Absorption, distribution, metabolism and excretion of an inhalation dose of [14C] 4,4'-methylenediphenyl diisocyanate in the male rat.
The received dose, tissue distribution, metabolism, routes and rates of excretion of [(14)C]-4, 4(')-methylenediphenyl diisocyanate (MDI) were investigated in the male rat following a 6-h inhalation exposure to [(14)C]-MDI at a target concentration of 2 mg m(-3). The mean dose received was equivalent to 0.078 mg MDI per animal, of this between 25 and 32% of radiolabelled material was available systemically. Radioactivity was distributed to all tissues examined with the highest proportions present in the respiratory and gastrointestinal tracts, suggesting that both oral ingestion and pulmonary absorption contributed to the systemic dose of [(14)C]-MDI derived material, with the oral ingestion and the majority of the internal dose resulting from ingestion of radiolabelled material by grooming the pelt after exposure. Radioactivity was excreted mainly via faeces (about 80% of the received dose). Excretion in bile and urine each accounted for less than 15% of the dose. MDI was extensively metabolized after uptake, with two routes of transformation evident; the proposed spontaneous formation of mixed molecular weight polyureas and the enzyme catalysed metabolism of systemically available MDI or MDI derivatives to give N-acetylated and N-acetylated hydroxylated products. No free MDA was detected in any of the biomatrices (urine, faeces, bile) investigated.
Gledhill
A
A
Central Toxicology Laboratory, Alderley Park, UK. Alex.Gledhill@syngenta.com
Wake
A
A
Hext
P
P
Leibold
E
E
Shiotsuka
R
R
D000042:Absorption; D000284:Administration, Oral; D000393:Air Pollutants / Q000493:pharmacokinetics; D000818:Animals; D002250:Carbon Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics; D003485:Cyanates / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D041981:Gastrointestinal Tract / Q000378:metabolism*; D017953:Isocyanates; D008297:Male; D008657:Metabolic Clearance Rate; D009928:Organ Specificity; D051381:Rats; D017208:Rats, Wistar; D012137:Respiratory System / Q000378:metabolism*; D012588:Scintillation Counting; D014018:Tissue Distribution
D000393:Air Pollutants; D002250:Carbon Radioisotopes; D003485:Cyanates; D017953:Isocyanates; C059330:methylene diisocyanate