueous dilution of product containing 1 .
ACKNOWLEDGMENT Jeffrey Moore. There was no correlation between the degree of irritation and the concentration of the Glycol present in the formulation. HAWLEY. CROSLEY. Butylene Glycol.C. CONCLUSION Based on the available data. DC 20005. 59th ed. REFERENCES 1. upon request: Administrator. a 25 percent aqueous solution produced no signs of irritation. Dipropylene Glycol. 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. 9th ed. Rahway. CTFA cosmetic ingredient CHEMICALS R. NJ: Merck and Co. 8th ed. Butylene Glycol produced mild skin fatigue in 2 of 200 test subjects but no evidence of skin sensitization. 6. (1976). Ethoxydiglycol. FRAGRANCE (1981). 21. Washof unpub70) ington.* Submission chemical description: 3rd ed. N. (1979). and HAYNES. Scientific Analyst and writer. of Chemistry (CTFA Code 2-17-l lished data. New York: Van Nostrand Rein- CRC Handbook G. (ed. 7.. (eds. FL: CRC Press. In a repeated insult patch test. 4. Supplemental exposure to ultraviolet light in some of the skin sensitization tests on product formulations produced no reactions suggestive of phototoxicity or photosensitization. And Hexylene Glycol was irritating to the respiratory tract at concentrations significantly higher than those generally found in cosmetic products. TOILETRY P.). 21..). Toiletry AND CODEX. (CTFA). (1982). (ed. 2. COSMETIC.W. Washington. WINDHOLZ. 1110 Vermont Avenue. M. 1981). Washington. CTFA.1982). FOOD WEAST. 3rd ed. hold. Suite 810. MD. Hexylene Glycol.G. (Sept. DC: Cosmetic.244 COSMETIC INGREDIENT REVIEW produced severe ocular irritation. 3. ingredient Dictionary. Boca Raton. Feeding studies in man indicated that Butylene Glycol was metabolized and nontoxic.F.. The Condensed Chemical Dictionary. and Dipropylene Glycol are safe as presently used in cosmetics. The Merck Index. ESTRIN. There were no reactions indicative of skin sensitization to the Glycols in any of the 1087 subjects tested under skin sensitization assays. (ed. The degree of irritation produced depended upon the particular formation. and Physics. (Sept.). CTFA cosmetic ingredient chemical description.’ Submission of unpublished (CTFA Code 2-l 7-175) *Available N. C. Butylene Glycol and Hexylene Glycol were irritating to the human eye. A number of product formulations containing the Glycols at concentrations up to 21. Butylene and Fragrance Association. DC: National Academy Press. Glycol. (1971). data. 5. prepared the technical analysis used by the Expert Panel in developing this report. Cosmetic Ingredient Review. . Cosmetic ASSOCIATION.4 percent have been tested in various human skin irritation and sensitization assays (Table 5).).
(1976). glycols.E. Exp.3-butanediol. 269. NELSON.A. HOLMAN.. 24. N. USMI... Proc. CHAMPION. 36.2010.A. J. (1980). in detoxication J. 33. MEHLMAN. D. Kirk-Othmer MD: Williams (1971). 98(3). M. data. M. FURIA.L. (1971). 175. WALLGREN. VOGEL. (1970).L. and HILSKA. P. (1974). 178. Hexylene (CTFA Code 2-17-176) Ethoxydiglycol.N.V. 1. Comparisons measures.. 177.. 4th ed. R.. cols. 27.O.. GOSSELIN. P. offoodAdditives. (1972). Converin the rat. and TSUKAMURA. Indus. Glucuronic acid excretion Exp. 118. Submission Submission 1.. (1976). 29. Respir. and LEVEILLE. Cleveland. (1982). 660-T. NATIONAL INSTITUTE FOR OCCUPATIONAL List. 26. A.3-Butylene butylene glycol. (1958). CTFA.3-Butylene H. PARKE. (FDA).. H. and MACKERER. (1970).B. and HANZLIK. Analysis glycol and glycoaldehyde plasma. Metabolic fate of 1. 17. (Dec..3-butanediol Chem. KLEAGER. Submission of unpublished data.). catabolism R. Liver tissue slices metabolism. and TOBIN. 16. and KILTS.S. Offic. Baltimore. J. 1982). 18. 1.. Neuronal after diethylene glyand liver protein synRes. OH: The Chemical Rubber 173. and CALVERY. 21. and BANERJEE. G. 34(12). alcohols.. dermal.D. Part Ill. 50. R. S. 177. 34. CTFA cosmetic ingredient chemical description.B. Observations on the chronic toxicities Exp. G.A. Fed. Drug Cosmet. 30. D. 21.A. and GLEASON. CODE OF (CTFA Code 2-17-172) Glycol. Acta Pharmacol. and WILLIAMS.E.W. J. Nutr. 21 CFR 177...3in the rat. 22(3). (eds. (hexyleneglycol) Studies by chronic oral administra80. of unpublished of unpublished data. C. 136-7. Differentiation of mycobacteria by susceptibility 216(2).60. Dis.. 101(12). H. Glycol. ROMSOS. MORRIS. Cutis 26(3). Cosmetics: Science and Technology. Effects of acute and treatment on central nervous system function: A comparison with ethanol. Inhibitory SAFETY effect of 1. M. P.3-butanediol C. HAHN. R. J. fncycl. 1974). 534. Computer printout of cosmetic product formulaFed. HARB.3-Butanediol sion to beta-hydroxybutyrate. M. (1947). co. chronic 1.220. (1968). Am. and lipid metabolism. CTFA. R. 35..A. 20. 25.. 2nd ed. R. Glycols Jechnol. 82-4. 10.S. R. Rev. (Nov.58. J. Chem. N. of Com- HODGE. 266. M. Drug Cosmet. 53. Assoc. Chem. Pathol. Ind. Gem.A. 9.. CC. BUDKE. 74. . Animal Toxic Substances oral. 1978). Commun. 2186-90. 2182-5.P.T. terscience. M. Glycerin.. REGULATIONS 176. 14.A.1210. MEHLMAN. BALSAM. 101(12). and TOAMA. FOOD tions. of 1. TOBIN. (1971). 115(6). 21. 243-4.. 96-8.FINAL REPORT: SAFETY ASSESSMENT OF THE CLYCOLS 245 8.. E. (Sept.1680. DC: US Government Printing Office. (May 1976).K. (CFR). in mouse 12. Proc. (1972). 2nd ed.J.P. CTFA cosmetic ingredient chemical description. AND DRUG glycol as a humectant in cosmetic creams.). 35(3). Ther. D. (1942). butanediol TATE.* WAGNER. (1980). and HARB. New York: Wiley-lnpropylene glycol.105. 505-6.. and MUNDY. Reactions to popular cosmetic humectants.J. 32. J. 176.E. KHAWAJA.. CTFA.3-butanediol macol.533-607. Glycol as a safe and useful ingredient N. Cosmet. The toxicity of 2-methyl-pentan-2. Washington. CHAPIN. Proc. FRYE. F.3-Butylene metics. 40-1. and in cos- and SAGARIN.3910. H. thesis in the developing offsprings treatment of pregnant rats with ethanol or 1. 31. 22. and ISGRIG.180. Ind. Evaluation of 1. Anal.A.48. 1975). Anal. Pharmacol.K.A. SHELANSKI.D. H. Clinical Toxicology mercial Products. 14. (1981). (1966).4-diol Toxicol. R.B..R. F. T.. ADMINISTRATION P. 19.. 290-304. & Wilkins. CRC Handbook FEDERAL 178. Pharmacol. (Nov.B. Phar306-14. 1982). Butanediol H. TOBIN. SMITH.200.H. LUDUENA. tonitrite and propylene giycol. MAILMAN. FISHER.. R. R. J. 171 1-8. ClR safety data test summary. TSUKAMURA. 1719-26. col monoethyl ether (carbitol) and some other glycols. and glycerol on several behavioral AYERS. 15. M. and polyhydric of ethylene Encycl.R. J. following 89. 1975). 573-80. Biochem.3-butylene AND HEALTH (NIOSH). and TATE. Ther.V. V. F. Pharmacol. LARSEN..K. Nutr. 11. R.. 341. 176. MEHLMAN.. of glyin the rat. (Sept. (ed. 89.J. BELO.A... GESSNER. glycol on microorganisms. 210.. Perfum. 34(12).S. Collaborative study on the GLC determination of propylene glycoi in cosmetics. (1981).210. (1981). Ther.1200.A. Metabolic fate of 1. FELLOWS. 28. A. The metabolism of tion to rats and mice.* (Sept. (1960). M. 12. J. R.C. 23. Psychopharmacologia 16(4). 10.L. L. 74(l). M. 13.A. Fed.K.
SCALA. Industrial of unpublished Glycol. 21. GAUNT. laboratory. CIR safety data test summary. 6.* of unpublished Glycol. V. Acute oral toxicity and ocular testing of product containing LEBERCO CTFA. (1971). col monoethyl ether in rats.E. mouse.-Forsch. of unpublished data. (April 22.D. irritation HEM. Glycol. 44. P. SD. Submission (<Aug. Primary skin irritation Primary skin irritaskin irritaButylene Derivatives Interscience. 1980). F. 53. 64.. Primary Primary skin irritaskin irritatest of (CTFA Code 2-17-29). (1967). Submission H. 55.. and THOMANN. (1978-1979). LEE. GRASSO. (ed.2. 50. of unpublished Glycol. CTFA. and pig.. Pharma- col. 56. 51. 16. (Nov. bits. Chronic oral toxicity of 1. I. G. S. data. (Nov. Zur Toxikologie Tissue Acute intraperitoneal evaluation of po(CTFA Code 2-l 7-77). toxicology HALL. 142.* of unpublished Glycol. 21. (1948). CIR safety data test summary. LABORATORIES. data by CTFA.* D. of unpublished of unpublished acetate. Eye irritation .. 880. Ind. G. 1977). 1977).’ (March 9. BANKER. 21.81). Submission Butylene LIBRARY OF MEDICINE Submission test of product containing NATIONAL CTFA.* (NLM). of diethylene glycol monoethyl ether in the rat.* (May 13. CTFA. 45. Product containing Dipropyl- data. Submission (CTFA Code 2-17-71). PEHEIM. P. Short-term 6(6). and CARPENTER. tests of skin care product containing LEBERCO LABORATORIES.* of unpublished Glycol. Primary skin irritation Primary skin irritation tion test of product containing test of p-oduct containing Butylene Butylene (CTFA Code 2-17-86). CTFA. Fed.” 36). 17. 1978). 1975). 880. 6. CIR safety data test summary. CIR safety data test summary.P. data. and derivatives. data. 63. (1974-1975). Toxicol. Drug Dev.A. J. 42. C. and WOODARD. 173.246 ocular tests of nail lotion containing 37. test of Butylene test of Butylene New York: (CTFA Code 2-l 7-76). (CTFA Code 2-17-166). J. 10. 48. tion test of body Jotion containing Ethoxydiglycol. Acute oral toxicity of unpublished (1982). Primary skin irritation Rabbit skin patch 2nd ed. 19. CTFA.F..A. Short-term 4(3).. 62.L. (CTFA Code 2-17-87). D. Hyg. Food Cosmet. of unpublished data. 57.J. 6. dermal. F. Toxicol. Sot. 263-8.K. CIR safety data test summary.. Acute oral toxicity of some glycols Acute oral toxicity tests of unpublished Hexylene of skin care product containing LEBERCO LANG. 1976).E. Submission Glycol. (CTFA Code 2-17-5). 60. toxicity 705. Submission (NOV. 11. (CTFA Code 2-17-l of unpublished Glycol. Submission of unpublished Butylene Glycol. toxicity R. 471-7. data. CIR safety data test summary. MULLER.A. CIR safety data test summary. CIR safety data test summary. 12.. CIR safety data test summary. ene Glycol. 58. A.B. 4. C.F. (1939). (1968). (Aug. 38. Cellosolve (Feb. P. CIR safety data test summary. LANSDOWN. Submission Arzneim. 1976). COLLEY. Toxicol. D.. Proc. AUSTIN.A. H.G.* COSMETIC INGREDIENT REVIEW (CTFA Code 2-l 7-160). Acute oral. 65.* data by CTFA. SMYTH. Fed. 689feeding with diethyleneglyJ. 43.3-Butanediol. (1947). In: Patty. 1979). 1980). ROWE. CIR safety data test summary. BRIGHT.’ (CTFA Code 2-17-25). 160-4. (CTFA Code 2-17-79).* CTFA.* Ethoxydiglycol. Hyg. Submission (1978-1979). LABORATORIES. 1975).S. Four-week subacute dermal toxicity study in rab- data.’ of unpublished Hexylene Hygiene and Toxicology. CALVERY. Am.). Acute toxicity E. STENGER. of unpublished data by CTFA. (1966)..R. of unpublished data. Food Cosmet. Submission tion test of product containing test of product containing CTFA. 1979). CTFA. and PAYNTER. data.* of unpublished (CTFA Code 2-17-27). A. tential parenteral vehicles. Biol.* (CTFA Code 2-17-l 34). LISLOTT. CTFA. Toxicol.* (CTFA Code 2-17-74). (Dec. CTFA. Ind. 1. CTFA... and GANGOLLI. V. 54. 41.* Glycol. 46. p. (1945). 39. O. test of body lotion containing (1977).. Commun. Primary Vol. 15..P. CARPENTER. (1963). Clycol. test of eye makeup remover containing E. data. 1976). Submission test of Butylene Glycol.O. of glycols.* (Dec. Submission (CTFA Code 2-17-31). JAMA 135. and NELSON. CTFA. 47. 15. The toxicology H.P. l(5). and POGUE. 1980). Further experience with the range finding test in the industrial 30. JOHNSON. 61.. (CTFA Code 2-17-84). 59. F.. Submission Hexylene MORRIS..4-pentanediol.G. (Dec. Clycol. AEPPLI. data. Submission Butylene (CTFA Code 2-l 7. 52. Submission Ethoxydiglycol. 1980).. data. Submission Hexylene tion test of eye makeup remover containing LEBERCO LABORATORIES. CIR safety data test summary.. Computerized data base. 1976). (Jan. 1561. G. Appl. CTFA. E. (Dec. Exp. CIR safety data test summary. 63. (CTFA Code 2-17-75). 49. Submission of unpublished data by CTFA. of 2-methyl-2.S. data. 40. WOODARD. Butylene Clycol. and FAIRWEATHER.P. J.. Toxicol. (Jan. des Athyleneglykol-Monoathylathers.
(CTFA Code 2-17-93).* Glycol. CTFA. (1981). (CTFA Code 2-17-83). 1978). 27. LABORATORIES. J.* Glycol.A.. The study of cumulative test of product con. Submission of unpublished data by CTFA. Submission data.’ (CTFA Code 2-17-80). CIR safety data test summary. PLAZONNET. Submission (Dec. 82. REPORT: SAFETY ASSESSMENT OF THE CLYCOLS data. CIR safety data test summary.* patch tests of nail lotion containing (1978). and GONIN. CIR safety data test summary. CTFA.. 1973). 86. CTFA. (1974). data. CIR safety data test summary. 1980). 3. 2nd ed. TOP TOP Submission Dipropylene (CTFA Code 2-17-167). Nutritional 2171-6. IL: Charles C Thomas. (March 31. metabolic studies KIES.* data. LABORATORIES. (CTFA Code 2-17-26). 81.. Submission of unpublished of unpublished test of test of Butylene Hexylene LAILLIER.* of unpublished Glycol. DE DOUAREC. data. patch test of body lotion containing Ethoxydiglycol. 16. C. Glycol. data by CTFA. 23. 336-50. 88. B. 1976). CTFA. 91. FOX. ToxiEye irritation Eye irritation test of test of of an objective method of studying eye irritation. Submission W. Submission (Aug.M.* (CTFA Code patch patch test with 2-17-126).* of unpublished Hexylene test of eye makeup remover containing test of body lotion containing (1978-1979). 75. (July 31. and SOELDNER. 1974).* (CTFA Code 2-17-161). 1972). Submission Submission Human skin irritation Human skin irrita- Butylene (CTFA Code 2-17-82). 1976). J. H. RESEARCH. Repeated insult Repeated insult test of personal cleanliness product containing (CTFA Code 2-17-125). Submission Glycol. R. 1980). Eur. Submission (Feb. 12. data by CTFA. product containing product containing LEBERCO LEBERCO CTFA. M. Proc. Submission remover containing Hexylene Glycol. CTFA. (CTFA Code 2-l 7-94). data. (July 1979). Submission of unpublished data.* of unpublished of unpublished Glycol. data. 1976). CTFA. 13. CIR safety data test summary. 87. (Dec. (1975.* (CTFA Code 2-17-70). (July 16. Submission of unpublished data. 16. product containing Butylene (Feb. tion test of Butylene tion test of Hexylene (CTFA Code 2-l 7-78).* Butylene in humans with 1. Submission LABORATORIES. 77. Submission M. (CTFA Code 2-17-3). Submission Butylene Butylene (Nov. Prophetic patch and repeat Glycol. 1981). of eye makeup taining Butylene of ten samples. CIR safety data test summary. data by CTFA. 1975). TESTKIT LABORATORIES. Allergic contact sensitization of unpublished data by CTFA. 5. (May 19. Submission of unpublished data. Clinical use test. CTFA.* (CTFA Code 2-17-135). CIR safety data test summary. CIR safety data test summary. 84.J.3-butanediol. 17. of unpublished of unpublished of unpublished Glycol.* (CTFA Code 2-17-30). 34(12). (Nov. 68.C. Submission of unpublished testing of product containing Ethoxydiglycol. CTFA. data. J. col. Prophetic and repeated insult tion test of product containing Submission Butylene of unpublished of unpublished data. Submission (Nov. (March 29. 79. 1976). 78. patch tests of product containing Toxicology (Feb. 71. Springfield. 1977). Human Human skin irritation irri(CTFA Code 2-17-128). CTFA. 1977).. Eye irritation Eye irritation 247 CTFA. 1976). 1975). CTFA. Submission Butylene Repeated insult patch test Repeated insult patch Rouge containing Glycol. 1980). 83. (CTFA Code 2-17-88).* Repeated insult 94. Sot. of unpublished of unpublished test of personal cleanliness RESEARCH.S. 67.M. TOBIN. Evaluation of ocular irProc. data. CIR safety data test summary. 92. 1973). Submission TOP RESEARCH. CIR safety data test summary.* Glycol. CTFA. TESTKIT test 90. CTFA. of unpublished data by CTFA. Human skin irritaHuman skin irritaHuman Human skin irritaskin irrita- tests of skin care product containing MEHLMAN. 85. (Jan. (CTFA Code 2-17-85). data. CIR safety data test summary. CTFA. CTFA. 1979).. Glycol. Submission of unpublished of a series of test materials. cumulative of the Eye. (July 1976).* tancy test of product containing irritant properties (CTFA Code 2-17-68). Butylene Butylene tion test of product containing tion test of product containing test of product containing 80. 29. (CTFA Code 2-l 7-95). 15.* Glycol.* 93.B.’ (CTFA Code 2-17-24). of unpublished of unpublished data by CTFA. Submission Glycol. (CTFA Code 2-17-6). 89. 15. Hexylene Glycol. CIR safety data test summary. Hexylene Glycol. 1973). in the rabbit: Development (Jan.* (CTFA Code 2-17-28). 72. insult CTFA. 73.* (May 1. 1976). CIR safety data test summary. (Jan.* of unpublished data. 76. of unpublished of unpublished data.* (CTFA Code 2-17-72). Rabbit eye irritation Rabbit eye irritation Rabbit eye irritation and Hexylene Glycol. ritation 69. CIR safety data test summary. CIR safety data test summary.* Glycol. GRANT. 17. (CTFA Code 2-17-69).. data. Submission Ethoxydiglycol.’ Fed. 70. (March 4. CIR safety data test summary. . (Aug. (Nov. Glycol. Repeated insult patch sun exposure of personal cleanliness product containing Hexylene Glycol.. (CTFA Code 2-17-73). data. 1978). HILL (Feb. 1980).FINAL 66. HILL HILL CTFA. 74. CIR safety data test summary. CTFA. data. Glycol.
INGREDIENT Human REVIEW use test of shaving use test of per- preparation containing Dipropylene Glycol. Submission of unpublished COSMETIC data. tion containing product containing Glycol. 1982). Submission of unpublished data. Glycol.248 95. CTFA.* (Feb. (CTFA Code 2-l 7-l 68). Glycol. 1981). 97. 1982). CTFA. Submission Hexylene (June 11. CTFA. (1978). Submission Dipropylene of unpublished of unpublished complaint experience on skin care prodcomplaint experience on shave prepara- (CTFA Code 2-17-137).* (CTFA Code 2-l 7-124). (CTFA Code 2-17-169). CIR safety data test summary. 96. Industry Human sonal cleanliness uct containing 98.* Hexylene (Sept. 26. CIR safety data test summary.’ . data. Industry data. CTFA.
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