Metabolism of estragole in rat and mouse and influence of dose size on excretion of the proximate carcinogen 1'-hydroxyestragole.

The major metabolic pathways of estragole have been established in rats and mice, and in both species the relative importance of the different pathways has been shown to be dose related. At low doses, estragole mainly undergoes detoxication reactions, notably O-demethylation and side-chain cleavage, but as the dose is increased, the extent of O-demethylation falls and other pathways, notably l'-hydroxylation, come into prominence. The disproportionate relationship between dose size and the elimination of the proximate carcinogenic metabolite l'-hydroxyestragole may influence the relationship between dose size and tumour incidence. These findings may have important implications for the safety assessment of this food flavouring, since the dose levels used in carcinogenicity studies have been very much larger than the estimated human daily intake. Moreover the percentage of an administered dose of estragole eliminated as 1-hydroxyestragole glucuronide in human urine is much lower than that found with even the lowest doses examined in rats in this study.