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


    ETHYL METHYLPHENYLGLYCIDATE

    Synonyms                 Aldehyde C-16; strawberry aldehyde

    Chemical name            Ethyl methylphenylglycidate

    Empirical Formula        C12H14O3

    Structural formula

    

    Molecular weight         206.24

    Definition               Ethyl methylphenylglycidate contains not less
                             than 98 per cent. C12H14O3.

    Description              Ethyl methylphenylglycidate is usually
                             prepared by the reaction of acetophenone and
                             the ethyl ester of monochloroacetic acid in
                             the presence of an alkaline condensing agent.
                             It is a colourless to pale yellow liquid with
                             a strong fruity odour suggestive of
                             strawberries.

    Biological Data

    Biochemical aspects

         In vito experiments using simulated gastric juice showed over
    80 per cent. cleavage of the epoxy-linkage after 1 hour; with
    intestinal fluid some 70 per cent. of the epoxy-linkage was destroyed
    in 3 hours. Ester hydrolysis occurred to only a minor degree (Oser,
    1967).

    Acute toxicity

                                                                       

    Animal          Route       LD50              References
                                (mg/kg 
                                body-weight)
                                                                       

    Rat             oral        5470              Jenner et al., 1964

    Guinea-pig      oral        4050              Jenner et al., 1964
                                                                       

    Short-term studies

         Rat. In a 12-week study on 15 males and 15 females using mixed
    esters no adverse effect was noted at a level of 21 mg/kg/day (Oser,
    1967). In another study lasting for 16 weeks, groups of 5 male and 5
    female rats were fed 0 and 1 per cent. of ester iIn their diet. Growth
    retardation, particularly of males was observed, as well as testicular
    atrophy (Hagan et al., 1967).

         In a 1-year study on 5 male and 5 female rats the ester was fed
    at 0 and 0.25 per cent. in the diet without producing any adverse
    effects on body-weight gain, organ weights and histology of major
    organs (Hagan et al., 1967).

    Long-term studies

         Rat. Groups of 20 male and 20 female rats were fed diets
    containing various proportions of ester for 2 years. At the 0.5 per
    cent. level paralysis of hind-quarters was observed as well as
    demyelinating degenerative changes in the sciatic nerve (Baer &
    Griepentrog, 1967).

    Comments

         The biochemical studies suggest little hydrolysis of the ester
    but substantial though not complete destruction of the epoxy-linkage.
    A no-effect level has only been established in a short-term study
    lasting for one year, while the long-term study has produced evidence
    of a possible cumulative demyelination effect. Further metabolic
    studies and adequate long-term studies are essential.

    EVALUATION

    Level causing no significant toxicological effect

         Rat. C.25 per cent. (= 2500 ppm) in the diet, equivalent to 125
    mg/kg body-weight/day.

    Estimate of acceptable daily intake for man

                                       mg/kg body-weight

         Temporary acceptance               0-0.6

    Further work required

         Within four years, biochemical and metabolic studies and adequate
    long-term studies with special emphasis on neurological effects, the
    effect on bone marrow and testicular tissue.

    REFERENCES

    Baer, F. & Griepentrog, F. (1967) Med. Ehrnährung, 8, 244

    Hagan, E. C., Hausen, W. H., Fitzhugh, O. G., Jenner, P. M., Jones, W.
    I., Taylor, J. M., Long, E. L., Nelson, A. A. & Brouwer, J.B. (1967)
    Fd Cosmet. Toxicol., 5(2), 141

    Jenner, P. M., Hagan, E. C., Taylor, J. M., Cook, E. L., & Fitzhugh,
    O. C. (1964) Fd Cosmet. Toxicol., 2, 327

    Oser, B. L. (1967) Unpublished report
    

    See Also:
       Toxicological Abbreviations
       ETHYL METHYLPHENYLGLYCIDATE (JECFA Evaluation)