Wy-14,643 was selected for inclusion in a series of studies on peroxisome proliferators because it is known to produce considerable peroxisome proliferation and hepatocarcinogenicity in rats. Male Sprague-Dawley rats were exposed to Wy-14,643 (greater than 98% pure) in feed for up to 3 months; male B6C3F1 mice and male Syrian hamsters were exposed to Wy-14,643 in feed for 2 weeks or up to 3 months. Animals were evaluated for clinical pathology, plasma concentrations of Wy-14,643, reproductive system effects, cell proliferation and peroxisomal enzyme analyses, and histopathology. Single and multiple-dose toxicokinetic studies of Wy-14,643 were conducted in additional groups of male Sprague-Dawley and Wistar Furth rats, B6C3F1 mice, and Syrian hamsters. Genetic toxicology studies were conducted in vivo in Tg.AC mouse peripheral blood erythrocytes.
In the 2-week studies, groups of five mice were fed diets containing 0, 10, 50, 100, 500, or 1,000 ppm Wy-14,643 (equivalent to average daily doses of approximately 2 to 184 mg Wy-14,643/kg body weight). Groups of five hamsters were fed diets containing 0, 10, 100, 500, 1,000, or 5,000 ppm Wy-14,643 (equivalent to average daily doses of approximately 1 to 550 mg/kg). All animals survived to the end of the studies. The mean body weight gain of 500 ppm mice was significantly less than that of the controls; hamsters exposed to 100 ppm or greater lost weight during the study. Feed consumption by 500 ppm mice was greater than that by the controls. Liver weights of all exposed groups of mice and hamsters were generally significantly increased.
In the 2-week studies, an increase in peroxisomal enzyme activity occurred in 10 ppm mice; increases in peroxisomal beta-oxidation, carnitine acetyltransferase, catalase, and acyl CoA oxidase occurred in all exposed mice compared to controls. Significantly increased BrdU-labeled hepatocyte percentages occurred in 100 and 1,000 ppm mice and 500 and 5,000 ppm hamsters; peroxisomal β-oxidation of lipids was increased in all exposed groups of mice and hamsters.
Gross lesions in the 2-week studies included liver foci in one 500 ppm mouse and one 1,000 ppm hamster and enlarged livers in one hamster in each of the 100 and 500 ppm groups and two 5,000 ppm hamsters. All 500 and 1,000 ppm mice had hepatocyte hypertrophy of the liver, and 1,000 ppm mice also had widespread individual cell necrosis. Minimal to mild multifocal vacuolation of the liver occurred in hamsters exposed to 500 ppm or greater.
In the 3-month core studies, groups of 10 male rats, mice, or hamsters were fed diets containing 0, 5, 10, 50, 100, or 500 ppm Wy-14,643 (equivalent to average daily doses of approximately 0.3 to 34 mg/kg for rats, 0.9 to 135 mg/kg for mice, and 0.4 to 42 mg/kg for hamsters). Groups of 15 male rats, mice, or hamsters designated for special studies received the same concentrations of Wy-14,643 for up to 13 weeks. Groups of six male rats, 36 male mice, or 12 male hamsters designated for plasma concentration studies were fed diets containing 50, 100, or 500 ppm Wy-14,643 for up to 9 weeks.
All core study animals survived to the end of the studies. Mean body weights were significantly decreased in all exposed groups except the 5 ppm groups and 10 ppm mice; hamsters in the 100 and 500 ppm groups lost weight during the study. Feed consumption by exposed rats and mice was generally similar to that by the controls; during week 14, hamsters exposed to 50 ppm or greater consumed slightly less feed than did the controls. The only clinical finding of toxicity was thinness of two 50 ppm and five 500 ppm hamsters. At all time points, the liver weights of exposed groups of core and special study rats, mice, and hamsters were generally significantly greater than those of the controls. Testis weights were significantly decreased in 500 ppm hamsters on day 34, in hamsters exposed to 5 ppm or greater at week 13 (special study), and in 100 and 500 ppm core study hamsters at the end of the study.
In the sperm motility evaluation, the cauda epididymis weight of 500 ppm rats, epididymis weights of 100 and 500 ppm rats and mice, and the testis weight of 500 ppm mice were significantly less than those of the controls. For hamsters, cauda epididymis, epididymis, and testis weights; spermatid heads per testis; and spermatid counts were significantly decreased in all exposed groups evaluated for sperm motility. Epididymal spermatozoal motility and concentration in the 100 and 500 ppm groups and spermatid heads per gram testis in the 500 ppm group were also significantly decreased. Serum concentrations of estradiol were significantly decreased in all exposed groups of hamsters, and concentrations of testosterone and luteinizing hormone were decreased in groups exposed to 50 ppm or greater.
At necropsy in the 3-month studies, liver foci were observed in three special study mice, including one 100 ppm mouse and one 500 ppm mouse on day 34 and one 100 ppm mouse at week 13. Liver discoloration and small testes were noted in 500 ppm hamsters on day 34, and hamsters exposed to 50 ppm or greater had enlarged livers and/or small testes at week 13 (special study) and at 3 months (core study). The incidences of cytoplasmic alteration in the liver were significantly increased in all exposed core groups of rats, mice, and hamsters; the severity of this lesion increased with increasing exposure concentration. The incidences of mitotic alteration of the liver in mice exposed to 50 ppm or greater and of liver pigmentation and oval cell hyperplasia in 500 ppm mice were significantly increased. Minimal regeneration of the corticomedullary junction of the renal tubule occurred in all exposed groups of rats. Significantly increased incidences of atrophy of the prostate gland, seminal vesicle, and testis occurred in 100 and 500 ppm hamsters. Degenerative myopathy of skeletal muscle was observed in the lumbar area and thigh of rats, mice, and hamsters and the lower leg of mice, primarily at 500 ppm.
Following single-dose gavage exposure to Wy-14,643, plasma concentrations were generally higher in mice than in rats, which in turn were higher than those in hamsters. This pattern of plasma concentrations was usually attributed to high bioavailability in mice, medium bioavailability in rats, and low bioavailabilty in hamsters following an oral exposure to Wy-14,643.
No increase in the frequency of micronucleated normochromatic erythrocytes was observed in the peripheral blood of male or female Tg.AC mice exposed to Wy-14,643 in feed or via dermal application for 6 months.