Subacute toxicity of methylene-bis-(2,6-diisopropylaniline) in the rat and hamster.

Methylene-bis-2,6-diisopropylaniline (MDPA), a chemical having potential application as a polyurethane chain extender or an epoxy curing agent, was administered daily by gavage to male Fischer 344 rats and male Syrian golden FVG hamsters. Rats were administered MDPA at 10.5, 21.0, 42.0, 63.0, or 87.5 mg/kg in corn oil for 5, 10, or 28 d. Hamsters received 87.5 or 875 mg MDPA/kg daily for the same periods. Histopathologic evaluation of rat tissue showed diffuse vacuolar change and periacinar vacuolar degeneration of the livers, with congestion, hemosiderosis, and hematopoiesis in the spleen. Hepatic periacinar vacuolar degeneration decreased in incidence and severity from d 5 to d 28, and livers of rats sacrificed 28 d after cessation of MDPA treatment (d 56) were normal. Hepatic vacuolar change was characterized by lipid inclusions. Electron microscopic evaluation found no structural abnormalities in hepatocytes with a moderate level of lipid vacuolization, while degeneration was seen in cells with extensive vacuolization. Stage III, stage IV, and maximal respiratory rates of mitochondria isolated from livers of test animals were higher than age-matched controls after 28 d treatment. At the high dose (875 mg/kg), MDPA produced liver lesions consisting of periacinar vacuolar change, vacuolar degeneration, hepatocytic swelling, and necrosis in hamsters. The high dose also produced acute toxic tubular nephrosis and a high mortality rate. At a dose (87.5 mg/kg) equuimolar to the high dose in the rat, however, the only lesion observed in the hamster was periacinar vacuolar change. In summary, the degenerative hepatic lesion produced in liver decreased in incidence with continued administration, and higher doses were required to produce this lesion in the hamster than in the rat.