Toxicity of lactide in dogs after 2 and 13 weeks of daily oral dosing

Two-week and 13-week studies were conducted to determine the toxicity of la ctide when the compound is administered orally in gelatin capsules to beagl e dogs. In the 2-week study, daily doses of 0. 10. 100. 400. 1000 and 2500 mg/kg body weight/day were administered to dogs of both sexes for 14 consec utive days. All dogs survived to the end of the study. Clinical signs consi stent with irritation of the alimentary tract occurred in dogs in the 1000 and 2500 mg/kg dose groups. Reductions in body weight gain and in absolute and relative thymus weights were observed in the same two dose groups, and reductions ill absolute and relative spleen weights were seen in the 2500 m g/kg dose group. These changes were considered to be secondary to the stres s resulting from irritation of the gastrointestinal tract. Gross and micros copic lesions were indicative of irritation, and included dark foci and hae morrhage of the stomach lining, and erosion and ulceration of the stomach a nd the oesophagus. Also noted in all high-dose dogs was renal tubular regen eration, which mag; represent repair of previous necrosis of the tubular ep ithelium. In the 13-week. study, no deaths occurred when dogs were given da ily oral doses of 0, 4. 20 or 100 mg/kg body weight/day. No clinical signs of toxicity were observed, and the compound had no effect on body weights. food consumption, or any of the clinical chemistry, haematology or urinalys is parameters assessed. Gross and microscopic findings considered to be pot entially related to lactide administration were minimal, and included a sto mach focus in one dog of each sex in the 100 mg/kg group. The stomach focus in the 100 mg/kg female dog was manifested microscopically as a stomach ul cer. Based on these results, the primary toxic effect of lactide a as consi dered to be irritation of the gastrointestinal tract, and the no-observed-a dverse-effect level (NOAEL) after subchronic oral dosing in dogs was consid ered to be 100 mg/kg/day. (C) 1999 Elsevier Science Ltd. All rights reserve d.