title: The JFFMA assessment of flavoring substances structurally related to menthol and uniquely used in Japan.
abstract: Using the procedure devised by the Joint FAO/WHO Expert Committee on Food Additives (JECFA), we performed safety evaluations on four flavoring substances structurally related to menthol (L-menthyl 2-methylbutyrate, DL-menthyl octanoate, DL-menthyl palmitate, and DL-menthyl stearate) uniquely used in Japan. While no genotoxicity study data were available in the literature, all four substances had no chemical structural alerts predictive of genotoxicity. Moreover, they all four are esters consisting of menthol and simple carboxylic acids that were assumed to be immediately hydrolyzed after ingestion and metabolized into innocuous substances for excretion. As menthol and carboxylic acids have no known genotoxicity, it was judged that the JECFA procedure could be applied to these four substances. According to Cramer's classification, these substances were categorized as class I based on their chemical structures. The estimated daily intakes for all four substances were within the range of 1.54-4.71 μg/person/day and 60-1250 μg/person/day, using the methods of Maximized Survey-Derived Intake and Single Portion Exposure Technique, respectively, based on the annual usage data of 2001, 2005, and 2010 in Japan. As the daily intakes of these substances were below the threshold of concern applied to class I substances viz., 1800 μg/person/day, it was concluded that all four substances raise no safety concerns when used for flavoring foods under the currently estimated intake levels.
authors.affiliation: Japan Flavor and Fragrance Materials Association, Sankei Nihonbashi Bldg. 6F, 4-7-1 Nihonbashi-Honcho, Chuo-ku, Tokyo 103-0023, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Mirokuji
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Abe
authors.affiliation: Japan Flavor and Fragrance Materials Association, Sankei Nihonbashi Bldg. 6F, 4-7-1 Nihonbashi-Honcho, Chuo-ku, Tokyo 103-0023, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okamura
authors.affiliation: Japan Flavor and Fragrance Materials Association, Sankei Nihonbashi Bldg. 6F, 4-7-1 Nihonbashi-Honcho, Chuo-ku, Tokyo 103-0023, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Saito
authors.affiliation: Japan Flavor and Fragrance Materials Association, Sankei Nihonbashi Bldg. 6F, 4-7-1 Nihonbashi-Honcho, Chuo-ku, Tokyo 103-0023, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Sekiya
authors.affiliation: Japan Flavor and Fragrance Materials Association, Sankei Nihonbashi Bldg. 6F, 4-7-1 Nihonbashi-Honcho, Chuo-ku, Tokyo 103-0023, Japan.
authors.forename: Shim-mo
authors.initials: SM
authors.lastname: Hayashi
authors.affiliation: Japan Flavor and Fragrance Materials Association, Sankei Nihonbashi Bldg. 6F, 4-7-1 Nihonbashi-Honcho, Chuo-ku, Tokyo 103-0023, Japan.
authors.forename: Shinpei
authors.initials: S
authors.lastname: Maruyama
authors.affiliation: Division of Risk Assessment, National Institute of Health Sciences, Tokyo 158-8501, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ono
authors.affiliation: Planning Department, Public Interest Incorporated Foundation, BioSafety Research Center, 582-2 Shioshinden, Iwata-shi, Shizuoka 437-1213, Japan.
authors.forename: Madoka
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Masakuni
authors.initials: M
authors.lastname: Degawa
authors.affiliation: Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-cho, Shiwa-gun, Iwate 028-3694, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Ozawa
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan. Electronic address: mshibuta@cc.tuat.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Shibutani
authors.affiliation: School of Food and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Tamio
authors.initials: T
authors.lastname: Maitani
mesh_terms: D005421:Flavoring Agents / Q000737:chemistry* / Q000633:toxicity; D007564:Japan; D008610:Menthol / Q000737:chemistry* / Q000633:toxicity; D015394:Molecular Structure
chemical_list: D005421:Flavoring Agents; D008610:Menthol
keywords: ADI; Cramer’s decision tree; EFSA; European Food Safety Authority; FEMA; Flavor and Extract Manufacturers Association; JASREC; JECFA; JFFMA; Japan Flavor and Fragrance Materials Association; Japanese unique flavoring substances; Joint FAO/WHO Expert Committee on Food Additives; Joint FAO/WHO Expert Committee on Food Additives (JECFA); MSDI; Maximized Survey-Derived Intake; Menthol; NOEL; SAR; SPET; Safety concerns; Single Portion Exposure Technique; Structure Activity Relationship analyses; The JFFMA Safety Re-evaluation Committee; WHO; World Health Organization; acceptable daily intake; no observed effect level