ACUTE, SUBACUTE, AND SUBCHRONIC INHALATION TOXICITY STUDIES OF RESPIRABLE POLYMERIC METHYLENE DIPHENYL DIISOCYANATE (POLYMERIC MDI) AEROSOLIN RATS

Short-term inhalation toxicity studies with respirable polymeric methy lene diphenyl diisocyanate (polymeric MDI) aerosol were performed in r ats. The 4-hr LC50 was found to be 490 mg polymeric MDI/m(3) (95.5% < 4.3 mu m). Exposure of(4-week-old) rats to 0, 2.2, 4.9, or 13.6 mg pol ymeric MDI/m(3) (95% < 5 mu m) for 2 weeks resulted in mortality, seve re growth retardation, and elevated lung weights at 13.6 mg/m(3); at 4 .9 mg/m(3) slight growth retardation and slightly elevated lung weight s were observed. A 13-week study with 6-week-old rats exposed to 0.35, 1.4, or 7.2 mg polymeric MDI/m(3) (95% < 5 mu m) revealed transient g rowth retardation and a slightly increased number of pulmonary alveola r macrophages occasionally accompanied by increased numbers of mononuc lear cells and fibroblasts in alveolar septa only at 7.2 mg/m(3). In a second 2-week study with 4- or 6-week-old rats exposed to 14.1 mg pol ymeric MDI/m(3) (95% < 5 mu m), 4-week-old rats died earlier and in gr eater numbers than 6-week-old rats. In a second 13-week study with 6-w eek-old rats, using exposure concentrations of 0, 4.1, 8.4, and 12.3 m g polymeric MDI/m(3) (95% < 5 mu m) and including a 4-week recovery pe riod, 12.3 mg/m(3) induced mortality, growth retardation, severe respi ratory 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/m(3) showed respiratory distress, lower body w eights in males, increased lung weights, and similar, but much less se vere, histopathological changes in the respiratory tract and mediastin al lymph nodes. Most of the histopathological changes seen at the high er concentrations were also seen at 4.1 mg/m(3) but to a very minor de gree and in a few rats only. At the end of the 4-week posttreatment pe riod the microscopical changes in nose, lungs, and mediastinal lymph n odes were still present but generally to a much less degree than at th e end of the exposure period. It was concluded that the dose-effect cu rve 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/m(3), the actual no-adverse-effect level being lower t han but most probably very close to 4.1 mg/m(3). (C) 1994 Society of T oxicology.