Metabolism, disposition, and mutagenicity of 2,6-diaminotoluene, a mutagenic noncarcinogen.
2,6-Diaminotoluene (2,6-DAT) is a major industrial chemical; approximately 100 million pounds are used annually in the synthesis of 2,6-toluene diisocyanate. 2,6-DAT is mutagenic in Salmonella typhimurium TA98 requiring metabolic activation, but has been previously shown to be a noncarcinogen in male and female F344 rats and male and female 86C3F1 mice dosed orally in 2-year bioassays. 2,6-DAT was rapidly and extensively absorbed following oral administration, indicating that its lack of carcinogenicity is not due to poor absorption from the gastrointestinal tract. 2,6-DAT was also rapidly excreted, with 85% of 2,6-DAT-associated radioactivity being recovered in the urine within 24 hr. Resolution of the urine by reverse phase HPLC demonstrated the presence of four metabolites, but none of the parent 2,6-DAT. Therefore, the lack of carcinogenicity of 2,6-DAT is not due to lack of biotransformation in vivo. Following separation by HPLC, the metabolites were analyzed by electron impact and fast atom bombardment mass spectroscopy and by NMR spectroscopy. The metabolites were identified as a) 3-hydroxy-2,6-DAT, b) 4-hydroxy-2-acetylamino-6-aminotoluene, c) 2-acetylamino-6-aminotoluene, and d) 2,6-di(acetylamino)-toluene. Metabolites b and d were found to be mutagenic in Salmonella typhimurium TA98 and then only in the presence of an activation system. Results of this study indicate that 2,6-DAT, which is a mutagen in in vitro tests, is also metabolized by the rat to compounds which are proximate mutagens.(ABSTRACT TRUNCATED AT 250 WORDS)
Cunningham
M L
ML
Systemic Toxicology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Burka
L T
LT
Matthews
H B
HB
D000818:Animals; D001711:Biotransformation; D005243:Feces / Q000032:analysis; D066298:In Vitro Techniques; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens; D010655:Phenylenediamines / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D014018:Tissue Distribution
D009153:Mutagens; D010655:Phenylenediamines; C025235:2,6-diaminotoluene