||A combined reproductive/developm ental/neurotoxicity study was conducted with 1,6-Hexamethylene diisocyanate (HDI) in the Sprague-Dawley rat. Specifically, 120 rats (15 sex/dose group) were exposed, via whole-body exposure, to either 0, 0.005, 0.050, or 0.300 ppm HDI for 6 hours/day during a 14-day premating phase, up to a 14-day mating phase, and a 21-day gestation phase. Following the gestation phase the dams were transferred to nesting cages and permitted to deliver. The dams and their litters were maintained for a 4-day lactation phase during which exposure to HDI was discontinued. Neurotoxicity evaluations were conducted on 10 animals/sex/dose group prior to exposure and following the premating phase. Prior to termination, neurotoxicity evaluations were conducted on the 10 males/group which had previously been tested, and those females which had been previously tested and had delivered pups (10/control, 8/level 1, 9/Ievel II, and 8/level III). The neurotoxicity examinations included a functional observation battery as well as the assessment of motor and locomotor activity. Body weight and clinical observations were recorded throughout the study. Following the mating phase (males) and on lactation day 4 (females and pups) the animals were sacrificed and a gross necropsy was performed. Tissues retained for microscopic examination from all adult animals included thereproductive organs, nasal turbinates (multiple sections), trachea, larynx, and lung. In those animals that underwent the final neurotoxicity testing, blood was taken for hematology and clinical chemistry evaluation and additional tissues were retained for microscopic examination, including the brain, spinal cord, stomach, small and large intestines, liver, kidneys, adrenals, spleen, heart, thymus, urinary bladder, lymph nodes, peripheral nerve, and a section ofbone marrow. With the exception of the tissues from the respiratory tract, for which all females from all dose groups were examined, the remaining tissues were initially examined in the control and high-dose groups. In addition to the endpoints noted above, the animals were evaluated for the effect of the test compound on mating, fertility, gestation length, litter size, pup sex ratio, and pup viability.