Route-dependent comparative metabolism of [14C]toluene 2,4-diisocyanate and [14C]toluene 2,4-diamine in Fischer 344 rats.
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)
Timchalk
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Dow Chemical Company, Midland, Michigan 48674.
Smith
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FA
Bartels
M J
MJ
D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D001835:Body Weight; D002851:Chromatography, High Pressure Liquid; D008401:Gas Chromatography-Mass Spectrometry; D007275:Injections, Intravenous; D008297:Male; D010655:Phenylenediamines / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution; D014051:Toluene 2,4-Diisocyanate / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*
D010655:Phenylenediamines; D014051:Toluene 2,4-Diisocyanate; C010914:2,4-diaminotoluene