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.



         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).


    (a)  Special studies


         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,
    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


         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).


         The evaluation of these substances is based on a one-year
    toxicity study in the rat, and on information concerning its


    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.


    Required by 1981.

         Further biochemical and metabolic studies in several species
    preferably including man using current techniques.


    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,

    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)