Route-Dependent Comparative Metabolism of [14C]Toluene 2,4-Diisocyanate and [14C]Toluene 2,4-Diamine in Fischer 344 Rats
| Autor: | C. Timchalk, F A Smith, Michael J. Bartels |
|---|---|
| Rok vydání: | 1994 |
| Předmět: |
Male
Administration Oral Urine Phenylenediamines Toxicology Gas Chromatography-Mass Spectrometry Excretion Route of administration Pharmacokinetics Oral administration Administration Inhalation Animals Organic chemistry Toxicokinetics Tissue Distribution Chromatography High Pressure Liquid Pharmacology Inhalation exposure Chromatography Inhalation Chemistry Body Weight Rats Inbred F344 Rats Injections Intravenous Toluene 2 4-Diisocyanate |
| Zdroj: | Toxicology and Applied Pharmacology. 124:181-190 |
| ISSN: | 0041-008X |
| DOI: | 10.1006/taap.1994.1022 |
| Popis: | This study was initiated to evaluate the pharmacokinetics/metabolism of 14C-labeled toluene 2,4-diisocyanate (2,4-[14C]-TDI) following oral and inhalation exposure in the rat. For comparison, the pharmacokinetics/metabolism of toluene 2,4-diamine (2,4-[14C]TDA) was also evaluated. Groups of 3 or 4 male rats were given either a single 60 mg/kg oral dose of 2,4-[14C]-TDI or were exposed to 2,4-[14C]TDI vapors at a target concentration of 2 ppm for a 4-hr period. Additional groups of male rats were given single 3 or 60 mg/kg oral doses or a single 3 mg/kg intravenous (iv) dose of 2,4-[14C]TDA. All rats were euthanized by 48 hr postexposure. Following oral administration of 2,4-[14C]TDI, > 93% of the administered radioactivity was recovered in the urine, feces, cage wash, and tissues. Approximately 8% of the oral dose was excreted in the urine while 81% was eliminated in the feces. It is estimated that during inhalation exposure, essentially all of the inhaled 2,4-[14C]TDI was retained by the animal. At 48 hr post-inhalation exposure approximately 15 and 47% of the recovered radioactivity was in the urine and feces, respectively. Following oral or inhalation exposure to 2,4-[14C]TDI, no radioactivity was eliminated as either expired 14C organics or 14CO2. Comparison of the 2,4-[14C]TDI inhalation group with the oral 2,4-[14C]TDI and 2,4-[14C]TDA treatment groups indicated that a larger percentage of the inhaled radioactivity was in the tissues/carcass (34% vs 2-4%) and the excretion of radioactivity into the urine was slower (t1/2 = 20 hr vs 5-8 hr) following TDI inhalation. The total amount of free+acetylated TDA metabolites detected in the urine specimens (0-12 hr) following oral and inhalation exposure to 2,4-[14C]TDI was 15 and 0.26 microgram eq 2,4-TDA, respectively. No free 2,4-TDA was detected in the urine specimen from the inhalation group. In comparison, 638 and 20 micrograms eq 2,4-TDA was detected in the urine specimen after oral administration of 60 and 3 mg/kg 2,4-[14C]TDA, respectively. Following 2,4-[14C]TDI inhalation and oral exposure approximately 90 and 65% of the quantitated urinary metabolites existed as acid-labile conjugates, respectively. In contrast, only 16-39% of the quantitated urinary metabolites existed as acid-labile conjugates following oral administration of 2,4-[14C]TDA. Inhalation exposure to 2,4-TDI primarily results in the formation of acid-labile conjugates with little or no 2,4-TDA being formed.(ABSTRACT TRUNCATED AT 400 WORDS) |
| Databáze: | OpenAIRE |
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