Effects of coumarin following perinatal and chronic exposure in Sprague-Dawley rats and CD-1 mice.

Coumarin, a naturally occurring substance most frequently used as a fragrance enhancer and stabilizer, was administered in the diet of Sprague-Dawley rats at dose levels of 0, 333, 1000, 2000, 3000, and 5000 ppm or in the diet of CD-1 mice at dose levels of 0, 300, 1000, or 3000 ppm. Rats receiving 333, 1000, and 2000 ppm coumarin were exposed to these dose levels in utero and during the lactational period, then chronically following weaning. Rats in the 3000- and 5000-ppm dose groups and all mice received only postweaning chronic exposure. All male rats were terminated after 104 weeks of postweaning exposure; female rats were terminated after 110 weeks: Male mice were terminated at Week 101 and female mice at Week 109. Among rats, survival was decreased at 333 ppm, but significantly increased among rats in the 3000- and 5000-ppm dose groups. Dramatic dose-related decreases in body weight gain were recorded for rats receiving 2000, 3000, and 5000 ppm, clearly indicating that the MTD (maximum tolerated dose, as indicated by a body weight decrement of greater than 10-15%) was exceeded. Food consumption also was decreased at the three highest dose levels, although body weight decrement was disproportionately large compared to changes in food consumption. Treatment-related decreases in hemoglobin were recorded from Week 6 onward. Minimal treatment-related changes in hematology and clinical chemistry were recorded. Increased liver weights were observed for male and female rats receiving 3000 or 5000 ppm and for females only at 1000 and 2000 ppm. Increased incidences of cholangiofibroma, cholangiocarcinoma, and parenchymal liver cell tumors were observed among male and female rats receiving 5000 ppm. One male rat receiving 3000 ppm developed a cholangiocarcinoma; no tumor increase was observed in males or females at 2000 ppm or below. Coumarin, at a dose clearly exceeding the MTD can, therefore, induce liver tumors in rats, although survival, relative to controls, was increased at the same dose levels. Among mice, a decrease in body weight gain was reported for males in the 1000- and 3000-ppm dose groups during the first 52 weeks of the study. No dose-related abnormalities in clinical signs, clinical pathology, hematology, or gross or microscopic pathology were noted.