A combined reproduction, neonatal development, and neurotoxicity study with 1,6-hexamethylene diisocyanate (HDI) in...

1,6-Hexamethylene diisocyanate (HDI), a chemical widely used in commercial polyurethane products, was evaluated in a combined reproductive/developmental/neurotoxicity study. Sprague-Dawley rats (n = 120; 15 per sex/dose group) were administered via whole-body inhalation exposure either 0, 0.005, 0.05, or 0.3 ppm HDI for 6 h/day during a 14-day premating phase, up to a 14-day mating phase, and a 21-day gestation phase. The dams and their litters were maintained for a 4-day lactation phase during which exposure to HDI was discontinued. Neurobehavioral testing (automated measures of activity and a functional observational battery) was conducted before exposure, after the premating phase, and before termination. Body weight and clinical observations were recorded throughout the study. Terminal examinations included a gross necropsy, hematology, and clinical chemistry. Tissues retained for microscopic examination included the reproductive organs, neural tissues, nasal turbinates (multiple sections), trachea, larynx, and lung. The animals were also evaluated for effects on mating, fertility, gestation length, litter size, pup sex ratio, and pup viability. In the 0.300 ppm dose group a statistically significant decrease in body weight was observed in the females on day 4 of the study. Also observed at this dose level, in both males and females, were microscopic alterations in the nasal cavity, primarily epithelial hyperplasia, squamous metaplasia, chronic-active inflammation, and more seriously, degeneration of the olfactory epithelium. Similar microscopic effects were also observed, albeit to a lesser extent, in the males and females of the 0.05 ppm dose level. No histopathologic effects were observed in the 0.005 ppm dose level. No effects on any reproductive or neurotoxicologic parameters, hematology, clinical chemistry, or any effects on pup growth and development were observed at any exposure level.