119. Methyl salicylate (FAO Nutrition Meetings Report Series 44a)

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 METHYL SALICYLATE Synonym Wintergreen oil Chemical name Methyl salicylate Empirical formula C₈H₈O₃ Structural formula MOLECULAR STRUCTURE 16

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 synthetically. 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 (mg/kg body-weight) 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). Comments 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. EVALUATION Level causing no toxicological effect Rat. 0.2 per cent. (= 2000 ppm) of the diet, equivalent to 100 mg/kg/day. Dog. 50 mg/kg/day Estimate of acceptable daily intake for man mg/kg body-weight Unconditional acceptance 0-0.5 REFERENCES 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, Interscience Webb, W. K. & Hansen, W. H. (1963) Toxicol. appl. Pharmacol., 5, 576 Williams, R. T. (1959) Detoxication Mechanism, Second Edition, Chapman & Hall, London

    See Also:
       Toxicological Abbreviations
       METHYL SALICYLATE (JECFA Evaluation)