Effects of Coumarin Following Perinatal and Chronic Exposure in Sprague-Dawley Rats and CD-1 Mice

Coumarin, a naturally occurring substance most frequently usedas a fragrance enhancer and stabilizer, was administered inthe 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 doselevels of 0, 300, 1000, or 3000 ppm. Rats receiving 333, 1000,and 2000 ppm coumarin were exposed to these dose levels in uteroand during the lactational period, then chronically followingweaning. Rats in the 3000- and 5000-ppm dose groups and allmice received only postweanlng chronic exposure. All male ratswere terminated after 104 weeks of postweaning exposure; femalerats were terminated after 110 weeks. Male mice were terminatedat Week 101 and female mice at Week 109. Among rats, survivalwas decreased at 333 ppm, but signilicantly increased amongrats in the 3000- and 5000-ppm dose groups. Dramatic dose-relateddecreases in body weight gain were recorded for rats receiving2000, 3000, and 5000 ppm, clearly indicating that the MTD (maximumtolerated dose, as indicated by a body weight decrement of greaterthan 10–15%) was exceeded. Food consumption also was decreasedat the three highest dose levels, although body weight decrementwas disproportionately large compared to changes in food consumption.Treatment-related decreases in hemoglobin were recorded fromWeek 6 onward. Minimal treatment-related changes in he matologyand clinical chemistry were recorded. Increased liver weightswere observed for male and female rats receiving 3000 or 5000ppm and for females only at 1000 and 2000 ppm. Increased incidencesof cholanglofibroma, cholangiocarcinoma, and parenchymal livercell tumors were observed among male and female rats receiving5000 ppm. One male rat receiving 3000 ppm devel oped a cholangiocarcinoma;no tumor increase was observed in males or females at 2000 ppmor below. Coumarin, at a dose clearly exceeding the MTD can,therefore, induce liver tumors in rats, although survival, relativeto controls, was increased at the same dose levels. Among mice,a decrease in body weight gain was reported for males in the1000- and 3000-ppm dose groups during the first 52 weeks ofthe study. No dose-related abnormalities in clinical signs,clinical pathology, hematology, or gross or microscopic pathologywere noted.