Disposition, elimination, and metabolism of tri-o-cresyl phosphate following daily oral administration in Fischer 344 male rats.
The disposition, elimination, and metabolism of 50 mg/kg (1.36 muCi/animal) of tri-o-cresyl [phenyl-U-14C] phosphate after ten daily oral doses was investigated in adult male Fischer 344 rats. Groups of three treated animals were killed at intervals of 24, 48, 72, and 96 h after the last administrations. Generally, the highest concentrations of radioactive material were excreted via the gastrointestinal tract and the bladder, particularly at the earlier time points. Liver, adipose, epididymis, sciatic nerve tissues; plasma; and red blood cells also contained high concentrations of radioactivity. The lowest concentrations were found in brain, spleen, testes, and heart. Four days after the last dose, the rats had excreted approximately all of the cumulative dose in either urine (63.1%) or feces (36.1%). TOCP and its metabolites in urine, feces, plasma, brain, testes, kidneys, and liver were analyzed by high-performance liquid chromatography and liquid scintillation. Metabolism studies performed 24, 48, 72, and 96 h after administration of the last dose showed that TOCP was the major compound identified in brain, testes, kidneys, plasma, and liver. Liver, additionally, had high levels of di-o-cresyl hydrogen phosphate and o-cresol. TOCP and o-cresol were the predominant compounds in feces; only trace amounts of TOCP were detected in urine. The major metabolites in urine were di-o-cresyl hydrogen phosphate, o-cresol, and o-hydroxy benzoic acid. Testes in rats given ten doses had significantly more TOCP and saligenin cyclic-o-tolyl phosphate than those from rats given a single dose. These results may account for testicular toxicity in rats given daily oral administrations of TOCP but not following a single oral dose.
Somkuti
S G
SG
Department of Pharmacology, Duke University Medical Center, Durham, NC 27710.
Abou-Donia
M B
MB
D000284:Administration, Oral; D000818:Animals; D002250:Carbon Radioisotopes; D002799:Cholinergic Fibers / Q000187:drug effects; D004334:Drug Administration Schedule; D008297:Male; D009420:Nervous System / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D013737:Testis / Q000187:drug effects; D014018:Tissue Distribution; D014317:Tritolyl Phosphates / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*
D002250:Carbon Radioisotopes; D014317:Tritolyl Phosphates; C025541:tri-o-cresyl phosphate