Histopathological evaluation of proliferative liver lesions in rats fed trans-anethole in chronic studies

In a two-year study of rats fed trans-anethole--a flavouring that is Generally Recognized As Safe by the US Food and Drug Administration--a slight increase in proliferative lesions of the liver was observed. These results were reviewed by a Pathology Working Group (PWG) and their findings are detailed here. The increased incidence of non-neoplastic lesions in male and female rats fed 0.25, 0.5 or 1.0% trans-anethole was considered by the PWG to be treatment related. Male and female rats fed 0.25% trans-anethole in their diet (25 to 29 times the postulated maximum human intake) had no significant treatment-related microscopic lesions in the liver, although there was a slight increase in parenchymal cell hyperplasia. Rats fed 0.5% trans-anethole had hepatic changes consistent with those caused by chronic exposure of rodents to compounds with enzyme-inducing activity. Male and female rats fed 1.0% trans-anethole revealed increased incidence and severity of hepatic changes as seen in the mid-dose rats, and a low incidence of hepatocellular neoplasms. These neoplasms were not increased in male rats in any dietary group or in female rats of the low- (0.25%) and mid-dose (0.5%) groups. The slightly increased incidence of hepatocellular neoplasms in the high-dose females is not considered to be of significance to human safety and it is concluded that trans-anethole does not constitute a carcinogenic risk for man. The slightly increased tumour incidence was seen only in the highest dose group of one sex; it has not been observed in studies of mice fed trans-anethole--the metabolism of trans-anethole in the mouse is similar to that in man. The extremely high exposure was associated with other liver changes which may have contributed to the findings.