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    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 -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)