P.M. Newberne

90-day dermal toxicity study and neurotoxicity evaluation of nitromusks in the albino rat.

Musk ketone, musk xylene, musk tibetene and moskene, synthetic musks used in fragrances, were applied dermally to rats in daily doses of 240 (musk ketone and musk xylene only), 75, 24 or 7.5 mg/kg body weight for 90 days. The chemically related musk ambrette, a known neurotoxin in rats, was used as a positive control. While musk ambrette was clearly neurotoxic and caused testicular atrophy, as had been previously reported, the other compounds tested caused neither effect. The only effects of application of these materials were some organ weight changes at the higher doses, but these were not associated with histopathological changes in any of the tissues. The no-effect levels were: musk ketone, 75 mg/kg for males and females; musk xylene, 75 mg/kg for males and 24 mg/kg for females; moskene, 24 mg/kg for males and 75 mg/kg (highest dose administered) for females; and musk tibetene, 75 mg/kg (highest dose) for males and females.

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.