Chronic toxicity studies with ziram in F344 rats and beagle dogs

Abstract

Groups of 80 male and 80 female F344 rats were given ziram at a constant dietary dose of 0, 20, 200 or 2000 ppm (0, 0.70, 6.9 and 74 mg/kg/day for males and 0, 0.83, 8.5 and 91 mg/kg/day for females) for 104 weeks. Eight males and 8 females in each group were killed after Weeks 26, 52 and 78. In the dog study, 6 male and 6 female beagle dogs were allotted to each group which received the chemical in gelatin capsule at a dose level of 0, 0.2, 1.0 or 5.0 mg/kg/day for 104 weeks. The rats in the 2000 ppm group showed retarded growth together with decreased food intake. In the 200 and/or 2000 ppm groups, males and/or females showed a variety of changes in clinical and pathological examinations as follows: slight anemia; increased levels of serum glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase, and decreased levels of total cholesterol and calcium; elevated weights of the thyroids, liver and spleen, and lowered weights of the kidney and calf muscle; increased incidences of hematopoiesis or extramedullary hematopoiesis in the bone marrow or spleen, hyperkeratosis in the forestomach, follicular hypertrophy of the thyroid, atrophy/degeneration of the sciatic nerve and calf muscle and retarded closure of epiphyseal plate of crus bone. Decreased occurrences were noted for the senile changes in the heart, liver and kidneys in both sexes, C-cell hyperplasia of the thyroid in males, and hyperplasia and adenoma/ fibroma of the mammary gland in females. In addition, similar depression in incidence was observed in adenoma/adenocarcinorna of the pituitary in males of all treated groups. In the dog study, males and/ or females in the 5.0 mg/kg/day group showed persistent diarrhea and/or mucous stool as well as significant elevations of serum alkaline phosphatase, GOT and total cholesterol during the treatment while no treatment-related symptoms were observed in the groups of 1.0 and 0.2 mg/kg/day. With these results. NOAEL was estimated as 20 ppm for F344 rats (0.70 mg/kg/day for males and 0.83 mg/kg/day for females) and 1.0 mg/kg/day for the beagle dogs of both sexes.