Acute, Subacute, and Subchronic Inhalation Toxicity Studies of Respirable Polymeric Methylene Diphenyl Diisocyanate (Polymeric MDI) Aerosol in Rats

Short-term inhalation toxicity studies with respirable polymericmethylene diphenyl diisocyanate (polymeric MDI) aerosol wereperformed in rats. The 4-hr LC50 was found to be 490 mg polymericMDI/m³ (95.5% <4.3 µm). Exposure of (4-week-old) ratsto 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 slightgrowth retardation and slightly elevated lung weights were observed.A 13-week study with 6-week-old rats exposed to 0.35, 1.4, or7.2 mg polymeric MDI/m³ (95% < 5 µm) revealed transientgrowth retardation and a slightly increased number of pulmonaryalveolar macrophages occasionally accompanied by increased numbersof mononuclear cells and fibroblasts in alveolar septa onlyat 7.2 mg/ m³ In a second 2-week study with 4 or 6-week-oldrats exposed to 14.1 mg polymeric MDI/m³ (95% < 5 µm),4-week-old rats died earlier and in greater numbers than 6-week-oldrats. In a second 13-week study with 6-week-old rats, usingexposure concentrations of 0, 4.1, 8.4, and 12.3 mg polymericMDI/ m³ (95% < 5 µm) and including a 4-week recoveryperiod, 12.3 mg/ m³ induced mortality, growth retardation, severerespiratory distress, increased lung weights, degeneration andhyperplasia of the nasal epithelium, accumulations of macrophagesin the lungs and mediastinal lymph nodes, and focal inflammatorychanges in the lungs. Rats exposed to 8.4 mg/ m³ showed respiratorydistress, lower body weights in males, increased lung weights,and similar, but much less severe, histopathological changesin the respiratory tract and mediastinal lymph nodes. Most ofthe histopathological changes seen at the higher concentrationswere also seen at 4.1 mg/m³ but to a very minor degree and ina few rats only. At the end of the 4-week posttreatment periodthe microscopical changes in nose, lungs, and mediastinal lymphnodes were still present but generally to a much less degreethan at the end of the exposure period. It was concluded thatthe dose-effect curve for repeated exposures of rats to respirablepolymeric MDI is very steep, and that the "no-observed-adverse-effectlevel" of polymeric MDI was 1.4 mg/m³ the actual no-adverse-effectlevel being lower than but most probably very close to 4.1 mg/m³.     

Chronic Inhalation Toxicity and Carcinogenicity Study of Respirable Polymeric Methylene Diphenyl Diisocyanate (Polymeric MDI) Aerosol in Rats

Four groups of 60 Wistar rats of each sex were exposed by inhalationto 0, 0.2, 1.0, or 6.0 mg/m³ respirable polymeric methylenediphenyl diisocyanate (polymeric MDI) aerosol (93.5% < 4.2µm)for 6 hr a day, 5 days a week for up to 24 months. In addition,satellite groups of 10 rats/sex/group received the same treatmentfor 12 months. There was no adverse effect on general health,survival, body weight, or hematological or clinical chemistryparameters. Lung weights were increased in both males and femalesexposed to 6.0 mg polymeric MDI/m³ for 12 or 24 months. Grossexamination at autopsy of males exposed to 6.0 mg polymericMDI/m³ for 24 months revealed an increased incidence of spottedand discolored lungs. Increased incidences of degeneration andbasal cell hyperplasia of the nasal olfactory epithelium, oftenaccompanied by hyperplasia of Bowman's glands, were found inthe 1.0 and 6.0 mg/m³ groups. Light and electron microscopicstudies of the lungs revealed accumulations of alveolar macrophagescontaining polymeric MDI-associated refractile yellowish materialat the level of the alveolar duct in all exposed groups. Alveolarduct epithelialization as well as fibrosis of tissues surroundingthe macro phage accumulations occurred at the 1.0 and 6.0 mg/m³exposure levels. In addition, increased incidences of calcareousdeposits and localized alveolar bronchiolization were seen inthe 6.0 mg/m³ group. Moreover, eight pulmonary adenomas (sixin males and two in females) and one pulmonary adenocarcinoma(in a male) were observed in the 6.0 mg/m³ exposure group. Thetime sequence of the spectrum of pulmonary changes indicatesthat recurrent alveolar wall damage by polymeric MDI and/orpolymeric MDI-containing alveolar macrophages leads to alveolarbronchiolization and ultimately to bronchioloalveolar tumors.No lung tumors were found in the lower concentration groupsand in the control group. The incidence and distribution ofother types of tumors were not influenced by polymeric MDI.It was concluded that in the present study, the "no-observed-adverse-effectlevel" of polymeric MDI was 0.2 mg/m³ and that chronic exposureto polymeric MDI at a level of 6.0 mg/m³ was related to theoccurrence of pulmonary tumors. It was also concluded that exposureto polymeric MDI at concentrations not leading to recurrentlung tissue damage will not produce pulmonary tumors.