The Japan Flavour and Fragrance Materials Association’s (JFFMA) safety assessment of acetal food flavouring substances uniquely used in Japan

Food Additives and Contaminants - Part A Chemistry, Analysis, Control, Exposure and Risk Assessment

Volumn 32, Issue 9, 2015, Pages 1384-1396

  Okamura, Hiroyuki ^a   Abe, Hajime ^b   Hasegawa Baba, Yasuko ^b   Saito, Kenji ^a   Sekiya, Fumiko ^a   Hayashi, Shim Mo ^a   Mirokuji, Yoshiharu ^a   Maruyama, Shinpei ^a   Ono, Atsushi ^c   Nakajima, Madoka ^d   Degawa, Masakuni ^d   Ozawa, Shogo ^e   Shibutani, Makoto ^b   Maitani, Tamio ^c  

^a Japan Flavour and Fragrance Materials Association (JFFMA)   (Japan)

^b TOKYO UNIVERSITY OF AGRICULTURE AND TECHNOLOGY   (Japan)

^c NATIONAL INSTITUTE OF HEALTH SCIENCES   (Japan)

^d UNIVERSITY OF SHIZUOKA   (Japan)

^e IWATE MEDICAL UNIVERSITY   (Japan)

Author keywords

acetals; Cramer s decision tree; food flavours; Joint FAO WHO Expert Committee on Food Additives (JECFA); safety; threshold of toxicological concern (TTC)

Indexed keywords

ACCIDENT PREVENTION; ACETALDEHYDE; DECISION TREES; FOOD ADDITIVES;

4-METHYL-2-PENTANONE; ACETALS; ANNUAL PRODUCTION; ESTIMATED DAILY INTAKES; FRAGRANCE MATERIALS; SAFETY ASSESSMENTS; SAFETY EVALUATIONS; THRESHOLD OF TOXICOLOGICAL CONCERN (TTC);

METABOLITES;

4 METHYL 2 PENTANONE; 4 METHYL 2 PENTANONE PROPYLENEGLYCOL ACETAL; ACETAL DERIVATIVE; ACETALDEHYDE; ACETALDEHYDE 2,3 BUTANEDIOL ACETAL; ACETOIN; ACETOIN DIMETHYL ACETAL; BUTANOL; FLAVORING AGENT; FRAGRANCE; HEXANAL; HEXANAL DIBUTYL ACETAL; HEXANAL GLYCERYL ACETAL; PROPYLENE GLYCOL; UNCLASSIFIED DRUG; FOOD ADDITIVE;

ABSORPTION; CARCINOGENICITY; CHEMICAL STRUCTURE; CHRONIC TOXICITY; COMPUTER MODEL; DECISION TREE; EXCRETION; FLAVOR; FOOD INTAKE; FOOD POISONING; FOOD SAFETY; GENOTOXICITY; HYDROLYSIS; JAPAN; METABOLISM; METABOLITE; MOLECULAR WEIGHT; NONHUMAN; PRIORITY JOURNAL; REVIEW; RISK ASSESSMENT; CHEMISTRY; HAZARD ASSESSMENT; HUMAN;

FLAVORING AGENTS; FOOD ADDITIVES; HAZARD ANALYSIS AND CRITICAL CONTROL POINTS; HUMANS; JAPAN; MOLECULAR STRUCTURE;

EID: 84941260315     PISSN: 19440049     EISSN: 19440057     Source Type: Journal    
DOI: 10.1080/19440049.2015.1067927     Document Type: Review

References (89)

1. J.Ashby, R.W.Tennant 1988. Chemical structure, Salmonella mutagenicity and extent of carcinogenicity as indicators of genotoxic carcinogenesis among 222 chemicals tested in rodents by the US NCI/NTP. Mutat Res. 204:17–115.
2. J.Ashby, R.W.Tennant. 1991. Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the US NTP. Mutat Res. 257:229–306.
3. W.F.Bosron, T.Li. 1980. Alcohol dehydrogenase. In: W.B.Jakoby, editor. Enzymatic basis of detoxication. Vol. 1. New York (NY): Academic Press; p. 231–248.
4. M.J.Brabec. 1993. Aldehydes and acetals. In: G.D.Clayton, F.E.Clayton, editors. Patty’s industrial hygiene and toxicology. Part B. 3rd ed. Vol. II. New York (NY): John Wiley & Sons, Inc.; p. 2629–2669.
5. G.Brambilla, E.Cajelli, R.Canonero, A.Martelli, U.M.Marinari. 1989. Mutagenicity in V79 Chinese hamster cells of n-alkanals produced by lipid peroxidation. Mutagenesis. 4:277–279.
6. P.J.Brooks, S.Zakhari. 2014. Acetaldehyde and the genome: beyond nuclear DNA adducts and carcinogenesis. Environ Mol Mutagen. 55:77–91.
7. T.M.Brooks, A.L.Meyer, D.H.Hutson. 1988. The genetic toxicology of some hydrocarbon and oxygenated solvents. Mutagenesis. 3:227–232.
8. W.D.Brown, J.V.Setzer, R.B.Dick, F.C.Phipps, L.K.Lowry. 1987. Body burden profiles of single and mixed solvent exposures. J Occup Med. 29:877–883.
9. Carnegie-Mellon Institute of Research. 1977a. Comparative toxicity to rats of methoxyacetone and five other aliphatic ketones in their drinking water. Sponsored by Union Carbide Corporation. Submitted to EPA under TSCA section 8D. EPA Document Number 87-8212140; Fiche No. OTS0206068.
10. Carnegie-Mellon Institute of Research. 1977b. Comparative pathology on rats given methoxyacetone and five other aliphatic ketones in their drinking water (ketone neurotoxicity). Sponsored by Union Carbide Corporation. Submitted to EPA under TSCA section 8D. EPA Document Number 87-8212141; Fiche No. OTS0206068.
11. G.M.Cramer, R.A.Ford, R.L.Hall. 1976. Estimation of toxic hazard – a decision tree approach. Food Cosmet Toxicol. 16:255–276.
12. M.Cronin, J.D.Walker, J.S.Jaworska, M.Comber, C.D.Watts, A.P.Worth. 2003. Use of QSARs in international decision-making frameworks to predict health effects of chemical substances. Environ Health Perspect. 111:1391–1401.
13. J.Dawson, R.P.Hullin. 1954. Metabolism of acetoin. I. The formation and utilization of acetoin and butane-2:3-diol in the decerebrated cat. Biochem J. 57:177–180.
14. R.De Simone. 1976. In vitro digestion tests on three acetals. Unpublished report from Hercules Inc. Submitted to WHO by Flavor and Extract Manufacturers Association of the United States.
15. F.K.Dietz, M.Rodriguez-Giaxola, G.J.Traiger, V.J.Stella, K.J.Himmelstein. 1981. Pharmacokinetics of 2-butanol and its metabolites in the rat. J Pharmacokinet Biopharm. 9:553–576.
16. D.M.Dillon, D.B.McGregor, R.D.Combes, E.Zeiger. 1992. Detection of mutagenicity in Salmonella of some aldehydes and peroxides. Environ Mol Mutagen. 19:15.
17. N.Enomoto, S.Takase, M.Yasuhara, A.Takada. 1991. Acetaldehyde metabolism in different aldehyde dehydrogenase-2 genotypes. Alcohol Clin Exp Res. 15:141–144.
18. C.J.Eriksson. 2015. Genetic-epidemiological evidence for the role of acetaldehyde in cancers related to alcohol drinking. Adv Exp Med Biol. 815:41–58.
19. J.L.Fang, C.E.Vaca. 1997. Detection of DNA adducts of acetaldehyde in peripheral white blood cells of alcohol abusers. Carcinogenesis. 18:627–632.
20. [FAO] Food and Agriculture Organization of the United Nations. 2015. Codex alimentarius, international food standards [Internet]. General standard for food additives. Codex Stan 192–1995. [cited 2015 Jun 23]. Available from http://www.codexalimentarius.net/gsfaonline/docs/CXS_192e.pdf
21. R.L.Felsted, N.R.Bachur. 1980. Ketone reductases. In: W.B.Jacoby, editor. Enzymatic basis of detoxification. Vol. I. New York (NY): Academic Press; p. 281–293.
22. I.Florin, L.Rutberg, M.Curvall, C.R.Enzell. 1980. Screening of tobacco smoke constituents for mutagenicity using the Ames’ test. Toxicology. 15:219–232.
23. [FSCJ] Food Safety Commission of Japan. 2005a. Evaluation results on the health risk assessment of acetaldehyde as food additive [Internet]. [cited 2015 Jun 23]. Available from http://www.fsc.go.jp/english/evaluationreports/additives_e3.html
24. [FSCJ] Food Safety Commission of Japan. 2005b. Evaluation results on the health risk assessment of butanol as food additive [Internet]. [cited 2015 Jun 23]. Available from http://www.fsc.go.jp/english/evaluationreports/additives_e3.html
25. T.Fukunaga, P.Sillanaukee, C.J.Eriksson. 1993. Problems involved in the determination of endogenous acetaldehyde in human blood. Alcohol Alcohol. 28:535–541.
26. C.C.Furnus, M.A.Ulrich, M.C.Terreros, F.N.Dulout. 1990. The induction of aneuploidy in cultured Chinese hamster cells by propionaldehyde and chloral hydrate. Mutagenesis. 5:323–326.
27. 2 in intact animals and in liver mince preparation. Comp Biochem Physiol B. 41:493–502.
28. J.Garst, P.Stapleton, J.Johnston. 1983. Mutagenicity of alpha-hydroxy ketones may involve superoxide anion radical. In: R.A.Greenwald, G.Cohen, editors. Oxy radicals and their scavenger systems. Cellular and medical aspects. Vol. II. Amsterdam: Elsevier Science Publishing; p. 125–130.
29. I.F.Gaunt, P.G.Brantom, I.S.Kiss, P.Grasso, S.D.Gangolli. 1972. Short-term toxicity of acetoin (acetyl methylcarbinol) in rats. Food Cosmet Toxicol. 10:131–141.
30. H.W.Haggard, D.P.Miller, L.A.Greenberg. 1945. The amyl alcohols and their ketones: their metabolic fates and comparative toxicities. J Ind Hyg Toxicol. 27:1–14.
31. C.Hansch. 1969. Quantitative approach to biochemical structure-activity relationships. Acc Chem Res. 2:232–239.
32. S.-M.He, B.Lambert. 1985. Induction and persistence of SCE-inducing damage in human lymphocytes exposed to vinyl acetate and acetaldehyde in vitro. Mutat Res. 158:201–208.
33. A.Helander, K.Lindahl-Kiessling. 1991. Increased frequency of acetaldehyde-induced sister-chromatid exchanges in human lymphocytes treated with an aldehyde dehydrogenase inhibitor. Mutat Res. 264:103–107.
34. [IARC] International Agency for Research on Cancer. 1999. IARC monographs on the evaluation of carcinogenic risks to humans. In: Scientific publication. Re-evaluation of some organic chemicals, hydrazine and hydrogen peroxide. Vol. 71. Lyon: IARC Press; p. 319–335.
35. [JFFMA] Japan Flavour and Fragrance Materials Association. 2003. Usage survey of food-flavouring ingredients in Japan [Internet]. Health and Labour Sciences Research Grant, 2003. Japanese. [cited 2015 Jun 23]. Available from http://mhlw-grants.niph.go.jp
36. [JFFMA] Japan Flavour and Fragrance Materials Association. 2006. Survey for production, usage and intake of food-flavouring ingredients in Japan [Internet]. Health and Labour Sciences Research Grant, 2006. Japanese. [cited 2015 Jun 23]. Available from http://mhlw-grants.niph.go.jp
37. [JFFMA] Japan Flavour and Fragrance Materials Association. 2011. Survey for usage and intake of food-flavouring ingredient in Japan [Internet]. Health and Labour Sciences Research Grant, 2011. Japanese. [cited 2015 Jun 23]. Available from http://mhlw-grants.niph.go.jp
38. J.R.W.Kapp RW, M.DJMarino, G.THGardiner, M.LWMasten, M.RHMcKee, T.TRTyler, I.JLIvett, Y.RRYoung. 1993. In vitro and in vivo assays of isopropanol for mutagenicity. Environ Mol Mutagen. 22:93–100.
39. G.V.Katz, D.Guest. 1994. Aliphatic carboxylic acids. In: G.D.Clayton, F.E.Clayton, editors. Patty’s industrial hygiene and toxicology. Part E. 4th ed. Vol. II. New York (NY): John Wiley & Sons; p. 3523–3671.
40. S.B.Kim, F.Hayase, H.Kato. 1987. Desmutagenic effect of α-dicarbonyl and α-hydroxycarbonyl compounds against mutagenic heterocyclic amines. Mutat Res. 177:9–15.
41. P.K.Knoefel. 1934. Narcotic potency of the aliphatic acyclic acetals. J Pharmacol Exp Ther. 50:88–92.
42. E.Komsta, I.Chu, V.E.Secours, V.E.Valli, D.C.Villeneuve. 1988. Results of a short-term toxicity study for three organic chemicals found in Niagara River drinking water. Bull Environ Contam Toxicol. 41:515–522.
43. Y.Konishi, S.Hayashi, S.Fukushima. 2014. Regulatory forum opinion piece*: supporting the need for international harmonization of safety assessments for food flavoring substances. Toxicol Pathol. 42:949–953.
44. S.Kunitoh, H.Asai, S.Imaoka, Y.Funae, T.Monna. 1996. Metabolism of acetaldehyde to acetate by rat hepatic P-450s: presence of different metabolic pathway from acetaldehyde dehydrogenase system. Alcohol Clin Exp Res. 20:22A–24A.
45. K.C.Leibman. 1971. Reduction of ketones in liver cytosol. Xenobiotica. 1:97–104.
46. A.W.Lington, C.Bevan. 1994. Alcohols. In: G.D.Clayton, F.E.Clayton, editors. Patty’s industrial hygiene and toxicology. Part D. 4th ed. Vol. II. New York (NY): John Wiley & Sons; p. 2585–2760.
47. C.Lynch, C.K.Lim, M.Thomas, T.J.Peters. 1983. Assay of blood and tissue aldehydes by HPLC analysis of their 2,4-dinitrophenylhydrazine adducts. Clin Chim Acta. 130:117–122.
48. L.J.Marnett, H.K.Hurd, M.C.Hollstein, D.E.Levin, H.Esterbauer, B.N.Ames. 1985. Naturally occurring carbonyl compounds are mutagens in Salmonella tester strain TA104. Mutat Res. 148:25–34.
49. A.Martelli, R.Canonero, M.Cavanna, M.Ceradelli, U.M.Marinari. 1994. Cytotoxic and genotoxic effects of five n-alkanals in primary cultures of rat and human hepatocytes. Mutat Res. 323:121–126.
50. T.Matysiak-Budnik, K.Jokelainen, P.Kärkkäinen, H.Mäkisalo, J.Ohisalo, M.Salaspuro. 1996. Hepatotoxicity and absorption of extrahepatic acetaldehyde in rats. J Pathol. 178:469–474.
51. Microbiological Associates Inc. 1986. Subchronic toxicity of methyl isobutyl ketone in Sprague Dawley rats. Final Report. Study No. 5221.04. Performed by Microbiological Associates, Inc. for Research Triangle Institute. Unpublished report dated July 15, 1986.
52. 50 of potassium 2-(1´-ethoxy)ethoxypropanoate in rats. Unpublished report from MB Research Laboratories. Submitted to WHO by Flavor and Extract Manufacturers Association of the United States.
53. K.Morgareidge. 1962. In vitro digestion of four acetals. Unpublished report. Submitted to WHO by Flavor and Extract Manufacturers Association of the United States.
54. W.Müller, G.Engelhart, B.Herbold, R.Jäckh, R.Jung. 1993. Evaluation of mutagenicity testing with Salmonella typhimurium TA102 in three different laboratories. Environ Health Perspect. 101:33–36.
55. I.C.Munro, R.A.Ford, E.Kennepohl, J.G.Sprenger. 1996. Correlation of structural class with no-observed-effect levels: a proposal for establishing a threshold of concern. Food Chem Toxicol. 34:829–867.
56. I.C.Munro, E.Kennepohl, R.Kroes. 1999. A procedure for the safety evaluation of flavouring substances. Food Chem Toxicol. 37:207–232.
57. O.Neubreuer. 1901. Concerning the pairing of glucuronic acid with materials of the aliphatic series. Arch Exp Pathol Pharmacol. 46:133–154.
58. H.Norppa, F.Tursi, P.Pfäffli, J.Maki-Paakkanen, H.Järventaus. 1985. Chromosome damage induced by vinyl acetate through in vitro formation of acetaldehyde in human lymphocytes and Chinese hamster ovary cells. Cancer Res. 45:4816–4821.
59. J.L.O’Donoghue, S.R.Haworth, R.D.Curren, P.E.Kirby, T.Lawlor, E.J.Moran, R.D.Phillips, D.L.Putnam, A.M.Rogers-Back, R.S.Slesinski, et al. 1988. Mutagenicity studies on ketone solvents: methyl ethyl ketone, methyl isobutyl ketone, and isophorone. Mutat Res. 206:149–161.
60. G.Obe, A.T.Natarajan, M.Meyers, A.D.Hertog. 1979. Induction of chromosomal aberrations in peripheral lymphocytes of human blood in vitro, and of SCEs in bone-marrow cells of mice in vivo by ethanol and its metabolite acetaldehyde. Mutat Res. 68:291–294.
61. G.Obe, H.Ristow. 1977. Acetaldehyde, but not ethanol, induces sister chromatid exchanges in Chinese hamster cells in vitro. Mutat Res. 56:211–213.
62. A.Ono, M.Takahashi, A.Hirose, E.Kamata, T.Kawamura, T.Yamazaki, K.Sato, M.Yamada, T.Fukumoto, H.Okamura, et al. 2012. Validation of the (Q)SAR combination approach for mutagenicity prediction of flavor chemicals. Food Chem Toxicol. 50:1538–1546.
63. M.Otsuka, T.Mine, K.Ohuchi, S.Ohmori. 1996. A detoxication route for acetaldehyde: metabolism of diacetyl, acetoin, and 2,3-butanediol in liver homogenate and perfused liver of rats. J Biochem. 119:246–251.
64. H.Riveros-Rosas, A.Julian-Sanchez, E.Pinã. 1997. Enzymology of ethanol and acetaldehyde metabolism in mammals. Arch Med Res. 28:453–471.
65. M.Saito. 1975. Studies on the metabolism of lower alcohols. Nichidai Igaku Zasshi 34:569–585. Japanese.
66. L.Schwartz. 1989. On the oxidation of acetones and homologous ketones from fatty acids. Arch Exp Pathol Pharmacol 40:168. German.
67. D.Scopinaro, P.Ghiani, A.De Cecco. 1947. Ketolytic fate of acetone. II. Acetone metabolism in normal subjects. Policlinico (Rome) Sez Med 54:70. Italian.
68. M.Soffritti, F.Belpoggi, L.Lambertin, M.Lauriola, M.Padovani, C.Maltoni. 2002. Results of long-term experimental studies on the carcinogenicity of formaldehyde and acetaldehyde in rats. Ann NY Acad Sci. 982:87–105.
69. T.Someya. 2012. The safety evaluation procedure for flavoring substances in Japan: overview and a future prospect. Foods Food Ingredients J Jpn 217:151–156. Japanese.
70. R.W.Tennant, J.Spalding, S.Stasiewicz, J.Ashby. 1990. Prediction of the outcome of rodent carcinogenicity bioassays currently being conducted on 44 chemicals by the national toxicology program. Mutagenesis. 5:3–14.
71. H.P.Til, R.A.Wouterssen, H.E.Falke. 1986. Short-term (4-week) oral toxicity study with acetaldehyde and formaldehyde in rats. Final report. Report No. V 86.588/250160. CIVO Institutes tno.
72. D.C.Topping, D.A.Morgott, R.M.David, J.L.O’Donoghue. 1994. Ketones. In: G.D.Clayton, F.E.Clayton, editors. Patty’s industrial hygiene and toxicology. Part C. 4th ed. Vol. II. New York (NY): John Wiley & Sons; p. 1739–1878.
73. M.Tsutsumi, A.Takada, S.Takase, K.Sugata. 1988. Hepatic aldehyde dehydrogenase isoenzymes: differences with respect to species. Alcohol. 5:33–38.
74. [USEPA] US Environmental Protection Agency. 1987. The office of solid waste [Internet]. Rat oral subchronic study of normal butanol. US EPA’s integrated risk information system. [cited 2015 Jun 23]. Available from http://www.epa.gov/iris/subst/0140.htm
75. D.Vicchio, P.S.Callery. 1989. Metabolic conversion of 2-propylpentanal acetals to valproic acid in vitro. Drug Metab Dispos. 17:513–517.
76. W.F.Von Oettingen. 1960. The aliphatic acids and their esters: toxicity and potential dangers: the saturated monobasic aliphatic acids and their esters. Am Med Assoc Arch Ind Health. 21:28–65.
77. J.Wangenheim, G.Bolcsfoldi. 1988. Mouse lymphoma L5178Y thymidine kinase locus assay of 50 compounds. Mutagenesis. 3:193–205.
78. W.W.Westerfeld, R.L.Berg. 1943. Observations on the metabolism of acetoin. J Biol Chem. 148:523–528.
79. [WHO] World Health Organization. 1996. A procedure for the safety evaluation of flavouring substances [Internet]. Forty-fourth Meeting of the Joint FAO/WHO Expert Committee on Food Additives, WHO Food Additives Series No. 35, Annex 5. [cited 2015 Jun 23]. Available from http://www.inchem.org/documents/jecfa/jecmono/v35je21.htm
80. [WHO] World Health Organization. 1998. Safety evaluation of certain food additives and contaminants [Internet]. The forty-ninth meeting of the Joint FAO/WHO Expert Committee on Food Additives. WHO Food Additives Series 40. [cited 2015 Jun 23]. Available from http://www.inchem.org/documents/jecfa/jecmono/v040je10.htm
81. [WHO] World Health Organization. 1999a. Safety evaluation of certain food additives [Internet]. The fifty-first meeting of the Joint FAO/WHO Expert Committee on Food Additives. WHO Food Additives Series 42. [cited 2015 Jun 23]. Available from http://www.inchem.org/documents/jecfa/jecmono/v042je15.htm
82. [WHO] World Health Organization. 1999b. Safety evaluation of certain food additives. The fifty-first meeting of the Joint FAO/WHO Expert Committee on Food Additives [Internet]. WHO Food Additives Series 42. [cited 2015 Jun 23]. Available from http://www.inchem.org/documents/jecfa/jecmono/v042je20.htm
83. [WHO] World Health Organization. 2002. Safety evaluation of certain food additives and contaminants [Internet]. The fifty-seventh meeting of the Joint FAO/WHO Expert Committee on Food Additives. WHO Food Additives Series 48. [cited 2015 Jun 23]. Available from http://www.inchem.org/documents/jecfa/jecmono/v48je16.htm
84. [WHO] World Health Organization. 2008. Safety evaluation of certain food additives and contaminants [Internet]. The sixty-eighth meeting of the Joint FAO/WHO Expert Committee on Food Additives. WHO Food Additives Series 59. [cited 2015 Jun 23]. Available from http://whqlibdoc.who.int/publications/2008/9789241660594_eng.pdf
85. [WHO] World Health Organization. 2011. Evaluation of certain food additives [Internet]. Seventy-third report of the Joint FAO/WHO Expert Committee on Food Additives, WHO Technical Report Series No. 960, 1–8. [cited 2015 Jun 23]. Available from http://whqlibdoc.who.int/trs/WHO_TRS_960_eng.pdf?ua=1
86. S.-J.Yin, C.-S.Liao, Y.-C.Lee, C.-W.Wu, S.-W.Jao. 1994. Genetic polymorphism and activities of human colon alcohol and aldehyde dehydrogenases: no gender and age differences. Alcohol Clin Exp Res. 18:1256–1260.
87. A.Yoshida, I.Y.Huang, M.Ikawa. 1984. Molecular abnormality of an inactive aldehyde dehydrogenase variant commonly found in orientals. Proc Natl Acad Sci USA. 81:258–261.
88. K.W.Young, B.Danielewska-Nikiel, I.C.Munro. 2006. An evaluation of the maximized survey-derived daily intake (MSDI) as a practical method to estimate intake of flavouring substances. Food Chem Toxicol. 44:1849–1867.
89. E.Zeiger, B.Anderson, S.Haworth, T.Lawlor, K.Mortelmans. 1992. Salmonella mutagenicity tests: V. Results from the testing of 311 chemicals. Environ Mol Mutagen. 19:2–141.