ESTRAGOLE
Explanation
This flavouring agent was assessed for the first time by the
Joint Expert Committee on Food Additives.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
Metabolism
Approximately 20% of a dose of estragole was excreted in the
urine of outbred CD-1 mice as a conjugate of 1'-hydroxy estragole
(Drinkwater et al., 1976).
Solheim & Scheline (1973) found that O-demethylation to
p-hydroxyallylbenzene and oxidation of the allylic side chain to
2-hydroxy-3-(p-methoxyphenyl) popionic acid or anisic acid (excreted
largely as p-methoxyhippuric acid) are the main metabolic reactions.
Other reactions yield 1-(p-methoxyphenyl) allyl alcohol,
p-methoxyphenyl acetic acid and the latter's glycine conjugate. At
least 60-65% (possibly 90%) of the doses administered were accounted
for.
TOXICOLOGICAL STUDIES
Special studies on pharmacological aspects
Estragole caused contractions of isolated frog muscles followed
by relaxation. This effect was reduced in potassium-depolarized
muscles or in the presence of quinidine or manganese. Estragole
appears to cause these effects by producing a persistent
depolarization of the muscle membrane (Zutshi et al., 1977).
Estragole was found to be strongly active in prolongation of
hexobarbital narcosis and zoxazolamine paralysis following
intraperitoneal doses of 2.5, 10, 40, 160 and 640 mg/kg in mice. This
implies that it inhibits hepatic microsomal enzyme functions (Fujii et
al., 1970).
Special studies on carcinogenicity
Estragole and its 1-hydroxy metabolite caused significant
increases in the incidences of hepatocellular carcinomas in male CD-1
mice that received the compound by subcutaneous injection at 1-22 days
of age. Doses given were 4.4 and 5.2 µmol (Drinkwater et al., 1976).
1-hydroxyestragole did not demonstrate liver-mediated
mutagenicity in a bacterial test system (Drinkwater et al., 1976).
Estragole has no cytotoxic activity against HeLa cells (Stoichev
et al., 1967). The ED50 (dose required for 50% cell growth inhibition)
was reported at 5.23 × 104 Molar. This value implies that it has less
potency as a tumour growth inhibitor than delta-9-tetrahydrocannabinol
(Nichols et al., 1977).
Special studies on dermal toxicity
Estragon oil applied full strength to intect or abraded rabbit
skin for 24 hours under occlusion was irritating (Shelanski, 1973). It
was also irritating when applied undiluted to the backs of hairless
mice (Urbach & Forbes, 1973). Tested at 4% in petrolatum, it produced
no irritation after a 48-hour closed-patch test in 25 human subjects
(Kligman, 1972).
Acute toxicity
LD50
Species/route of Mouse Rat Rabbit
administration g/kg g/kg g/kg
Oral 1.25 1.23
Jenner et al. Opdyke et al.
(1964) (1976)
Dermal 1.82 5
Jenner et al. Opdyke et al.
(1964) (1976)
Intraperitoneal 1.26 1.03
Coujelle et al. Coujelle et al.
(1958) (1958)
Chronic/sub-chronic toxicity
Rats given four daily oral doses of 605 mg/kg showed minor liver
damage (Taylor et al., 1964).
OBSERVATIONS IN MAN
A maximation test (Kligman, 1966) was carried out on 25
volunteers. The material was tested at a concentration of 4% in
petrolatum and produced no sensitization reactions (Kligman, 1972).
Comments
A single sample of estragole has been tested in the CD-1 strain
of mouse by the intraperitoneal and oral route which resulted in
increased incidence of hepatocellularcarcinoma.
Because no no-effect level has been demonstrated no ADI could be
established. In view of the importance of the compound and the limited
amount of data, the Committee would be pleased to see this work
repeated in another strain of mouse.
EVALUATION
No ADI allocated.
REFERENCES
Coujelle, M. & Meynier D. (1958) Comptes rendus hebdomadaires
des seances, Academie des Sciences, 246, 1465
Drinkwater, N. R. et al. (1976) J. Nat. Cancer Inst., 57 (6), 1323-1331
Fujii, K. et al. (1970) Toxicol. Appl. Pharmacol., 16 (2), 482-494
Jenner, P. M. et al. (1964) Food Cosmet Toxicol., 2, 237-343
Kligman, A. M. (1966) J. invest. Derm., 47, 393
Kligman, A. M. (1972) Report to RIFM, 1 November
Nichols, D. E., Mason, D. L. & Jackson, L. B. (1977) Life Sciences, 21
(9), 1245-1248
Opdyke, D. L. J. (1976) RIFM mongraphs on fragrance materials, Food
Cosmet. Toxicol., 14, 603
Shelanski, M. V. (1973) Report to RIFM, 30 January
Solheim, E. & Scheline, R. R. (1973) Xenobiotica, 3 (8), 493-510
Stoichev, S. et al. (1967) Bulg. Sci., 20 (12), 1341-1344
Taylor, J. M., Jenner, P. M. & Jones, W. I. (1964) Toxicol. Appl.
Pharmacol., 6, 378
Urbach, F. & Forbes, P. D. (1973) Report to RIFM, 8 February
Zutshi, S. K. & Bhagwat, A. W. (1977) Curr. Sci., 46 (7), 223-224