EUGENYL METHYL ETHER

    Explanation

         Eugenyl methyl ether (synonyms: methyl eugenol: 4-allylveratrole)
    was considered at the twenty-third meeting of the Joint WHO/FAO Expert
    Committee on Food Additives but lack of relevant data from short- and
    long-term studies precluded the evaluation of this compound. No
    toxicological monograph was prepared.

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

    Metabolism

         The metabolism of eugenyl methyl ether was studied in the rat and
    the major metabolic reactions were oxidation of the allylic side
    chain to 2-hydroxy-3-(3,4-dimethoxyphenyl)-propionic acid (I),
    3,4-dimethoxybenzoic acid and 3,4-dimethoxycinnamic acid, the two
    latter being largely excreted as glycine conjugates. Other reactions
    were 0-demethylation to eugenol and 3-hydroxy-4-methoxyallylbenzene in
    equal amounts, oxidation to 1-(3,4-dimethoxyphenyl-2-propen-1-ol)
    and 3,4-dimethoxyphenylacetic acid, and hydroxylation to a
    hydroxy-3,4-dimethoxyallylbenzene (Solheim & Scheline, 1976). It is
    noteworthy that the formation of I was believed to occur via the
    formation of an epoxide and subsequent reduction to the dihydrodiol.

    Effects on hepatic microsomal enzymes

         As judged from prolongation of hexobarbital sleeping time and
    zoxazolamine paralysis time in mice, eugenyl methyl ether was found to
    be a strong inhibitor of hepatic microsomal enzyme function (Fujii et
    al., 1970). Similarly, the compound was found to increase ethanol
    sleeping time by 72% when administered at a dose level of 100 mg/kg
    (Sato & Kemp, 1969).

    TOXICOLOGICAL STUDIES

    Special studies on irritation

         Methyl eugenol applied undiluted to intact or abraded rabbit skin
    for 24 hours under occlusion was irritating (Keating, 1972) but no
    irritation was observed in a 48-hour closed-patch test on humans in
    which the compound was applied at a concentration of 8% in petrolatum
    (Kligman, 1972).

    Special studies on mutagenicity

         Eugenyl methyl ether and the corresponding epoxide were examined
    for mutagenic activity against Salmonella typhimurium strains using
    the Ames' technique without metabolic activation. Eugenyl methyl ether
    was non-mutagenic but the epoxide induced point base-pair mutations
    though not frame-shift mutations (Dorange et al., 1977).

    Special studies on sensitization

         No sensitization was detected in a maximization test on 25 human
    volunteers in which the compound was tested at a concentration of 8%
    in petrolatum (Kligman, 1972).

    Acute toxicity
                                                            

                            LD50
    Animal      Route    (mg/kg bw)       Reference
                                                            

    Mouse       i.p.         >640     Fujii et al., 1970

    Rat         Oral        1 560     Jenner et al., 1964

                Oral          810     Keating, 1972

    Rabbit      Dermal     >5 000     Keating, 1972
                                                            

    Comments

         No results of short-term or long-term studies were available. It
    is not possible, therefore, to evaluate this compound for an ADI for
    man. It is noteworthy that the metabolic studies indicated that an
    epoxide was produced as an intermediate (Solheim & Scheline, 1976) and
    this epoxide was mutagenic in the S. typhimurium assay (Dorange et
    al., 1977). Furthermore, the structure of eugenyl methyl ether is
    similar to that of safrol, a known hepatocarcinogen and the compound
    was given a high priority for testing by the Chemical Selection
    subgroup of the NCI's Clearing House on Environmental Carcinogens.

    FURTHER WORK OR INFORMATION

         Short-term and long-term tests, including carcinogenicity,
    reproduction tests and teratology.

    REFERENCES

    Dorange, J.-L. et al. (1977) Pouvoir mutagene de metabolites de la
         voie epoxyde-diol du safrol et d'analogues. Etudes sur
         Salmonella typhimurium, Comptes rend. seances Soc. Biol.,
         171, 1041

    Fujii, K. et al. (1970) Structure-activity relations for
         methylenedioxyphenyl and related compounds on hepatic microsomal
         enzyme function as measured by prolongation of hexobarbital
         narcosis and zoxazolamine paralysis in mice, Toxicol. app.
         Pharmacol., 16, 482

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

    Keating, J. W. (1972) Report to RIFM cited by Opdyke, 1975

    Kligman, A.M. (1972) Report to RIFM cited by Opdyke, 1975

    Opdyke, D. L. J. (1975) Fragrance raw material monographs. Methyl
         eugenol, Fd. Cosmet. Toxicol., 13, 857

    Sato, T. A. & Kemp, W. (1969) Effects of alkylmethoxybenzene and
         alkylmethylenedioxybenzene essential oils on pentobarbital and
         ethanol sleeping time, Arch. int. Pharmacodyn., 180, 232

    Solheim, E. & Scheline, R. R. (1976) Metabolism of alkenebenzene
         derivatives in the rat. II. Eugenol and isoeugenol methyl ethers,
         Xenobiotica, 6, 137-150
    

    See Also:
       Toxicological Abbreviations
       EUGENYL METHYL ETHER (JECFA Evaluation)