THREE-MONTH SUBACUTE ORAL TOXICITY STUDY OF MOFEZOLAC (N-22) IN DOGS

Mofezolac (N-22) is a new developed analgesic and antiinflammatory agent. A subacute oral toxicity test of N-22 was carried out at dose-levels of 0, 2, 6 and 20 mg/kg/day using male and female beagle dogs. Treatment for 3 months was followed by 1 month recovery period except in the case of both sexes receiving 20 mg/kg/day. The results obtained from the present study were as follows. 1. Observation of general conditions revealed vomiting, sporadic bloody feces, anemia, recumbency and hyposthenia in both sexes receiving 20 mg/kg/day. Anemia or erosion of tongue was observed in each female receiving 6 mg/kg/day. 2. Respectively 3 dogs of both sexes receiving 20 mg/kg/day died during dosing period. In these animals, perforating ulcers were observed in the pars pylorica ventriculi or duodenum, and loss of blood, peritonitis and aggravation of general exhaustion were considered as causes of death. 3. Body weight tended to decrease in both sexes receiving 20 mg/kg/day, and food and water consumption levels decreased in males receiving 2 mg/kg/day or above and females receiving 20 mg/kg/day. 4. Urinalysis demonstrated an increasing tendency for specific gravity of urine and a decreasing tendency for urine volume in males receiving 2 mt/kg/day or above. 5. Hematological examination showed decreases in red blood cell count and Hb concentration in males receiving 2 mg/kg/day or above, and in Ht values in males receiving 6 mg/kg/day or above. 6. Serum biochemical examination revealed decreases in total protein and albumin in both sexes receiving 20 mg/kg/day. 7. There were no remarkable changes in hepatic and renal function, ophthalmological findings or electrocardiogram. 8. In the ortan weights, significant decrease in thymus weights was observed in the dead animals receiving 20 mg/kg/day. 9. Pathologically, the dead animals receiving 20 mg/kg/day were found to exhibit peritonitis with perforating ulcers in the pars pylorica ventriculi or duodenum. In the surviving animals of this group, scar ulcers in the pars pylorica ventriculi and small intestine were evident on necropsy, and histopathology revealed neutrophils infiltration and thrombosis in blood vessels in the thickened submucosal stomach tissues. Moreover, localized hepatocyte necrosis and intrasinusoidal cellular infiltration in liver, as well as interstitial cellular infiltration, degeneration and dilatation of the renal tubules in the kidney were observed. In females receiving 6 mg/kg/day, the changes in kidney were similar to those in surviving animals receiving 20 mg/kg/day, and male of the group showed atrophy of thymus. 10. Almost all changes observed in the 6 and 2 mg/kg/day groups during dosing period recovered 1 month after the end of dosing. Thus the changes were reversible. 11. From the above results, the toxic dose level was estimated to be 20 mg/kg/day for both sexes, and the no-effect dose to be less than 2 mg/kg/day for males, and 2 mg/kg/day for females, in beagle dogs treated orally with N-22 for 3 months.