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


    Synonym                       Wintergreen oil

    Chemical name                 Methyl salicylate

    Empirical formula             C8H8O3

    Structural formula


    Molecular weight              152.15

    Definition                    Methyl salicylate contains not less than
                                  98 per cent. C8H8O3.

    Description                   The volatile oil obtained by maceration
                                  and subsequent steam distillation from
                                  the leaves of Gaultheria procumbens
                                  Linné (Fam. Ericaceae), or from the
                                  bark of Betula lenta Linné (Fam.
                                  Betulaceae). It is also produced
                                  It is a colourless, yellowish or reddish
                                  liquid, having the characteristic odour
                                  and taste of wintergreen.

    Biological Data

    Biochemical aspects

         The orally administered ester undergoes very rapid and nearly
    complete hydrolysis in rats and dogs, salicylate being the only
    significant finding in the blood of rats 20 minutes after an
    intragastric dose, and in dogs within an hour of oral dosing. In man,
    hydrolysis is somewhat slower after oral administration, some 21 per
    cent. of salicylate as the ester being present in plasma after 90

    minutes. The liver appears to be the main site of hydrolysis in rats,
    rabbits, dogs and monkeys, the extent varying from 79-99 per cent.,
    while plasma hydrolyzes some 15 per cent. (Davison et al., 1961). Dogs
    excrete 0.2-0.5 per cent. of the ester in their urine after oral
    administration and 14 per cent. after i.m. administration. Rabbits
    excrete it mainly as glucuronate (12-55 per cent.); also as ethereal
    sulfate (10 per cent.), conjugated before hydrolysis, and as other
    metabolites, e.g. salicyluric acid (Williams, 1959).

    Acute toxicity


    Animal       Route       LD50              References

    Mouse        oral        1110              Davison et al., 1961

    Rat          oral        887               Jenner et al., 1964

    Rat          oral        1250              Giroux et al., 1954

    Guinea-pig   oral        700 (MLD)         Houghton, 1905

    Guinea-pig   oral        1060              Jenner et al., 1964

    Guinea-pig   s.c.        1500(MLD)         Houghton, 1905

    Rabbit       oral        1300              Castagnou et al., 1952

    Rabbit       oral        2800              Leone, 1916

    Dog          oral        2100              Leone, 1916

    The adult human oral LD50 is estimated at 0.5 g/kg body-weight
    (Patty, 1963). The ester is potentially the most toxic salicylate for
    infants and children, as 4 ml can be fatal (Davison et al., 1961;
    Jacobziner, 1963). 

    Short-term studies

         Rat. Groups of 10 males and 10 females were fed 0, 0.1 and 1.0
    per cent. in their diet for 17 weeks. Both sexes showed a significant
    reduction in growth rate at the 1.0 per cent. level, but histological
    examination of the major organs revealed no abnormality. In another
    experiment on 3 male and 3 female rats kept on a diet containing 2 per
    cent. ester for up to 10 weeks, bone growth was specially studied by
    X-ray and histology. Growth was reduced; there was excessive density
    of bone with very reduced chondroclastic and osteoclastic activity

    (Webb & Hansen, 1963). These together with decreased food intake, poor
    weight gain and high mortality, were confirmed in other groups of rats
    fed 1.12 per cent. and 2.0 per cent. ester in their diet for 10 weeks
    (Harrison et al., 1963).

         Dog. Groups of 1 male and 1 female were fed 50, 100, 250, 500,
    800 and 1200 mg/kg body-weight/day of ester for up to 10 weeks. No
    adverse effects were noted at levels including 250 mg/kg/day, but
    there was increasing dose-dependent fatty metamorphosis of the liver
    at higher test levels (Webb & Hansen, 1964).

         In a 2-year study, groups of 2 males and 2 females were given 0,
    50, 150, and 250 mg/kg body-weight/day of ester orally. Some growth
    retardation. and liver enlargement was noted at the 150 and 250 mg/kg
    level,  and histology revealed enlarged hepatic parenchymal cells
    (Webb & Hansen, 1963).

    Long-term studies

         Rat. Groups of 25 males and 25 females were kept for 2 years on
    diets containing 0, 0.1, 0,5, 1.0 and 2.0 per cent. ester. Animals did
    not survive 49 weeks at the highest level. At the 1.0 per cent. level,
    growth rates were considerably reduced and enlargement of male testes
    and female hearts and kidneys were noted. Excess cancellous bone
    formation was seen at the 2.0, 1.0 and 0.5 per cent. levels (Webb &
    Hansen, 1963). Another 2-year feeding study revealed no adverse
    effects, including bone changes, up to a level of 0.21 per cent. ester
    in the diet (Packman et al., 1961).


         Man appears to handle methyl salicylate metabolically similarly
    to other animals although hydrolysis is comparatively slow.  Long-term
    studies on rats and the 2-year study on dogs are adequate for the
    establishment of an acceptable daily intake. However, in view of some
    inconsistencies in the reported studies, the following additional work
    is desirable: short-term studies in dogs, including, levels of 100 and
    150 mg/kg body-weight/day, and reproduction studies in rats.


    Level causing no toxicological effect

         Rat. 0.2 per cent. (= 2000 ppm) of the diet, equivalent to 100

         Dog. 50 mg/kg/day

    Estimate of acceptable daily intake for man

                                       mg/kg body-weight

         Unconditional acceptance            0-0.5


    Castagnou, R., Larceban, S. & Queynent, A. (1952) Bull. Soc. Pharm.
    Marseille 3, 30

    Davison, C., Zimmerman, E. F. & Smith, P. K. (1961) J. Pharm. Exp.
    Therap., 132, 207

    Ciroux, J., Granger, R. & Monnier, P. (1954) Trav. Soc. Pharm.
    Montpellier, 14, 383

    Harrison, J. W. E., Abbott, D. D. & Packman, E. W. (1963) Fed.
    Proc., 22, 554

    Houghton, E. M. (1905) Amer. J. Physiol., 13, 331

    Jacobziner, H. (1963) New York State J. Med., 63, 295

    Jenner, P. M., Hagan, E. C., Taylor, J. M., Cook, E. L. & Fitzhugh, O.
    G. (1964) Fd Cosmet. Toxicol., 3, 327

    Leone, G. (1916), Arch. farm. sper., 22, 327

    Packman, E. W., Abbott, D. D., Wagner, B. M. & Harrison, J. W. E.
    (1961) Pharmacologist 3, 62

    Patty, F. A. (1963) Industrial Hygiene and Toxicology, Vol. II,

    Webb, W. K. & Hansen, W. H. (1963) Toxicol. appl. Pharmacol., 5,

    Williams, R. T. (1959) Detoxication Mechanism, Second Edition, Chapman
    & Hall, London

    See Also:
       Toxicological Abbreviations