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