d-CARVONE and 1-CARVONE Explanation d-Carvone and 1-carvone were reviewed at the eleventh meeting of the Joint FAO/WHO Expert Committee on Food Additives, specifications were prepared, and a conditional acceptable daily intake for man (ADI) of 0-1.25 mg/kg bw was established (FAO/WHO, 1967; FAO/WHO, 1968). Since this previous review, new data on d-carvone and 1-carvone have become available and are included in this monograph. BIOLOGICAL DATA BIOCHEMICAL ASPECTS When there is unsaturation in the ring, hydroxylation of that ring is the primary metabolic pathway followed (F.E.M.A., 1976). This has been shown to be true for carvone (Hildebrandt, 1902; Williams, 1959). Carvone was metabolized by the rabbit to 1,5-dimethyl-1,5- hexadien-1,6-dicarboxylic acid and a carbinol in which one ethylene linkage was saturated and the keto group was reduced (Fischer & Bielig, 1940; Opdyke, 1973; Opdyke, 1978). Carvone was found to be present in the urine of healthy adult humans (Zlatkis & Liebich, 1971; Zlatkis et al., 1973). TOXICOLOGICAL STUDIES (a) Special studies Mouse In a 24-week screening test, groups of 20 female A/He mice received in the first eight weeks of the test period, a total dose of 1.2 or 6.0 g/kg bw of (+) carvone or (-) carvone in 24 thrice-weekly i.p. injections. The higher dose had previously been calculated to be the maximum tolerated dose. There was no increase in the incidence of tumours of the lung, liver, kidney, spleen, thymus, intestine, or salivary or endocrine glands. Survival was depressed in the case of (+) carvone to approximately 80%, and in the case of (-) carvone to approximately 60% (Stoner et al., 1973). Animal Route LD50 mg/kg bw References Mouse s.c. 2 675 Wenzel & Ross, 1957 Rat Oral 1 640a Jenner et al., 1964 Rat Oral 3 710b Opdyke, 1978 Guinea-pig Oral 766a Jenner et al., 1964 Rabbit Dermal 4 000c Opdyke, 1978 a Oral LD50 reported on "carvone", identified as p-mentha-6, 8-dien-2-one. b Oral LD50 reported on d-carvone. c Dermal LD50 reported as 4 ml/kg for d-carvone. (b) Acute toxicity (c) Short-term studies Rat Groups of five male and five female rats were maintained on diets containing carvone (p-mentha-6,8-dien-2-one) at a level of 1000 ppm (approximately equivalent to 50 mg/kg bw) for 27-28 weeks, and at a level of 2500 ppm (approximately equivalent to 125 mg/kg bw) for one year. No adverse effects were observed in these rats as judged by growth, appearance, food intake, haematology, final body weights, or gross and microscopic examination of the major organs. Rats maintained on a diet containing carvone at a level of 10 000 ppm (approximately equivalent to 500 mg/kg bw) for 16 weeks showed growth depression and testicular atrophy (Hagan et al., 1967). Comments The evaluation of these substances is based on a one-year toxicity study in the rat, and on information concerning its metabolism. EVALUATION Level causing no toxicological effect Rat: 0.25% in the diet equivalent to 125 mg/kg bw. Estimate of temporary acceptable daily intake for man 0-1 mg/kg bw. FURTHER WORK OR INFORMATION Required by 1981. Further biochemical and metabolic studies in several species preferably including man using current techniques. REFERENCES FAO/WHO (1967) Toxicological Evaluation of Some Flavouring Substances and Non-Nutritive Sweetening Agents, FAO Nutrition Meetings Report, Series No. 44a; WHO/Food Add./68.33 FAO/WHO (1968) Specifications for the Identity and Purity of Food Additives and their Toxicological Evaluation: Some Flavouring Substances and Non-Nutritive Sweetening Agents. Eleventh Report of the Joint FAO/WHO Expert Committee on Food Additives, FAO Nutrition Meetings Report Series No. 44; Wld Hlth Org. techn. Rep. Ser., No. 383 F.E.M.A. (1976) Scientific Literature Review of Alicyclic Compounds of Carbon, Hydrogen and Oxygen in Flavour Usage. Published by the National Information Services under Contract with the Food and Drug Administration Fischer, F. G. & Bielig, H. J. (1940) Biochemical hydrogenations. VII. Hydrogenation of unsaturated compounds in the animal body, Hoppe-Seyler's Z. Physiol. Chem., 266, 73-98 (in German) Hagan, E. C. et al. (1967) Food flavourings and compounds of related structure. II. Subacute and chronic toxicity, Food Cosmet. Toxicol., 5, 141-157 Hildebrandt, H. (1902) On the behaviour of carvone and santalol in the animal body, Hoppe-Seyler's Z. Physiol. Chem., 36, 441-451 (in German) Jenner, P. M. et al. (1964) Food flavourings and compounds of related structure. I. Acute oral toxicity, Food Cosmet. Toxicol., 2, 327-343 Opdyke, D. L. J. (1973) Fragrance raw materials monographs. 1-Carvone, Food Cosmet. Toxicol., 11, 1057-1058 Opdyke, D. L. J. (1978) Fragrance raw materials mongraphs. d-Carvone, Food Cosmet. Toxicol., 16, Suppl. 1., 673-674 Wenzel, D. G. & Ross, C. R. (1957) Central stimulating properties of some terpenones, J. Am. Pharm. Assoc., 46, 77-82 Williams, R. T. (1959) Detoxication Mechanisms. The Metabolism and Detoxication of Drugs, Toxic Substances and Other Compounds. Second Edition, Chapman & Hall Ltd., London Zlatkis, A. & Liebich, H. M. (1971) Profile of volatile metabolites in human urine, Clin. Chem., 17(7), 592-594 Zlatkis, A. et al. (1973) Profile of metabolites in urine by gas chromatography - mass spectrometry, Anal. Chem., 45, 763-767
See Also: Toxicological Abbreviations Carvone, d- and carvone, 1- (FAO Nutrition Meetings Report Series 44a)