Studies on the metabolism of the neurotoxic tri- o-cresyl phosphate. Distribution, excretion, and metabolism in male cats after a single, dermal application

Abstract

The metabolism of a single, dermal dose of 50 mg/kg of [ 14 C] tri-o- cresyl phosphate (TOCP) was studied in male rats. TOCP was applied to an unprotected, preclipped area on the back of the neck. Three animals were sacrificed on each of 0.5, 1, 2, 5 and 10 days following application. Radioactivity disappeared biexopentially from the dosing site with a faster initial rate; 73% of the dose disappeared in the first 12 h followed by a slower phase with a half-life of 2.03 days. No radioactivity was detected in the expired air. TOCP was absorbed from the skin and subsequently distributed throughout the body. Generally, the highest concentrations of radioactivity were associated with bile, gall bladder, urinary bladder, kidneys, and liver; the lowest were found in the neural tissues, muscle, and spleen. Within the 10-day experimental period, approximately 28% and 20% of the applied dose were recovered in the urine and feces, respectively. TOCP and its metabolites in the urine, feces, bile, and plasma were analyzed by high performance liquid chromatography and liquid scintillation counting. TOCP was the predominant compound in the feces (26.3% of total fecal radioactivity); it was detected in a smaller percentage in the urine (2.3% of total urinary radioactivity). The major metabolite in the urine was o-cresol followed by di- o-cresyl hydrogen phosphate and o-cresyl dihydrogen phosphate; in the feces di- o-cresyl hydrogen phosphate was the predominant metabolite followed by o-cresyl dihydrogen phosphate. Trace amounts of saligenin cyclic- o-tolyl phosphate, hydroxymethyl, and di(hydroxymethyl) TOCP were also detected in the urine and feces. Other metabolites identified in the urine and feces were the stepwise oxidation products of the methyl group of o-cresol. Unlike the feces, the bile contained mostly metabolites with only trace amounts of TOCP detected at 12 h and 24 h following application. o-Cresyl dihydrogen phosphate and di- o-cresyl hydrogen phosphate were the prevalent metabolites in the bile and plasma. While di(hydroxymethyl) TOCP was present in trace amounts in plasma, an appreciable amount of saligenin cyclic- o-tolyl phosphate, believed to be the active neurotoxic metabolite, was detected. This study shows that skin is an important port of entry for TOCP. Since TOCP represents organophosphorous chemicals capable of producing delayed neurotoxicity in test animals and in humans, it is essential that industrial hygiene control prevents skin contamination of workers handling these chemicals.