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HYDROFLUOROCARBON-404A 62 inhaler via an oropharyngeal tube. Except for signs of anxiety that were attributed to the delivery systems, there were no exposure-related clinical signs or effects on body weights, food consumption, eye, heart function, respiratory rate, pulse rate, clinical pathology, organ weights, or tissue histopathology. Reproductive and Developmental Toxicity In 1996, the NRC evaluated several inhalation toxicity studies (Hodge et al. 1979a; Lu and Staples 1981; Wickramaratne 1989a,b) conducted in animals to examine the reproductive and developmental effects of HFC-134a. In studies of pregnant rats exposed to HFC-134a during days 6-15 of gestation, NOAELs for maternal toxicity were 30,000 ppm (Lu and Staples 1981) and 50,000 ppm (Hodge et al. 1979a). A LOAEL of 100,000 ppm was identified for maternal toxicity, which included reduced responses to noise stimuli and uncoordinated movements (Lu and Staples 1981). With respect to fetal toxicity in rats, significant reductions in fetal body weight and slightly delayed skeletal ossification were observed at 50,000 ppm in one study (Hodge et al. 1979a); in another study, significant reductions in fetal body weight and significant increases in several skeletal variations were observed at 300,000 ppm but not at 100,000 ppm. In a study with rabbits exposed to HFC-134a during gestation, there was no evidence of maternal toxicity at 2,500 ppm, but statistically significant reductions in food consumption and body-weight gain were observed at 10,000 ppm (Wickramaratne 1989a,b). No fetal toxicity was observed in rabbits exposed to HFC-134a at 10,000 ppm. Additional reproductive and developmental toxicity studies have been published. In a study by Collins et al. (1995), groups of 28 pregnant rabbits were exposed to HFC-134a at concentrations of 0, 2,500, 10,000, or 40,000 ppm for 6 hr per day on days 7-19 of pregnancy. The rate of body-weight gain in the groups exposed to HFC-134a at 10,000 ppm and 40,000 ppm was lower than that in the controls, but the reduction was partially compensated for in the 40,000-ppm group by an increase in body weights after exposure was stopped. The investigators concluded that the difference between maternal body-weight gain in rabbits exposed to HFC-134a at 40,000 ppm and in controls was small and represented slight maternal toxicity and that the very small reduction in body-weight gain observed at 10,000 ppm represented a minimal maternal effect. There were no adverse effects on reproduction, and there was no evidence of fetal toxicity or teratogencity.
HYDROFLUOROCARBON-404A 63 Alexander et al. (1996) conducted a fertility study with rats. Groups of 30 male rats and 30 female rats were exposed daily by snout only for 1 hr to HFC-134a at concentrations of 0, 2,500, 10,000, or 50,000 ppm throughout gametogenesis (10 and 3 weeks before pairing for males and females, respectively) and mating. In this parental generation (F0 generation), males continued to be exposed until week 18 and females were exposed until termination. Fourteen pregnant rats from each exposure group were killed on day 20 postcoitum and their uterine contents and ovaries examined. The remaining females were allowed to litter and rear their young (F1 generation). To allow for parturition, exposure to HFC-134a was stopped after dosing on day 20 of pregnancy and resumed on days 1-21 postpartum. One male and one female rat from each litter (12 litters per group) were raised to maturity and mated, and survival and development were evaluated in the resulting progeny (F2 generation). One F2 rat of each sex from each litter (8 litters per group) was raised to sexual maturity. No clinical signs of toxicity were observed in the F0, F1, or F2 generations. A slight but statistically significant decrease in body-weight gain was observed in F0 males after 2 weeks of exposure to HFC-134a at 10,000 and 50,000 ppm, and cumulative and overall weight gains were also reduced in males exposed at 50,000 ppm. However, no effect on weight gain was observed in F0 females. No significant effects on body weight were observed in the F1 or F2 generations. With regard to breeding performance, no effects were observed on estrous cycles, mating, precoital times, conception, and gestation length in the F0 or F1 generations. No significant changes in the number of live-born pups, sex ratio, survival postpartum, or development (i.e., pinna detachment, upper incisor eruption, eye opening, reflex development, cleavage of the balanopreputial skinfold, and vaginal opening) were observed in the F0 and F1 litters. No exposure-related abnormalities were observed in any of the postmortem examinations of the F0, F1, or F2 generations. In addition, when the uterine contents of pregnant F0 rats sacrificed before term were examined, the number of corpora lutea, implants, embryonic deaths, live young, sex ratio, litter weights, and fetal body weights did not differ significantly from controls, and the incidence, type, and distribution of visceral or skeletal abnormalities did not increase. A study of perinatal and postnatal exposure to HFC-134a was also conducted (Alexander et al. 1996). Groups of 41 mated female rats formed the F0 generation. These rats were exposed daily (snout only) for 1 hr to HFC-134a at concentrations of 0, 1,800, 9,900, or 64,400 ppm on days 17-20 of pregnancy and then on days 1-21 postpartum. One male and one female
