Delayed neurotoxicity of O-ethyl O-4-nitrophenyl phenylphosphonothioate: Subchronic (90 days) oral administration in hens

Delayed neurotoxicity in hens was produced following daily oral administration of 0.1, 0.5, 1.0, 2.5, 5.0, and 10.0 mg/kg of technical (85%) O-ethyl O-4-nitrophenyl phenylphosphonothioate (EPN) in gelatin capsules for 90 days. Daily, three groups of hens were given empty gelatin capsules, 10 mg/kg of tri-o-cresyl phosphate (TOCP), or 1 mg/kg of parathion (O,O-diethyl O-4-nitrophenyl phenylphosphorothioate) and served as gelatin capsule controls, positive controls, and negative controls, respectively. TOCP-Treated hens developed delayed neurotoxicity, and those given parathion showed leg weakness with subsequent recovery when the administration of this agent had stopped. The clinical condition of most ataxic hens deteriorated during the 30-day observation period following the end of the oral administration of EPN. Severity of the clinical condition depended on the size of the daily ingested dose, i.e., while hens given small doses showed only ataxia, those treated with large doses progressed to paralysis and died. Days of administration and “total administered dose” before onset of ataxia depended on the daily dose. Degeneration of myelin and axons in the spinal cord was the most consistent histologic change and was identical to that found in TOCP control hens. Only one hen showed sciatic nerve degeneration. Livers from two hens given the highest dose of EPN manifested a moderate degree of hemosiderosis. Plasma cholin esterase was significantly inhibited in all surviving hens given EPN or TOCP at the end of the observation period. A group of hens treated daily with 0.01 mg/kg of EPN showed no abnormality in gait or behavior, and its plasma cholinesterase activity was not significantly different from that of the control. Hens treated with parathion had plasma cholinesterase activity comparable to that of the control 30 days after the administration of the last dose.