Available online at www.sciencedirect.com Food and Chemical Toxicology 45 (2007) S318–S361 www.elsevier.com/locate/foodchemtox Review A toxicologic and dermatologic assessment of salicylates when used as fragrance ingredients q The RIFM Expert Panel D. Belsito a, D. Bickers b, M. Bruze c, P. Calow d, H. Greim e, J.M. Hanifin f, A.E. Rogers g, J.H. Saurat h, I.G. Sipes i, H. Tagami j a University of Missouri (Kansas City), c/o American Dermatology Associates, LLC, 6333 Long Avenue, Third Floor, Shawnee, KS 66216, USA b Columbia University Medical Center, Department of Dermatology, 161 Fort Washington Avenue, New York, NY 10032, USA c Malmo University Hospital, Department of Occupational & Environmental Dermatology, Sodra Forstadsgatan 101, Entrance 47, Malmo SE-20502, Sweden d Institut for Miliovurdering, Environmental Assessment Institute, Linne´sgade 18, 1st floor, Copenhagen 1361 K, Denmark e Technical University of Munich, Institute for Toxicology & Environmental Hygiene, Hohenbachernstrasse 15-17, Freising-Weihenstephan D-85354, Germany f Oregon Health Sciences University, Department of Dermatology L468, 3181 SW Sam Jackson Park Road, Portland, OR 97201-3098, USA g Boston University School of Medicine, Department of Pathology and Laboratory Medicine, 715 Albany Street, L-804, Boston, MA 02118-2526, USA h Hospital Cantonal Universitaire, Clinique et Policlinique de Dermatologie, 24, Rue Micheli-du-Crest, Geneve 14 1211, Switzerland i Department of Pharmacology, University of Arizona, College of Medicine, 1501 North Campbell Avenue, P.O. Box 245050, Tucson, AZ 85724-5050, USA j 3-27-1 Kaigamori, Aoba-ku, Sendai 981-0942, Japan Abstract An evaluation and review of a structurally related group of fragrance materials. Ó 2007 Published by Elsevier Ltd. Keywords: Safety; Review; Salicylates; Fragrance Contents 1. Chemical identity and exposure (Table 1). S319 1.1. Estimated consumer exposure. .............................................................. S323 2. Absorption, distribution and metabolism, and potential for enzyme induction. S323 2.1. Absorption . ........................................................................... S323 2.1.1. Percutaneous absorption (Tables 2–5)................................................ S323 2.1.2. Oral absorption. S325 2.1.3. Inhalation absorption . S326 2.2. Distribution and pharmacokinetics ........................................................... S326 2.3. Metabolism (Fig. 1)...................................................................... S327 3. Toxicological studies . S329 3.1. Acute toxicity (Tables 6a–6c)............................................................... S329 3.2. Subchronic toxicity (Table 7)............................................................... S330 3.2.1. Dermal studies . S330 q All correspondence should be addressed to: A.M. Api, 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA. Tel.: +1 201 689 8089; fax: +1 201 689 8090. E-mail address: [email protected] 0278-6915/$ - see front matter Ó 2007 Published by Elsevier Ltd. doi:10.1016/j.fct.2007.09.066 D. Belsito et al. / Food and Chemical Toxicology 45 (2007) S318–S361 S319 3.2.2. Oral studies . S333 3.2.3. Summary of subchronic toxicity studies. S333 3.3. Chronic toxicity (Table 8) ................................................................. S334 3.3.1. Repeated-dose toxicity of salicylate metabolites . S335 3.4. Mutagenicity and genotoxicity . ............................................................. S335 3.4.1. Bacterial studies (Table 9)........................................................ S335 3.4.2. Mammalian studies (Table 10)..................................................... S336 3.4.3. Summary of the genotoxicity data . S336 3.5. Carcinogenicity ......................................................................... S337 3.5.1. Non-standard carcinogenicity studies . S337 3.5.2. Anti-carcinogenic effects . S337 3.5.3. Summary of the carcinogenicity data . S337 3.6. Reproductive and developmental toxicity (Table 11).............................................. S337 3.6.1. Summary of the reproductive and developmental toxicity . S339 3.7. Skin irritation .......................................................................... S341 3.7.1. Human studies (Table 12)........................................................ S341 3.7.2. Animal studies (Table 13) ........................................................ S341 3.7.3. Summary of the skin irritation data . S341 3.8. Mucous membrane (eye) irritation (Table 14)................................................... S345 3.9. Skin sensitization ........................................................................ S345 3.9.1. Human studies (Table 15)........................................................ S345 3.9.2. Cross sensitization. S345 3.9.3. Animal studies (Table 16) ........................................................ S345 3.9.4. Summary of the skin sensitization data . S346 3.10. Phototoxicity and photoallergenicity (Tables 17–19) .............................................. S351 3.10.1. Human studies . S351 3.10.2. Animal studies . S351 3.11. Environmental toxicity .................................................................... S352 4. Summary . S353 5. Conclusion . S354 Conflict of interest statement . S355 References . S355 1. Chemical identity and exposure (Table 1) individual chemicals. The group summary is an evaluation of relevant data selected from the large bibliography of This report summarizes scientific data relevant to the studies and reports on the individual chemicals. The risk assessment of the use of salicylates as fragrance ingre- selected data were deemed to be relevant based on the dients (Table 1). The 17 salicylates considered here nature of the protocols, quality of the data, statistical sig- include alkyl (i.e., methyl-, ethyl-, butyl-, isobutyl-, pen- nificance, and appropriate exposure. These data are pre- tyl-, isoamyl-, hexyl-, and ethyl hexylsalicylate), alkenyl sented in tabular form in the group summary. The (i.e., cis-3-hexenyl-, trans-2-hexenyl-, 1,3-dimethyl-3-bute- Fragrance Material Reviews on each individual salicylate nyl, and 3-methyl-2-butenyl salicylate), aromatic ring contain a comprehensive summary of published and (i.e., benzyl-, phenyl-, p-cresyl- and phenethyl salicylate) unpublished reports and comprehensive bibliographies. and other (i.e., 4-methylsalicylate) derivatives of salicylic Salicylates are ingredients of many fragrances. They may acid. Most of these substances are used as fragrance be found in decorative cosmetics, fine fragrances, sham- and flavor ingredients. This report presents and synthe- poos, toilet soaps and other toiletries as well as in non-cos- sizes animal and human data, including studies by various metic products such as household cleaners and detergents. routes of exposure, and emphasizes the risk assessment Many of the salicylates assessed in this report have been for use of salicylates as fragrance ingredients. The scien- evaluated and approved for use as flavor ingredients in tific evaluation focuses on dermal exposure, which is con- foodstuffs. In the United States, 5 of the 17 salicylates sidered to be the primary exposure route for fragrance (ethyl salicylate, isobutyl salicylate, isoamyl salicylate, ben- materials. Where relevant, toxicity, metabolism and bio- zyl salicylate, and phenethyl salicylate) have been approved logical fate data from other routes of exposure have also for use as flavors by the Food and Drug Administration been considered. (FDA) in accordance with (21 CFR 172.515). In addition, The current format for these RIFM publications methyl (2475), ethyl (2458), butyl (3650), isobutyl (2213), includes a summary evaluation paper of the chemical isoamyl (2084), benzyl (2151), phenyl (3960), phenethyl group and individual Fragrance Material Reviews on the (2868) salicylate have been granted Generally Recognized S320 D. Belsito et al. / Food and Chemical Toxicology 45 (2007) S318–S361 Table 1 Material identification, summary of volume of use, and dermal exposure Material Synonyms Structure Worldwide Dermal systemic exposure in Maximum metric tons cosmetic products (mg/kg/day) skin level (%) Benzyl salicylate Benzoic acid, 2-hydroxy-, >1000 0.4023 6.71 phenylmethyl ester; CAS# 118-58-1 Benzyl 2-hydroxybenzoate; Molecular weight: Benzyl o-hydroxybenzoate; 228.25 Log Kow 2-Hydroxybenozic acid; (calculated): 4.31 Phenylmethyl 2- hydroxybenozate; Salicylic acid, benzyl ester Butyl salicylate Benzoic acid, 2-hydroxy-, butyl <0.01 0.0005a 0.02 ester; CAS# 2052-14-4 n-Butyl o-hydroxybenzoate; Molecular weight: 194.23 LogKow n-Butyl salicylate (calculated): 4.08 p-Cresyl salicylate Benzoic acid, 2-hydroxy-, < 0.01 0.0003 0.001 4-methylphenyl ester; CAS# 607-88-5 p-Tolyl salicylate Molecular weight: 228.25 LogKow (calculated): 4.37 1,3-Dimethyl-3- Benzoic acid, 2-hydroxy-, 1,3- 0.1–1.0 0.0005a 0.02 butenyl salicylate dimethyl-3-butenyl ester CAS # 80118-10-1 Molecular weight: 220.26 LogKow (calculated): 4.91 Ethyl hexyl Benzoic acid, 2-hydroxy-, 2- 0.1–1.0 0.0005a 0.02 salicylate ethylhexyl ester; Dermoblock OS; Escalol 587; 2-Ethylhexyl 2- hydroxybenzoate; CAS# 118-60-5 2-Ethylhexyl salicylate; Molecular weight: Eusolex OS; 250.34 LogKow Heliosol 2; (calculated): 5.97 Neo Heliopan; Type OS; Neotan L; Salicylic acid 2-ethylhexyl ester; Trivent OS Ethyl salicylate Benzoic acid, 2-hydroxy-, ethyl 1–10 0.0002 0.14 ester; CAS# 118-61-6 Ethyl 2-hydroxybenzoate; Molecular weight: Ethyl o-hydroxybenzoate: 166.18 LogKow Ethyl salicylate;