FIFTY-TWO-WEEKS ORAL CHRONIC TOXICITY STUDY OF PROPIVERINE HYDROCHLORIDE IN RATS

An oral chronic toxicity study of propiverine hydrochloride (P-4), a new anti-pollakiuria agent, was carried out at dose levels of 0(control), 0.5, 5 and 50mg/kg/day using male and female rats. They were treated for 52 weeks, followed by 5 weeks recovery period. The results obtained from the present study were as follows. 1. There were no deaths related to P-4. Mydriasis, transitory salivation were observed in both sexes receiving 50mg/kg/day, and soil of the abdomen was also noted in females receiving 50mg/kg/day. 2. Body weight gain was suppressed from initiation of administration in both sexts receiving 50mg/kg/day. 3. There were no significant or remarkable changes in food consumption, hematology and ophthalmology. 4. Urinary findings in animals receiving 50mg/kg/day showed increases of urine and potassium excretion volumes and decrease of urine osmotic pressure in both sexes, negativity of urine protein and decrease of urobilinogen value in females. 5. Biochemical findings in animals receiving 50mg/kg/day showed increase of ured-nitrogen (Urea N) in both sexes and decrease of triglyceride (TG), total cholesterol (T. cho), free cholesterol (F. cho), non-esterified fatty acids (NEFA) and phospholipid (PL) in males. 6. The absolute and/or relative weights of the liver increased in animals receiving 50mg/kg/day. Histopathological examination in animals receiving 50mg/kg/day revealed intranuclear eosinophilic inclusions and cytoplasmic eosinophilic substance in renal proximal tubular epithelium and midzonal lipid droplets in liver. Histochemical examination in animals receiving 50mg/kg/day revealed the slight increase of γ-GTP positive area in peripheral zone of liver. Electron-microscopic examination in animals receiving 50mg/kg/day revealed intranuclear and intracellular large and homogeneous spherical-like structure with low electron density in renal proximal tubular epithelium, and slight hyperplasia of smooth endoplasmic reticulum with dilatation of cisternae and deposition of large lipid droplets in hepatocytes, but there was no difference of VLDL dnd its distributions in hepatocytes among groups. 7. Aftef 5 weeks recovery period, above-mentioned changes were almost disappeared and considered to be reversible. 8. From the above results, the non-effective dose level of P-4 was estimated to be 5mg/kg/day for both sexes.