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HYDROFLUOROCARBON-236FA 18 the dogs prevented full evaluation of the cardiac effects of HFC-236fa. The results of this study provided evidence that HFC-236fa might cause cardiac sensitization (including a fatality) in dogs following 5-min exposures to concentrations at or above 150,000 ppm. Under the conditions of this study, 100,000 ppm may be considered a NOAEL. Subchronic Toxicity Available data indicate that HFC-236fa is also of low toxicity following intermittent, subchronic exposure. Smith et al. (1997) reported on a subchronic toxicity study in which groups of five male and five female rats were exposed (nose only) to HFC-236fa at 50,000 ppm for 6 hr per day for 5 consecutive days. The rats were observed for an additional 14 days. Although some rats reportedly exhibited signs of respiratory-tract irritation, no gross clinical abnormalities or gross pathological correlates were observed. Under the conditions of this study, the 50,000-ppm exposure may be considered a NOAEL. In a 2-week whole-body inhalation exposure study, groups of five male and five female young adult rats were exposed to HFC-236fa (purity >99.9%) at target concentrations of 0, 5,000, 20,000, or 50,000 ppm for 6 hr per day, 5 days per week for 2 weeks (Valentine 1995). The control group was exposed to clean air only. Mean airflow in the 350 L chamber was approximately 64 L/min over the duration of the experiment, and oxygen was maintained at approximately 19%. Temperature and relative humidity were maintained at acceptable levels. Analytical concentrations varied only slightly (±10%) from the target values. No rats died during the course of the exposure, and there were no significant changes in body weight that could be attributed to the HFC exposure. Alerting response (response to a sudden auditory stimulus) was abolished or diminished in all the rats in the 50,000-ppm group on test days 1 and 2. By test days 3 and 4, alerting responses had returned to normal or near-normal in these rats. Throughout the remainder of the test period, rats in the 50,000-ppm group exhibited only transient decrements in alerting responses (observed in only one of three observation intervals for each exposure). With the exception of transient decrements in the 20,000-ppm group on test days 1 and 2, normal alerting responses were observed in all the rats in all the groups during the actual exposure period. With the exception of one rat in the highest-exposure group, normal alerting response was observed at 30-50 min after the daily exposure, indicating that any decrements observed
HYDROFLUOROCARBON-236FA 19 were quickly reversible, although considered exposure related. On the basis of these findings, the NOAEL for decrement in alerting response was 5,000 ppm. Clinical pathological evaluations revealed no exposure-related, toxicologically relevant findings immediately after the last exposure. A 60% decrease in hepatic β-oxidation was detected in male rats in the 50,000-ppm group, but there were no gross or histopathological correlates suggesting peroxisome proliferation. Under the conditions of this study, 5,000 ppm may be considered a NOAEL and 20,000 ppm a LOAEL; the latter is based on diminution of alerting response. Valentine (1996) also reported a 90-day whole-body inhalation study of HFC-236fa. In this study, groups of 10 male and 10 female rats were exposed to HFC-236fa at nominal concentrations of 0, 5,000, 20,000, or 50,000 ppm (analytical concentrations were 0, 4,980, 20,000, and 50,300 ppm, respectively) for 6 hr per day, 5 days per week for 14 weeks. Two additional groups of 10 male rats were added on day 50 for assessment of peroxisomal and mitochondrial β-oxidation activity. One group served as a control group, and the other was exposed as previously described to HFC-236fa at 50,000 ppm for 2 weeks. Five rats from each of these two groups were sacrificed immediately after exposure, and all remaining rats were sacrificed after a 2-week post- exposure period. Environmental and air-flow conditions in the 350-L chamber were as described for the 2-week study. Although minor excursions of temperature and humidity beyond the desired ranges occurred, they were not great as to compromise the validity of the study results. No rats died as a result of exposure to the test article, and there were no significant and sustained changes in body weights of exposed rats. Although varied, nonspecific clinical signs (alopecia, ocular and nasal discharges, and staining) were observed in some rats in most groups immediately before or after the exposure sessions, these observations were of inconsistent occurrence and considered to be spurious. Rats exposed at 5,000 or 20,000 ppm exhibited normal alerting responses. On study day 1, most rats in the 50,000-ppm group exhibited a diminished response. During the first 2 weeks of the study, one to three rats in the 50,000-ppm group exhibited a diminished alerting response that was generally limited to the last 2 hr of the daily exposure period, and that was reversible within 30 to 50 min following cessation of exposure. By study day 18, rats in the 50,000-ppm group were no longer exhibiting any alterations in alerting response. Clinical chemistry evaluations revealed significant decreases in serum cholesterol of males in the 50,000-ppm group and significant decreases in serum triglycerides in males in all the exposure groups and in females in the
