Absorption, distribution, excretion and metabolism of a single oral dose of [14C]tri-o-cresyl phosphate (TOCP) in the male rat.
A single oral dose of 50 mg/kg of [14C]TOCP was administered in corn oil to male rats. Three animals were sacrificed at each of 2, 6 and 12 h and 1, 2 and 5 days following dosing, and tissues and excreta were analyzed for 14C. Within 5 days, 63 and 36% of the dose were recovered in the urine and feces, respectively. Initially, the highest concentrations of radioactivity were observed in the gastrointestinal tract, its contents, the urinary bladder, liver and kidneys. Appreciable concentrations of 14C were detected in plasma, red blood cells, lungs and adipose tissues, while neural tissues, muscle, spleen and testes contained lower concentrations of radioactivity. Among neural tissues, the sciatic nerve contained the highest concentrations of 14C at all time points studied. The concentration of TOCP in plasma was at maximum by 6 h then declined biexponentially with terminal half-life of 46 h. The predominant metabolites in plasma were o-cresyl dihydrogen phosphate, di-o-cresyl hydrogen phosphate and o-hydroxybenzoic acid (salicylic acid). Small concentrations of the neurotoxic metabolite of saligenin cyclic-o-tolyl phosphate, were detected in plasma at all but the last time point analyzed. Most of the radioactivity extracted from the livers of rats sacrificed at 2 and 4 h were metabolites. No TOCP was detected in the urine or feces collected within 3 days after dosing. The major metabolite in the urine and feces was o-cresyl dihydrogen phosphate followed by di-o-cresyl hydrogen phosphate, salicylic acid, o-hydroxybenzyl alcohol and o-cresol. This study supports the hypothesis that the insensitivity of the rat to TOCP-induced delayed neurotoxicity may be attributed, in part, to the disposition and metabolism of this chemical.
Abou-Donia, MB; Nomeir, AA; Bower, JH; Makkawy, HA
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