FAO Nutrition Meetings
    Resort Series No. 44A
    WHO/Food Add./68.33


    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

    d,1-MENTHOL and 1-MENTHOL

    Chemical name                 d,1-3-p-Menthanol

    Empirical formula             C10H20O

    Structural formula


    Molecular 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

    (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.


         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.


    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


    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