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