States. It is used clinically in the treatment of high-protein as a fragrance enhancer and stabilizer, was administered in the diet of Sprague-Dawley rats at dose levels of 0, 333, 1000, 2000, edema (Jamal et al., 1989), chronic brucellosis, and immune 3000, and 5000 ppm or in the diet of CD-1 mice at dose levels of suppression (Moran et al., 1987). In isolation (Thornes et 0, 300, 1000, or 3000 ppm. Rats receiving 333, 1000, and 2000 al., 1989) or in combination with cimetidine (Marshall et ppm coumarin were exposed to these dose levels in utero and al., 1987a, b, c;Dexeus et al., 1990), coumarin is currently during the lactational period, then chronically following weaning. undergoing several clinical trials for the treatment of several Rats in the 3000-and 5000-ppm dose groups and all mice received types of malignancies in humans, including the treatment of only postweaning chronic exposure. All male rats were terminated lung and kidney carcinoma. Due to its use as a drug, there after 104 weeks of postweaning exposure; female rats were termiis information in the literature concerning its toxicity, metab- have been conducted to examine the chronic toxicity and at 333 ppm, but significantly increased among rats in the 3000-carcinogenicity of coumarin, none were conducted in accorand 5000-ppm dose groups. Dramatic dose-related decreases in body weight gain were recorded for rats receiving 2000, 3000, and dance with current scientific guidelines. A GLP-compliant 5000 ppm, clearly indicating that the MTD (maximum tolerated study was therefore undertaken. (Since this study was comdose, as indicated by a body weight decrement of greater than 10-pleted, the U.S. National Toxicology Program has conducted 15%) was exceeded. Food consumption also was decreased at the a bioassay of coumarin in F344 rats and B6C3F1 mice.) chymal liver cell tumors were observed among male and female rats receiving 5000 ppm. One male rat receiving 3000 ppm devel-Animals and Treatments oped a cholangiocarcinoma; no tumor increase was observed in Rats. Rats were housed five per cage in suspended wire-mesh cages.males or females at 2000 ppm or below. Coumarin, at a dose Animal rooms were maintained at 22ЊC and 50% relative humidity, with a clearly exceeding the MTD can, therefore, induce liver tumors in 12-hr/12-hr light/dark cycle. Each cage was identified by cage card and rats, although survival, relative to controls, was increased at the each rat was individually identified by earmark and tattoo. Ad libitum access same dose levels. Among mice, a decrease in body weight gain to food and tap water was provided. was reported for males in the 1000-and 3000-ppm dose groups All animals for the chronic study were derived from Sprague-Dawley during the first 52 weeks of the study. No dose-related abnormali-rats received from Charles River (Charles River, Manston, Kent, UK) and ties in clinical signs, clinical pathology, hematology, or gross or bred at Huntingdon Research Centre, Huntingdon, Cambridgeshire, Enmicroscopic pathology were noted. ᭧ 1996 ...