CHRONIC TOXICITY STUDIES WITH ZIRAM IN F344 RATS AND BEAGLE DOGS

Groups of 80 male and 80 female F344 rats were given ziram at a consta nt dietary dose of 0, 20, 200 or 2000 ppm (0, 0.70, 6.9 and 74 mg/kg/d ay for males and 0, 0.83, 8.5 and 91 mg/kg/day for females) for 104 we eks. Eight males and 8 females in each group were killed after Weeks 2 6, 52 and 78. In the dog study, 6 male and 6 female beagle dogs were a llotted to each group which received the chemical in gelatin capsule a t 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 s howed a variety of changes in clinical and pathological examinations a s follows; slight anemia; increased levels of serum glutamic oxaloacet ic transaminase (GOT) and glutamic pyruvic transaminase, and decreased levels of total cholesterol and calcium; elevated weights of the thyr oids, liver and spleen, and lowered weights of the kidney and calf mus cle; increased incidences of hematopoiesis or extramedullary hematopoi esis in the bone marrow or spleen, hyperkeratosis in the forestomach, follicular hypertrophy of the thyroid, atrophy/degeneration of the sci atic 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 obs erved in adenoma/adenocarcinoma of the pituitary in males of all treat ed 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 signi ficant elevations of serum alkaline phosphatase, GOT and total cholest erol during the treatment while no treatment-related symptoms were obs erved in the groups of 1.0 and 0.2 mg/kg/day. With these results, NOAE L 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 b oth sexes.