Route-Dependent Comparative Metabolism of [ 14C]Toluene 2,4-Diisocyanate and [ 14C]Toluene 2,4-Diamine in Fischer 344 Rats

Abstract

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 14CO 2. 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 ( t 1 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 μg eq 2,4-IDA, respectively. No free 2,4-IDA was detected in the urine specimen from the inhalation group. In comparison. 638 and 20 μg eq 2,4-IDA 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-IDA being formed. This suggests that the metabolic disposition of inhaled 2,4-TDI is quite different than the disposition observed following orally administered 2,4-TDI or iv and orally administered 2,4-TDA. The route-dependent differences in 2,4-TDI disposition and metabolism may explain why TDI was not carcinogenic in rodents following inhalation exposure.