The pharmacokinetics and placental transfer of a single intravenous dose of 5.0 mg/kg (10 micro Ci/kg) ring-labeled [(14)C]chlorpyrifos were investigated in pregnant Sprague-Dawley rats at 11-13 days of gestation. Three rats were killed at 5, 15 or 30 min, or 1, 2, 4, 8, 12, 18, 24, 36, 48, 72 or 96 h after dosing. Radioactivity and 3,5,6-trichloropyridinol (TCP) were detected in all tissues 5 min after dosing. Chlorpyrifos was only found in maternal plasma and liver. Peak maternal plasma concentration of radioactivity ( micro g chlorpyrifos equivalents/ml) was 157 at 5 min, compared with 1.9 for fetal plasma at 15 min. The maximum concentrations of radioactivity ( micro g chlorpyrifos equivalents/g), detected in most tissues within 12 h of dosing, were, in descending order: liver (30), brain (29), placenta (21), and fetus (2). All peaks occurred at 5 min except for fetus and fetal plasma, which were at 15 min. TCP was detected by HPLC as the major compound identified in plasma and tissues. The maximum concentration detected was in plasma, at 12.4 micro g/ml, and for the following tissues was: liver 4.3 ng/g fresh tissue, fetus 4 ng/g, placenta 2.97 ng/g, brain 1.68 ng/g, and fetal plasma 0.52 ng/g. All TCP peaks occurred at 5 min except for fetus at 30 min and fetal plasma at 15 min. Parent chlorpyrifos was detected in maternal plasma and liver at maximum concentrations of 5.1 micro g/ml and 0.40 micro g/g, respectively, at 5 min. Chlorpyrifos was detectable in maternal plasma up to 36 h after dosing, and in liver up to 24 h after dosing. Pharmacokinetic analysis best described radioactivity, chlorpyrifos, and TCP as disappearing biexponentially from plasma and tissues. The terminal elimination half-lives of radioactivity, chlorpyrifos and TCP from maternal plasma were 16, 18, and 16 h, respectively. The results indicate that (1). chlorpyrifos undergoes a rapid metabolism to its major metabolites (TCP); (2). chlorpyrifos and its metabolites are distributed to all maternal and fetal tissues and plasma; and (3). the elimination of chlorpyrifos and TCP is slow, with redistribution from lipid stores a likely determinant of elimination rates.
The toxicokinetics and metabolism of a single 1 mg (2.7 muCi/kg) oral dose of uniformly phenyl-labeled [14C]EPN (O-ethyl O-4-nitrophenyl [14C]phenylphosphonothioate) have been studied in 1-week old chicks. One control and three treated chicks were killed at each of the following time intervals: 0.5, 2, 4, 8, and 12 days. Radioactivity was rapidly absorbed from the gastrointestinal tract and distributed in all tissues. 14C in tissues reached a peak of 16.9% of the dose after 0.5 day and decreased to 0.6% at 4 days. The tissues of the gastrointestinal tract had the highest concentration of radioactivity, followed by bile and liver. Among nervous tissues, concentration of the 14C was highest in the peripheral nerves. The spinal cord had the next highest concentration, while the brain had the least. After 4 days 91.3% of the 14C had been eliminated in the combined urinary-fecal excreta. By the end of the 12-day experiment this percentage reached 93.1%. No 14C was detected in the expired CO2. Following the oral administration of [14C]EPN, a monophasic body level curve was observed. The half-life for the elimination of 14C from chick body was 16 h, corresponding to a rate constant of 0.04 h -1. Most of the excreted 14C materials were identified as O-ethyl phenylphosphonic acid, phenylphosphonic acid, and O-ethyl phenylphosphonothioic acid.
The absorption, distribution, elimination, and metabolism of the insecticide O-ethyl O-4-nitrophenyl phenylphosphonothionate (EPN) were studied in the hen. A daily dermal dose of 0.5 mg/kg (0.56 μCi/dose) of [14C]EPN (O-ethyl O-4-nitrophenyl [14C] phenylphosphonothioate) was applied for 10 consecutive days to hens. Three treated hens were killed at each of the following time intervals: 1,5,10, and 15 days after the administration of the last dose. A total of 65% of the cumulative dose was excreted in the combined urinary and fecal excrement 15 days after the last dose. Small amounts of radioactivity were deposited in the egg yolk (0.8%) and the egg albumen (0.3%). No 14C02 was detected in the expired air. Radioactivity in the tissues reached a peak of 12% of the total administered dose one day after the last dose; 14C decreased to 1.5% of the total dose (12% of the peak value) 15 days after the administration of the last. dose. The concentration of radioactivity was highest in the liver, followed by the kidney, gall bladder, bile, small intestine, ceca, large intestine, and skin. Relatively low concentrations of 14C were detected in the central and peripheral nervous tissues. O-Ethyl phenylphosphonic acid (EPPA) was identified as the major urinary-fecal metabolite followed by phenylphosphonic acid (PPA) and O-ethyl phenylphosphonothioic acid (EPPTA). EPN accounted for most of the radioactivity in tissues except in the liver. In this tissue most of the radioactivity was identified as EPPA, EPPTA, and PPA.
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