A subchronic toxicity study of Rokanol B-2 in rats

The toxicity of Rokanol B-2 was assessed following its administration to rats via oral gavage. A preliminary study of acute toxicity was performed to determine suitable dosing regimen/dose levels for future repeated-dose toxicity studies. For this purpose rats (15 males and 7 females) received single doses of 2,000, 1,500, 1,000 or 500 mg/kg and were killed after 2 or 14 days. No deaths occurred during the observation time. Dose-related irritation to the stomach mucosa was found. For the subchronic toxicity assessment, Rokanol B-2 was administered at daily doses of 8, 40 or 200 mg/kg to 59 male and 56 female Wistar rats by oral gavage, 5 days per week for 90 days. An interim experiment was performed after 28 days of dosing. Five animals/sex/group were terminated and necropsied. Blood samples for clinical chemistry and haematology were obtained and lungs, heart, adrenals, kidneys, liver, spleen, stomach, intestine, testes (males), uterus and ovaries (females) were weighed and prepared for histopathological examination. After 90 days of dosing all remaining animals were killed and necropsied. Blood samples were taken for evaluation of haematology and clinical chemistry, and selected organs (same as above) prepared for subsequent histological examination. In the high-dose group (200 mg/kg/day) a statistically significant reduction in body weight gain and food consumption, an increased weight of the liver in the males and disturbances in haematological parameters in the females were observed. Ulcerations of the mucous membrane of the stomach and hyperkeratosis, and in a few cases, pseudopapillomatous epithelial proliferation of foregaster and exudate in the submucosa of the stomach were noted. In the mid-dose group (40 mg/kg/day) some disturbances in hematological parameters in females and histopathological changes in rats of both sexes similar, but to a lesser degree, to changes observed in high-dose animals were indicated. In the low-dose group (8 mg/kg/day) no significant treatment-related effects were observed. The results of this study indicate that Rokanol B-2 possessed an overall low degree of systemic toxicity when administered orally to rats for 90 days. The NOAEL, observed in this study, was estimated as 8 mg/kg/day.