TOXICITY AND CARCINOGENICITY OF RIDDELLIINE FOLLOWING 13 WEEKS OF TREATMENT TO RATS AND MICE

Toxicity studies of riddelliine, a member of a class of pyrrolizidine alkaloids, were conducted because riddelliine has been found to contam inate human food sources. Groups of male and female Fischer rats were administered riddelliine by gavage in phosphate buffer at doses up to 10 mg/kg, and B6C3F1 mice at doses up to 25 mg/kg, five times a week. The animals were necropsied after 13 weeks of treatment or after a 7 o r 14 week recovery period. Body weight gains were inversely related to dose in both rats and mice. Body weight of the 1.0 and 3.3 mg/kg fema le rats and 10.0 and 25.0 mg/kg mice remained depressed during the 14 week recovery period. At 13 weeks, significant findings included dose- related hepatopathy and intravascular macrophage accumulation in rats and hepatocytomegaly in mice. During the 14 week recovery period these lesions persisted and hepatic foci of cellular alteration in male rat s and bile duct proliferation in female rats and male and female mice increased in severity. In the 10 mg/kg group of female rats adenomas o f the liver occurred in two of ten at 13 weeks and in one of five at t he 14 week recovery period. In separate studies, the frequency of micr onucleated erythrocytes in peripheral blood was increased in male mice administered a single dose (150 mg/kg) of riddelliine. Increases in u nscheduled DNA and S-phase syntheses were detected in primary hepatocy tes from rats and mice treated with riddelliine at doses up to 25.0 mg /kg for 5 or 30 days. In mating trials in rats and mice, pup weights f rom treated dams at birth and during suckling were lower than controls . Thus, riddelliine is genotoxic and carcinogenic and may cross the pl acenta and/or be found in milk, causing developmental toxicity in rode nts.