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, ß 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)