ToxSci Advance Access originally published online on August 12, 2003
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Toxicological Sciences 76, 51-64 (2003)
Copyright © 2003 by the Society of Toxicology
BIOTRANSFORMATION AND TOXICOKINETICS |
Kinetics of Monochloroacetic Acid at Subtoxic and Toxic Doses in Rats after Single Oral and Dermal Administrations
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* Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, and
Section of Environmental Toxicology, GSF-Institut für Toxikologie, Neuherberg, Germany
Rats were administered a single oral (10 [subtoxic] or 225 [toxic, LD20] mg/kg) or dermal (125 mg/kg, LD20) dose of 14C-monochloroacetic acid (MCA) and the time-course (0.25, 0.75, 2, 4, 8, 16, and 32 h postadministration) of radioactivity determined in plasma, tissues, and excreta. At the subtoxic oral dose, concentration of 14C-MCA peaked at 0.1% of dose by 2 h. Most tissue profiles of MCA paralleled that of plasma with few exceptions. At the toxic oral dose, tissue concentrations remained initially below those seen after the subtoxic dose, because stomach retained most of the toxic dose for up to 8 h. Peak plasma concentration was reached within 0.25 h without an apparent subsequent uptake phase. Most of the dermal dose rapidly penetrated into the skin (>95% within 0.25 h) and remained sequestered there and released slowly. Concentration in plasma peaked at 0.36% of dose by 0.75 h and remained constant for up to 4 h. Peak tissue concentrations were reached between 2 and 4 h. Within 0.75 h, 9% of the dermally absorbed dose was metabolized by liver and eliminated through bile, all of which was subsequently reabsorbed. Two percent of MCA appeared in colon by 0.75 h, apparently as a result of direct transport through GI-wall in retrograde movement. About 70–80% of radioactivity recovered from the small intestine of orally dosed rats was parent compound. Fecal elimination was negligible (
1%). Urinary excretion was 64–72% of the dose. At the toxic oral dose, urinary excretion was initially slow and accelerated after 8 h. The plasma half-life was 2 h for oral and 4 h for dermal administration. Differential oral low and high dose kinetics was due to delayed stomach emptying and not to saturation of metabolic pathways. Dose-responses were steep, with no overt toxicity (coma/death) up to 200 (oral) and 100 (dermal) mg/kg, whereas 100% mortality occurred at 450 (LD50 > 400 and < 450) and 175 (LD50 145) mg/kg after oral and dermal exposure, respectively.
Key Words: chloroacetic acid; chloroacetate; oral toxicity; dermal toxicity; low dose kinetics; high dose kinetics; oral absorption and sequestration; dermal absorption and sequestration; therapeutic inferences.
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