Four-day repeated inhalation and recovery study of methyl isocyanate in F344 rats and B6C3F1 mice.

F344 rats and B6C3F1 mice of both sexes were exposed by inhalation to 0, 1, and 3 ppm methyl isocyanate (MIC) for 4 consecutive days (6 hr/day) followed by a recovery period of 91 days. Five mice and rats/sex/group except the 3 ppm group (5 rats/sex on Day 7 and 2 males on Day 28) were killed on Days 7, 28, 49, and 91 after the exposure and examined histopathologically. Forty-nine of 56 male rats, 51 of 56 female rats, and 1 of 56 male mice in the 3 ppm group died by 28 days; early death animals were also examined histologically. Exposure-related changes occurred in rats and mice of both sexes in the 3 ppm group only. Lesions of the nasal cavity in rats and mice were characterized by regeneration of the olfactory and respiratory epithelia secondary to epithelial erosion. By Day 28 the olfactory and respiratory epithelia in mice appeared normal, while in rats incomplete regeneration of the olfactory epithelium was still present. Regeneration of the respiratory epithelium in the trachea of rats occurred in the 3 ppm group and the epithelium appeared to return to normal by Day 28. Lung lesions in rats consisted of mural and/or intraluminal fibrosis secondary to extensive erosion of the respiratory epithelium in the major bronchi to the terminal bronchioles. Acute inflammation of the small airways, occasional hyaline membranes of alveolar walls, and pulmonary atelectasis were also seen. Alveolar fibrosis was observed in rats found dead from Day 14 on and in male rats killed on Day 28. Atrophy of the thymus and spleen, atrial thrombosis of the heart, and hepatocellular necrosis were frequently seen in rats dying following MIC exposure. The lung lesions in mice were qualitatively similar to those in rats, but were restricted to the major bronchi. Minimal intraluminal or mural fibrosis was still present in mice on Day 91. In a separate study, a single 6-hr exposure of five male rats to 3 ppm MIC was followed by a recovery period of 7 days. The lesions of the respiratory system were essentially the same as those in the 3 ppm group killed on Day 7 after the 4-day repeated exposure of MIC, but the alveolar lesions were more severe.