4,4'-methylenebis(2-chloroaniline) (MOCA): the effect of multiple oral administration, route, and phenobarbital induction on macromolecular adduct formation in the rat.
Cheever-KL; DeBord-DG; Swearengin-TF
Fundam Appl Toxicol 1991 Jan; 16(1):71-80
A study was conducted to quantitate tissue macromolecular adduct formation after induction of drug metabolizing enzymes or long term oral administration of 4,4'-methylenebis(2-chloroaniline) (101144) (MOCA), a model aromatic amine, in the rat. Male Sprague-Dawley- rats were administered carbon-14 (C-14) labeled MOCA at 28.1 micromole/kilogram (micromol/kg) daily for up to 28 days either by gavage at a constant 5 milliliters/kilogram volume of dosing solution or by intraperitoneal injection. The radioactivity present in tissue 24 hours after a single oral dose of 281 micromol/kg was highest in the rat liver with 15.3 picomoles/milligram (pmol/mg) liver. The kidney was second highest with 7.6pmol/mg kidney. The 28 day in-vivo MOCA albumin binding was significantly higher than the MOCA globin binding after repeated oral administration of the compound. However, the rate of accumulation of globin adducts was linear, whereas the formation of MOCA albumin adducts appeared to plateau after 14 days of exposure. The formation of MOCA globin adducts was seven to 12 fold lower after daily administration of 28.1micromol/kg doses for 10 days than after a single 281micromol/kg dose of MOCA. The results indicated that enzymatic induction by phenobarbital resulted in a significant increase in covalent binding of C-14 to globin after administration of C-14 labeled MOCA. After hydrolysis the macromolecular adduct cleavage product was the parent compound. In the rat the globin biological half life for adducted C- 14 labeled MOCA was far greater than that of albumin, suggesting the quantification of the globin MOCA adducts may provide a more valuable index of cumulative long term industrial exposure.
NIOSH-Author; Amines; Laboratory-animals; Anilines; Metabolic-study; Curing-agents; Carcinogens; Mutagens; Tissue-distribution; Dose-response
Fundamental and Applied Toxicology