© 1994 Oxford University Press
research-article |
Acute, Subacute, and Subchronic Inhalation Toxicity Studies of Respirable Polymeric Methylene Diphenyl Diisocyanate (Polymeric MDI) Aerosol in Rats1
*TNO Toxicology and Nutrition Institute P O Box 360, 3700 AJ Zeist, The Netherlands
Institute of Industrial Toxicology Bayer A G.Wuppertal, Germany
Received April 15, 1992; accepted August 20, 1993
Short-term inhalation toxicity studies with respirable polymeric methylene diphenyl diisocyanate (polymeric MDI) aerosol were performed in rats. The 4-hr LC50 was found to be 490 mg polymeric MDI/m3 (95.5% <4.3 µm). Exposure of (4-week-old) rats to 0, 2.2, 4.9, or 13.6 mg polymeric MDI/m3 (95% < 5 µm) for 2 weeks resulted in mortality, severe growth retardation, and elevated lung weights at 13.6 mg/m3 at 4.9 mg/m3 slight growth retardation and slightly elevated lung weights were observed. A 13-week study with 6-week-old rats exposed to 0.35, 1.4, or 7.2 mg polymeric MDI/m3 (95% < 5 µm) revealed transient growth retardation and a slightly increased number of pulmonary alveolar macrophages occasionally accompanied by increased numbers of mononuclear cells and fibroblasts in alveolar septa only at 7.2 mg/ m3 In a second 2-week study with 4 or 6-week-old rats exposed to 14.1 mg polymeric MDI/m3 (95% < 5 µm), 4-week-old rats died earlier and in greater numbers than 6-week-old rats. In a second 13-week study with 6-week-old rats, using exposure concentrations of 0, 4.1, 8.4, and 12.3 mg polymeric MDI/ m3 (95% < 5 µm) and including a 4-week recovery period, 12.3 mg/ m3 induced mortality, growth retardation, severe respiratory distress, increased lung weights, degeneration and hyperplasia of the nasal epithelium, accumulations of macrophages in the lungs and mediastinal lymph nodes, and focal inflammatory changes in the lungs. Rats exposed to 8.4 mg/ m3 showed respiratory distress, lower body weights in males, increased lung weights, and similar, but much less severe, histopathological changes in the respiratory tract and mediastinal lymph nodes. Most of the histopathological changes seen at the higher concentrations were also seen at 4.1 mg/m3 but to a very minor degree and in a few rats only. At the end of the 4-week posttreatment period the microscopical changes in nose, lungs, and mediastinal lymph nodes were still present but generally to a much less degree than at the end of the exposure period. It was concluded that the dose-effect curve for repeated exposures of rats to respirable polymeric MDI is very steep, and that the "no-observed-adverse-effect level" of polymeric MDI was 1.4 mg/m3 the actual no-adverse-effect level being lower than but most probably very close to 4.1 mg/m3.