EUGENOL
Explanation
Eugenol was reviewed at the eleventh meeting of the FAO/WHO Joint
Expert Committee on Food Additives, specifications were prepared and a
conditional ADI of 0-5 mg/kg bw was established (Anon. 1967).
Since the previous review, new data have become available and are
included in this summary.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
Intraperitoneal injection of a single 450 mg/kg dose of 14C
methoxy labelled eugenol resulted in rapid distribution to all organs.
Both ether and water soluble materials were recovered from most
tissues and excretions. Only 0.2-1.0% of the dose was eliminated as
expired 14CO2 (Weinberg et al., 1972). Over 70% of a lethal dose of
eugenol was recovered on death, from the urine of rabbits (Schroder &
Vollmer, 1932).
Administration of single 200 mg doses to rats led to increased
urinary output of ethereal glucuronides of 33-35 mg/rat in 12 hours
compared to a control value of 4 mg/rat. Ester glucuronide values were
unchanged (Yuasa, 1974).
Incubation of eugenol with rat liver epithelial cells resulted in
production of 4-(2'-3'-dihydroxy)propyl-2-methoxyphenol (Janiaud,
1936).
The pharmacologic effects of eugenol include the previously
reviewed inhibition of ß-D-glucosiduronic acid conjugation in rats
receiving 150 mg/animal (Hartiala et al., 1966).
Hydroxylating activity of liver homogenate on dimethylaminopyrine
or hexobarbital was depressed in tissue from mice dosed with 160 mg/kg
and sacrificed after one hour (Jaffe et al., 1968).
Eugenol had no effect on aminopyrine-N-demethylation activity in
the liver of rats given about 10% of the LD50 three times daily for
2-2/3 days. There was a slight decrease in hexobarbital lateral
deflection time and in urinary ascorbic acid content (Gruebner, 1972).
Other effects include:
Animal Dose Route Effect Reference
Dog ca. 50 mg/kg i.v. Choleresis Chabrol, 1931
Mice 100-350 mg/kg i.p. Reduction in Caujolle &
rectal Meynier, 1960
temperature
Mice 50 mg/kg i.p. Increase in Seto, 1969
sleeping
time
pentobarbital
-131%
ethanol-120%
Rat 100 mg/kg i.p. No effects on deMello et al.,
spontaneous 1973
motor activity
160 mg/kg i.p. Severe depression
and paralysis of
hind quarters
200 mg/kg i.p. Catatonia
Frog 0.1-100% direct Blockage of Kozam, 1977
exposure transmission
of nerve of evoked
impulses in
exposed sciatic
nerve
TOXICOLOGICAL STUDIES
Special studies on mutagenicity
Eugenol was negative in a salmonella assay employing four mutant
strains (TA 1530, TA 1531, TA 1532, TA 1964) both directly and after
the use of mouse liver postmitochondrial fraction for activation. It
was also inactive in a host-mediated assay (Green & Savage, 1978).
Acute toxicity
Animal Route (mg/kg bw) References
Mouse Oral 3 000 Jenner et al., 1964
i.p. 500 Caujolle & Meynier,
1960
i.p. 630 Fujii et al., 1970
Rat Oral 1 930 Sober et al., 1950
Oral 2 680 Taylor et al., 1964
Guinea-pig Oral 2 130 Jenner et al., 1964
The acute toxic effects include desquamation of the gastric
mucosa (Hitchcock, 1952), and punctate haemorrhages in dogs (Hartiala
et al., 1966), gastric inflammation and depression of secretory
capacity (Sobers 1950), liver discoloration and mottling in rats
(Taylor et al., 1964) liver congestion in dogs (Lauber & Hollander,
1950).
Subchronic studies
Ten male and 10 female rats given 89.7 mg/kg eugenol for 12 weeks
showed no adverse effects (Trubek Laboratories, 1958).
Twenty male rats were given increasing doses from 1400 to
4000 mg/kg bw for 34 days. There was considerable mortality, slight
liver enlargement and adrenal enlargement. Histology showed enlarged
liver cells. The forestomach showed moderately severe hyperplasia and
hyperkeratosis of the stratified squamous epithelium with focal
ulceration (Hagan et al., 1965).
In another study groups of 10 males and 10 females were fed diets
containing 0, 0.1 and 1.0% eugenol for 19 weeks without any adverse
effect on growth rate, haematology, organ weights and histology of
major tissues (Hagan et al., 1967).
Special studies on carcinogenicity
In ingestion and injection studies in progress, eugenol-treated
mice have shown no effects different from the control groups (Miller,
1979).
In a study not meeting current standards, eugenol did not
potentiate the tumorigenic effects of methylcholanthrene (Hitchcock,
1952). In the United States of America, the NCI has a carcinogenicity
study in rats and mice under way.
Comments
High doses are hepatotoxic to dogs and rats. The short-term
studies provide some basis for toxicological evaluation. The data on
metabolites are incomplete but suggest no special concern. Various
mutagenicity tests gave negative results. Carcinogenicity studies are
in progress.
EVALUATION
Level causing no toxicological effect
Rat: 1% in the diet equivalent to 500 mg/kg bw
Estimate of temporary acceptable daily intake for man
0-2.5 mg/kg bw
FURTHER WORK OR INFORMATION
Required by 1982
Completion of ongoing carcinogenic studies.
REFERENCES
Anon. (1978) Scientific Literature Review of Eugenol and Related
Substances in Flavor Usage
Anon. (1967) Toxicological Evaluation of Some Flavouring Substances
and Non-Nutritive Sweetening Agents; FAO Nutrition Meetings,
Report Series No. 44A, WHO/FAO Add./68.33
Cambel, P., Sgouris, J. T. & Conray, C. E. (1952) Effects of Histamine
and eugenol on gastric mast cell diapedesis and leucopedesis in
the albino rat, W. J. Fla. Acad. Sc., 15, 147-148
Caujolle, F. & Maynier, D. (1960a) Hypothermic activity in the eugenol
and safrole series, Ann. Pharm. Fr., 18, 601-612
Chabrol, E. et al. (1931) Cholagog action of guaiacol derivatives, C.
R. Soc. Biol., 107, 1240-1243
de Mello, C. A. et al. (1973) Behavioral observations on
compounds found in nutmeg, Psychopharmacologia, 31 (4), 349-363
Fujii, K. et al. (1970) Structure-activity relations for
methylenedioxy-phenyl and related compounds on hepatic microsomal
enzyme function, as measured by prolongation of hexobarbital
narcosis and zoxazolamine paralysis in mice, Toxicol. Appl.
Pharmacol., 16, 482-494
Goeransson, K. et al. (1967) Some cases of eugenol hypersensitivity,
Sven. Tandiak. T., 60, 545-549
Green, N. R. & Savage, J. R. (1978) Screening of safrole, eugenol,
their ninhydrin positive metabolites and selected secondary
amines for potential mutagenicity, Mutation Research, 57,
115-121
Gruebner, I., Klinger, W. & Ankermann, H. (1972) Various substances
and substance classes with inducer properties. II. Arch. Int.
Pharmacodyn. Ther., 196 (2), 288-297
Hagan, E. C. et al. (1965) Toxic properties of compounds related
to safrole, Toxicol. Appl. Pharmacol., 7 (1), 18-24
Hagan, E. C. et al. (1967) Food flavorings and compounds of related
structure. II. Subacute and chronic toxicity, Food Cosmet.
Toxicol., 5 (2), 141-157
Hartiala, K. J. W., Pulkkinen, M. & Ball, P. (1966) Inhibition of
beta-D-glucosiduronic acid conjugation (rat and guinea pig) by
eugenol, Nature, 210 (5037), 739-740
Hitchcock, C. R. (1952) Failure of eugenol and heat to potentiate
gastric tumor induction by 20-methylcholanthrene in mice, J.
Natl. Cancer Inst., 12 (4), 723-733
Jaffe, H. et al. (1968) In vivo inhibition of mouse liver microsomal
hydroxylating systems by methylenedioxyphenyl insecticidal
synergists and related compounds, Life Sci., 7 (19), 1051-1062
Janiaud, P. et al. (1976) Comparative study in rat liver cell culture
of the metabolism of different analogs and metabolites of a
natural hepatocancerogen; safrole, Meeting of the Biol. Soc.
Dijon
Jenner, P. M. et al. (1964) Food flavorings and compounds of related
structure. I. Acute oral toxicity, Food Cosmet. Toxicol., 2
(3), 327-343
Kozam, G. (1977) The effect of eugenol on nerve transmission, Oral
Surg., 44, 799
Lauber, F. U. & Hollander, F. (1950) Toxicity of the Mucigogue,
eugenol, administered by stomach tube to dogs, Gastroenterol.,
15 (3), 481-486
Miller, J. A. (1979) Personal communication, February 16
Mortenson, H. (1969) Case of allergic stomatitis due to eugenol,
Tandlaegebladet, 72, 1155-1158
Schroder, V. & Vollmer, H. (1932) The excretion of thymol, carvacrol,
eugenol and guaiacol and the distribution of these substances in
the organism, Arch. Exp. Path. Pharmakol., 168, 331-353
Seto, T. A. Keup. (1969) Effects of Alkylmethoxybenzene and
Alkylmethylene-dioxybenzene essential oils on pentobarbital and
ethanol sleeping time, Arch. Int. Pharmacodyn. Ther., 180
(1), 232-240
Sober, H. A., Hollander, F. & Sober, E. K. (1950) Toxicity of eugenol:
Determination of LD50 on rats, Proc. Soc. Exp. Biol. Med.,
73 (1), 148-151
Sober, H. A., Hollander, F. & Sonnenblick, B. P. (1950) Response of
gastric mucous barrier in pouch dogs to repeated topical
application of eugenol, Am. J. Physiol., 162 (1), 120-130
Taylor, J. M., Jenner, P. M. & Jones, W. I. (1964) A comparison of
the toxicity of some allyl, propenyl and propyl compounds in the
rat, Toxicol. Appl. Pharmacol., 6 (4), 378-387
Trubeck Laboratories (1958) Unpublished report. Toxicological
screening of components of food flavors. Class IX. Aromatic
aldehydes (Eugenol).
Weinberg, J. E. et al. (1972) (14C)-eugenol. I. Synthesis,
polymerization, and use, J. Dent. Res., 51 (4), 1055-1061
Yuasa, A. (1974) Exp. studies on glucuronidation. III. Jpn. J. Vet.
Sci., 36 (5), 427-432
See Also:
Toxicological Abbreviations
Eugenol (FAO Nutrition Meetings Report Series 44a)
Eugenol (WHO Food Additives Series 17)
EUGENOL (JECFA Evaluation)
Eugenol (IARC Summary & Evaluation, Volume 36, 1985)