SummaryÐThis publication is the fourth in a series of safety evaluations performed by the Expert
Panel of the Flavour and Extract Manufacturers' Association (FEMA). In 1993, the Panel initiated a
comprehensive program to re-evaluate the safety of more than 1700 GRAS ¯avouring substances under
conditions of intended use. In this review, scienti®c data relevant to the safety evaluation of trans-ane-
thole (i.e. 4-methoxypropenylbenzene) as a ¯avouring substance is critically evaluated by the FEMA
Expert Panel. The evaluation uses a mechanism-based approach in which production of the hepatotoxic
metabolite anethole epoxide (AE) is used to interpret the pathological changes observed in dierent
species and sexes of laboratory rodents in chronic and subchronic dietary studies. Female Sprague±
Dawley rats metabolize more trans-anethole to AE than mice or humans and, therefore, are the most
conservative model for evaluating the potential for AE-induced hepatotoxicity in humans exposed to
trans-anethole from use as a ¯avouring substance. At low levels of exposure, trans-anethole is eciently
detoxicated in rodents and humans primarily by O-demethylation and