Methyl isocyanate subchronic vapor inhalation studies with Fischer 344 rats.

Groups of Fischer 344 rats were exposed to 3.1, 0.6, 0.15, or 0.0 (control) ppm of methyl isocyanate (MIC) vapor 6 hr per day for two 4-day sessions separated by a 2-day rest. There were no deaths during the study. The rats were killed the morning following the last exposure day. The 3.1-ppm-exposed rats had decreased body weight, food consumption, and blood oxygen saturation (males only). Increased hemoglobin concentration (males only) and lung weights were also observed in this group of rats. Multiple histologic lesions, limited to the respiratory tract, were observed in rats of the 3.1-ppm group only. The lesions consisted of necrosis, suppurative inflammation, squamous metaplasia, and intraluminal and submucosal fibroplasia (bronchi and bronchioles only) which extended from the anterior nasal cavity to the terminal bronchioles. In a second study, rats were exposed to 3.0 ppm MIC, 6 hr per day, for either one or two 4-day sessions and sacrificed on postexposure Days 1, 15, 43, and 85. All rats survived the 4- or 8-day exposure regimen, although significant decreases in body weight and encrustation of the eyes, nose, or mouth area were observed. During the first 15 days postexposure, male mortality was 63%; only 6% of the MIC-exposed females died. The cause of death was interpreted to be a combination of pulmonary vascular and inflammatory changes coupled with anorexia. For survivors, recovery from the necrotizing and irritating effects of MIC vapor was observed. Squamous metaplasia of respiratory epithelium, observed in rats sacrificed at the end of the exposure period, was replaced by tall pseudostratified columnar (regenerative) epithelium beginning in the bronchi and bronchioles as well as the distal trachea. Collagen maturation and condensation of the intraluminal and submucosal fibroplasia occurred during the postexposure period. The results of these investigations support the current threshold limit value for MIC of 0.02 ppm.