FAO Nutrition Meetings Resort Series No. 44A WHO/Food Add./68.33 TOXICOLOGICAL EVALUATION OF SOME FLAVOURING SUBSTANCES AND NON-NUTRITIVE SWEETENING AGENTS Geneva, 21-28 August 1967 The Eleventh Report of the Joint FAO/WHO Expert Committee on Food Additives is published as FAO Nutrition Meetings Report Series, 1967, No. 44; Wld Hlth Org. techn. Rep. Ser., 1968, 383. This Report contains general considerations, including the principles adopted for the evaluation, and a summary of the results of the evaluations of a number of food additives. Additional information, such as biological data and a toxicological evaluation, considered at that meeting, is to be found in this document. Food and Agriculture Organization of the United Nations World Health Organization 1967 d,1-MENTHOL and 1-MENTHOL Chemical name d,1-3-p-Menthanol Empirical formula C10H20O Structural formulaMolecular weight 156.27 Description Menthol is an alcohol obtained from various mint oils or prepared synthetically. It may be either levorotatory (1-menthol) from natural or synthetic sources, or racemic (d1-menthol) produced synthetically. It occurs as colourless, hexagonal crystals, usually needle-like, or in fused masses, or as a crystalline powder. It has a pleasant, peppermint-like odour. Biological Data Biochemical aspects In the dog, 5 per cent. of orally administered menthol metabolizes to 1-menthyl-5-glucuronide (Williams, 1959). For other animals, the reported proportions vary. In the rabbit, the larger the ingested dose, the less conjugation (Quick, 1924). Other workers reported 31-34 per cent. glucuronide excretion in rats after oral or continuous i.v. dosing (Harken, 1961). Rabbits are said to eliminate 48 per cent. of 1-menthol and 59 per cent. of d1-menthol as glucuronide (Williams, 1938). Menthol is absorbed percutaneously, and extracts a local anaesthetic action in mice (Macht, 1939). Acute toxicity Animal Route LD50 References (mg/kg body-weight) (a) 1-menthol Mouse s.c. 5000-6000 Flury, 1920 i.p. 2000(LD) Macht, 1939 Rat oral 3300 Herken, 1961 s.c. 1000-2500 Flury, 1920 i.p. 710 Herken, 1961 1500(LD) Macht, 1939 Guinea-pig i.p. 4000(LD) Macht, 1939 Cat oral 800-1000 Flury, 1920 i.p. 800-1000 Flury, 1920 i.v. 34(LD) Macht, 1939 Rabbit i.p. approx. 2000 Herken, 1961 (b) d1-menthol Mouse s.c. 1400-1600 Flury & Seel, 1926 Rat oral 2900 Herken, 1961 3180 Jenner et al., 1964 i.p. 750 Herken, 1961 Cat oral 1500-1600 Flury & Seel, 1926 i.p. 1500-1600 Flury & Seel, 1926 Rabbit i.p. approx. 2000 Herken, 1961 Short-term studies Rat. Groups of 40 male and 40 female rats received 0, 100 and 200 mg/kg body-weight of either 1- or d1-menthol in their diet for 5-1/2 weeks. There was no adverse effect on weight gain, excretion of glucuronide, water and electrolytes, nor interference with CNS reactions to cardrazol or electric shock, or on i.v. hexobarbital sleeping time as compared with controls (Herken, 1961). Long-term studies None available. Observations in man Smoking 80 mentholated cigarettes resulted in irritability, gastrointestinal upsets, tremors, ataxia, bradycardia and toxic psychosis. Taking 64 mg of menthol three times a day produced tiredness and apathy within 3 days and nausea, exhaustion and bradycardia in 7 days (Luke, 1962). Chronic urticaria with basophil leucopenia on challenge has been reported after contact with menthol in toothpaste, mentholated cigarettes, peppermint sweets, etc. (Papa & Shelley, 1964; McCowan, 1966). The usual human oral dose is 60-120 mg. Comments Metabolic studies are not very revealing. There is much human experience from long-established therapeutic use. Further metabolic studies and adequate long-term studies are desirable. EVALUATION Level causing no toxicological effect Rat. 200 mg/kg body-weight of d1- pr 1-menthol/day. Estimate of acceptable daily intake for man mg/kg body-weight Unconditional acceptance 0-0.2 Conditional acceptance 0.2-2 REFERENCES Flury, F. (1920) Abderhalden's Handbuch der Biologischen Arbeitsmethoden,39, 1365 Flury, F. & Seel, H. (1926) Münch. Med. Wschr., 48, 2011 Herken, H. (1961) Report to Schering, AG Jenner, P. M., Hagan, E. C., Taylor, J. M., Cook, E. L. & Fitzhugh, O. G. (1964) Fd Cosmet. Toxicol., 2, 327 Luke, E. (1962), Lancet, i, 110 Macht, D. I. (1939) Arch. Int. Pharmacodyn., 63, 43 McGowan, E. M. (1966) Arch. Derm.,94, 62 Papa, C. M. & Shelley, W. B. (1964) J. Amer. med. Ass., 189, 546 Quick, A.J. (1924) J. biol. Chem., 61, 681 Williams, R. T. (1938) Biochem. J., 32, 1849 Williams, R. T. (1959) Detoxication Mechanisms, Second edition, Chapman & Hall, London
See Also: Toxicological Abbreviations