SUBCHRONIC INHALATION TOXICITY STUDY OF CAPROLACTAM (WITH A 4-WEEK RECOVERY) IN THE RAT VIA WHOLE-BODY EXPOSURES

This study was designed to assess the potential subchronic inhalation toxicity of caprolactam when administered as a 3-mu m aerosol from an aqueous solution to Sprague-Dawley CD rats (10/sex/group) via whole-bo dy exposure. The study was enhanced with the inclusion of motor activi ty measurements and a functional observational battery to assess the n eurotoxic potential of caprolactam. The rats were exposed at least 65 times over a 13-week period for 6 h per day, 5 days per week, to targe t concentrations (3 mu m, mass median aerodynamic diameter) of 0, 25, 75, and 250 milligrams per cubic meter (mg/m(3)). An additional 10 ani mals/sex/group were similarly exposed and then held for a 4-week recov ery period. Exposure levels were determined gravimetrically six times daily; one daily sample was analyzed by high-pressure liquid chromatog raphy, No deaths were observed in the study during the exposure or rec overy periods. Treatment-related responses such as labored breathing a nd nasal discharge were seen during many of the exposures. Similar res ponses as well as moist rales were seen during the nonexposure periods during the 13 weeks of exposure. However, these responses abated duri ng the 4-week recovery period. There were no clearly treatment-related responses observed with ophthalmoscopic examinations, body weight mea surements, food consumption measurements, neurobehavioral evaluations, clinical pathology evaluations, organ weight measurements, or macrosc opic pathology examinations. Microscopic findings that were considered related to exposure to the test material were seen in the nasoturbina l tissues (hypertrophy/hyperplasia of goblet cells in the respiratory mucosa and intracytoplasmic eosinophilic material in epithelial cells of the olfactory mucosa) of the two higher-exposure group animals and in the laryngeal tissues (squamous/squamoid meta-plasia/hyperplasia of the pseudostratified columnar epithelium covering the ventral seromuc ous gland) of all three exposure group animals. These changes were con sidered to be adaptive responses to an irritant (caprolactam). The ker atinization of the metaplastic epithelium in the larynx was considered to be an adverse effect. By the end of the 4-week recovery period, th ere was complete regression of the keratinization in the larynx, but r ecovery of the adaptive nasoturbinal effects had not completely resolv ed. In conclusion, the whole-body exposure of Sprague-Dawley rats to c aprolactam as a respirable aerosol for 6 h/day, 5 days/week, for 13 we eks at gravimetrically determined levels of 24, 70, and 243 mg/m(3) re sulted in respiratory tract effects (laryngeal) at the highest exposur e level with complete recovery within 4 weeks postexposure, The result s indicate that the no-observed-adverse-effect level for caprolactam i s 70 mg/m(3), based on upper respiratory effects, with 243 mg/m3 repre senting a no-observed-effect level for systemic toxicity, neurotoxicit y, and lower respiratory tract effects. (C) 1998 Society of Toxicology .