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    ETHYLMETHYLPHENYLGLYCIDATE

    Explanation

         Ethylmethylphenylglycidate (EMPG) was first evaluated for
    acceptable daily intake by the Joint FAO/WHO Expert Committee on Food
    Additives in 1967 and 1974 (see Annex I, Refs. 14 and 34). A
    toxicological monograph was issued in 1968 (see Annex I, Ref. 15).

         Since the previous evaluation additional data have become
    available and are summarized and discussed in the following monograph.
    The previously published monograph has been expanded and is reproduced
    in its entirety below.

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

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

    TOXICOLOGICAL STUDIES

    Special studies on carcinogenicity

         See under long-term studies.

    Acute toxicity

                                                                
                              LD50
    Animal        Route    (mg/kg bw)     Reference
                                                                

    Rat           Oral        5 470       Jenner et al., 1964

    Guinea-pig    Oral        4 050       Jenner et al., 1964
                                                                

    Short-term studies

    Rat

         In a 12-week study on 15 male and 15 female rats using mixed
    esters, no adverse effect was noted at a level of 21 mg/kg/day (Oser,
    1967). In another study lasting 16 weeks, groups of five male and five
    female rats were fed 0 and 1% of ester in their diet. Growth

    retardation, particularly of males, was observed, as well as
    testicular atrophy (Hagan et al., 1967). In a one-year study on five
    male and five female rats, the ester was fed at 0 and 0.25% in the
    diet without any adverse effects on body weight gain, organ weights
    and histology of major organs (Hagan et al., 1967).

         A well-defined sample of EMPG was fed to groups of 15 male and 15
    female rats at dietary levels of 0 (control), 0.02, 0.1 and 0.5% for
    15 weeks and was found to have no effect on growth rate, food or water
    consumption of the animals. There was no evidence of any impairment of
    neuromuscular function. This finding was confirmed by histological
    examination of the sciatic and brachial nerve and of the central
    nervous system, no part of which showed any evidence of demyelination
    or other changes. Similarly, no evidence of testicular damage, either
    from the weight of the organs or from histological findings, was
    observed.

         The only effects observed were organ weight changes in animals
    fed a dietary level of 0.5%. These changes consisted of increased
    absolute and relative stomach, small intestine and caecum weights, and
    increased relative liver and kidney weights in the female rats and
    increases in absolute and relative kidney weight and relative liver
    weight in male rats. Although none of these changes was associated
    with any histological abnormalities, they cannot be disregarded. The
    no-untoward-effect level in this study was, therefore, 0.1% EMPG. It
    must be stressed that these findings are specific for the material
    used for this study and cannot be applied generally to materials
    termed "strawberry aldehyde" (Mason et al., 1978).

    Long-term studies

    Rat

         Groups of 20 male and 20 female rats were fed diets containing
    various proportions of EMPG for two years. At the 0.5% level paralysis
    of hindquarters was observed as well as demyelinating degenerative
    changes in the sciatic nerve (Bär & Griepentrog, 1967).

         Groups of 48 male and 48 female rats were given diets containing
    0 (control), 0.02, 0.1 and 0.5% EMPG for two years. There was no
    treatment-related effect on mortality, haematology, renal function,
    serum chemistry or organ weights. General observations, tests of motor
    coordination and histological examination of nerve tissues provided no
    evidence of neuropathy. Histological change in the pancreas, adrenal
    glands, lymph nodes and liver showed some increase in incidence in
    treated animals, but the lesions were of types encountered in aging
    rats. There was an increase of pituitary tumours in treated females
    and of testicular interstitial cell tumours in the males, but

    consideration of their background incidence in untreated rats and the
    lack of any dose relationship in their occurrence in this study
    indicated that these findings were unlikely to be related to
    treatment.

         It is concluded, therefore, that this study did not demonstrate a
    carcinogenic effect in rats given dietary levels of up to 0.5% EMPG
    and that the no-untoward-effect level was 0.1% of the diet, providing
    an EMPG intake of approximately 35 mg/kg/day in males and 60 mg/kg/day
    in females (Dunnington et al., 1981).

    Comments

         Since the last evaluation, short- and long-term studies in the
    rat have become available. In both studies there was no evidence of
    any impairment of the neuromuscular function. Histological
    examinations of nerve tissue did not confirm the findings of previous
    studies in which demyelination was reported to occur (Griepentrog,
    1969). The failure to show similar affects may be related either to
    different strains of rats used or to differences in the specifications
    of the test material.

         The only effects observed were organ weight changes, lower body
    weight in females and increased incidence of histological changes in
    the lymph nodes, pancreas, adrenal glands and liver in rats fed a
    dietary level of 0.5%. The no-untoward-effect level for
    ethlymethylphenylglycidate from the studies considered was 0.1%.

         No evaluation is possible at this time because clear
    specifications of the test compound are not available.

    EVALUATION

    Estimate of acceptable daily intake for man

         Not allocated.

    REFERENCES

    Bär, F. & Griepentrog, F. (1967) Die Situation in der gesundheitlichen
         Beurteilung der Aromatisierungsmittel für Lebensmittel, Med. u.
         Ernähr., 8, 244-251

    Dunnington, D. et al. (1981) Long-term toxicity study on ethyl
         methylphenyl glycidate (strawberry aldehyde) in rat, Food
         Cosmet. Toxicol., 19, 691-699

    Griepentrog, F. (1969) Neurotoxische Wirkungen durch den Aromastoff
         Athylmethylphenylglycidat ("Aldehyd C16") bei Ratten, Med. u.
         Ernähr., 10, 89-90

    Hagan, E. C. et al. (1967) Food flavourings and compounds of related
         structure. II - Subacute and chronic toxicity, Food Cosmet.
         Toxicol., 5, 141-157

    Jenner, P. L. et al. (1964) Food flavourings and compounds of related
         structure. I - Acute oral toxicity, Food Cosmet. Toxicol., 2,
         327-343

    Mason, P. L. et al. (1978) Studies on the purity and short-term
         toxicity of ethyl methylphenyl glycidate (strawberry aldehyde) in
         rat, Food Cosmet. Toxicol., 16, 331-336

    Oser, B. L. (1967) Unpublished report
    


    See Also:
       Toxicological Abbreviations