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    TRANS-ANETHOLE

    Explanation

         Anethole was evaluated for acceptable daily intake by the joint
    FAO/WHO Expert Committee on Food Additives (FAO, 1968) in 1967 and
    given a conditional ADI of 0-1.25 mg/kg bw. Specifications were also
    prepared.

    BIOLOGICAL DATA

    Biochemical aspects

         Anethole is rapidly absorbed and distributed in the rat, (Le
    Bourhis, 1973; Fritsch, 1975) and in the mouse (Le Bourhis, 1968;
    Strolin-Benedetti & Le Bourhis, 1972, Le Bourhis, 1973).

         The same authors report rapid metabolism in both species. The
    principal metabolites from oral administration in the rat are:

                                           % Dose in urine

    (1)  p-Hydroxypropenyl benzene               32

    (2)  p-Hydroxycinnamic acid                  15

    (3)  p-Methoxybenzoic acid                   4

    (4)  p-Methoxyhippuric acid                  43

    (5)  p-Methoxyacetophenone                   Trace

    Metabolites (1) and (2) appear largely as the glucuronide or sulfate.
    Virtually identical results were obtained by the i.p. route (Solheim &
    Scheline, 1973). Administration to rats of ring or methoxy side-chain
    14C-labelled anethole confirms that virtually all ring metabolites
    are eliminated via the renal system within 48 hours, with substantial
    demethylation and consequent appearance of the methoxy 14C in the
    breath, and to a small extent, the body and faeces (Strolin-Benedetti
    & Le Bourhis, 1972).

         In five human subjects given a 500 mg dose the 24-hour
    metabolites were anisic acid (52%) and p-hydroxybenzoic acid (5%).
    Anethole was not detectable in the blood (Le Bourhis, 1973).

         Metabolism in rabbits appears similar (Axelrod, 1956; Le Bourhis,
    1970).

         The pharmacologic effects of trans-anethole most often noted
    are reduction in motor activity, lowering of body temperature and
    hypnotic, analgesic, and anticonvulsant effects. By either the i.p. or
    oral route, administration of more than 10% of LD50 by that route
    appears necessary for significant effects. (Boissier et al., 1961;
    Seto, 1969; Gruebner, 1972; Le Bourhis & Soene, 1973).

    TOXICOLOGICAL STUDIES

    Special studies

         In a 24-week screening test, groups of 20 female A/He mice
    received in the first eight weeks of the test period, a total dose of
    2.4 or 12.0 g/kg bw of anethole in 24 thrice-weekly i.p. injections.
    The higher dose had previously been calculated to be maximum tolerated
    dose. There was no increase in the incidence of tumours of the lung,
    liver, kidney, spleen, thymus, intestine, or salivary or endocrine
    glands. Survival was reduced to approximately 70% (Stoner et al.,
    1973).

         In oral and injection studies in mice now in progress, anethole
    appears not to produce results different from the controls (Miller,
    1979).

    Short-term studies

         Rats (number not given) receiving anethole in the diet at 0.25%
    for one year showed no adverse effects, while those receiving 1.0% for
    15 weeks showed slight hydropic alterations of hepatic cells (Taylor,
    1964).

         Groups of five male and five female rats maintained on diets
    containing trans-anethole at 0, 0.1, 0.3, 1.0 and 3.0 for 90 days
    showed no effects at 0.1%, but dose-related hepatic cell oedema
    degeneration, and regeneration at 0.3% and higher. In a parallel
    experiment with the cis isomer, similar changes were noted at 0.03%
    and higher (Shelanski, 1958).

    Long-term studies

         Groups of 25 male and female rats maintained at 0.2, 0.5, 1.0 and
    2.0% for 12-22 months showed no effects at any level in clinical
    chemistry, haematology, histopathology or mortality. Slower weight
    gain and decreased fat storage were noted only at the 1.0 and 2.0%
    levels. In a paired feeding study anethole reduced the rate of weight
    gain (Le Bourhis, 1973).

    Comments

         Anethole is of special toxicological interest because of its
    close structural relationship to substances shown to be carcinogenic
    such as safrole, dihydrosafrole, iso-safrole,  aserone and estragole.
    Evidence requested in the eleventh report (FAO, 1968) on the
    metabolism of anethole is available and shows that it is rapid.
    Long-term studies in mice and rats, while not totally satisfactory,
    indicate that trans-anethole is probably not a carcinogen and the
    Committee concluded that a lower safety factor was acceptable. The
    previous conditional ADI was converted to a temporary ADI.

    Acute toxicity
                                                                                                     

                                       LD50
    Animal         Route            (mg/kg bw)               References
                               trans-          cis-
                               isomer          isomer
                                                                                                 

    Mouse          Oral        1 820-5 000                Levenstein, 1960;
                                                          Jenner, 1964;
                                                          Boissier, 1967

    Mouse          i.p.          650            95        Caujolle & Meynier, 1958
                               1 410           135        Boissier, 1967

    Rat            Oral        2 090-3 208     150        Taylor et al., 1964;
                                                          Shelanski, 1958
                                                          Boissier, 1967

    Rat            i.p.          900            65        Boissier, 1967
                               2 670            70        Caujolle, 1958

    Guinea-pig     Oral        2 160                      Jenner, 1964
                                                                                                 
        EVALUATION

    Level causing no toxicological effect

    Rat: 0.5% in diet equivalent to 250 mg/kg bw.

    Estimate of temporary acceptable daily intake for man

    Temporary ADI of 2.5 mg/kg bw.

    FURTHER WORK OR INFORMATION

    Required by 1983.

    Adequate long-term feeding study.

    REFERENCES

    Anon. (1967) Toxicological Evaluation of Some Flavouring Substances
         and Non-Nutritive Sweetening Agents; FAO Nutrition Meetings
         Report Series No. 44A, WHO/Food Add./68.33

    Axelrod, J. (1956) Enzymic cleavage of aromatic ethers, Biochem. J.,
         63, 634-639

    Boissier, J. R., Simon, P. & Le Bourhis, B. (1967) Experimental
         psychotropic effect of isomeric cis- and trans-anetholes,
         Therapie, 22(2), 309-323

    Caujolle, F. & Meynier, D. (1958) Toxicity of tarragon oil and the
         anetholes (cis- and trans-), Acad. Sci. (Paris), 246, 1465-1468

    Fritsch, P., De Saint-Blanquat, G. & Derache, R. (1975)
         Gastrointestinal absorption, in the rat, of anisole, trans-
         anethole butylhydroxyanisole, and safrole, Food Cosmet.
         Toxicol., 13(3), 359-364

    Gruebner, I., Klinger, W. & Ankermann, H. (1972) Various substances
         and substance classes with inducer properties. II. Arch. Int.
         Pharmacodyn. Ther., 196(2), 288-297

    Jenner, P. M. et al. (1964) Food flavourings and compounds of related
         structure. I. Acute oral toxicity, Food Cosmet. Toxicol.,
         2(3), 327-343

    Le Bourhis, B. (1968) The metabolism of trans-anethole, Ann. Biol.
         Clin., 26(5-6), 711-715

    Le Bourhis, B. (1970) Identification of a few metabolites of trans
         anethole in man, the rabbit, and the rat, Ann. Pharm. Fr.,
         28(5), 355-361

    Le Bourhis, B. (1973) Biological properties of trans-anethole. An
         attempt to determine an acceptable daily dosage, Parfums,
         Cosmet. Savons. Fr., 3(8-9), 450-456

    Le Bourhis, B. & Soene, A.M. (1973) Studies on the psychotropic action
         of some aromatic compounds used in food, Food Cosmet. Toxicol.,
         11(1), 1-9

    Levenstein, I. (1960) Leberco Laboratories. Unpublished report.

    Miller, J. A. (1979) Personal communication, February 16

    Seto, T. A. (1969) Effects of alkylmethoxybenzene and alkylmethylene-
         dioxybenzene essential oils on pentobarbital and ethanol sleeping
         time, Arch. Int. Pharmacodyn. Ther., 180(1), 232-240

    Shelanski, M. V. (1958) Industrial Biology Research and Testing
         Laboratories. Unpublished report.

    Solheim, E. & Scheline, R. R. (1973) Metabolism of alkenebenzene
         derivatives in the rat. I. rho-Methoxyalylbenzene (estragole) and
         rho-methoxypropenylbenzene (anethole), Xenobiotica, 3(8),
         493-510

    Stoner, G. D. et al. (1973) Test for carcinogenicity of food additives
         and chemotherapeutic agents by the pulmonary tumor response in
         strain A mice, Cancer Res., 33(12) 3069-3085

    Strolin-Benedetti, M. & Le Bourhis, B. (1972) Body distribution and
         excretion of trans-anethole-14C, C. R. Acad. Sci. Ser. D.,
         274(16), 2378-2381

    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
    


    See Also:
       Toxicological Abbreviations
       Trans-anethole (WHO Food Additives Series 28)
       trans-ANETHOLE (JECFA Evaluation)