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HYDROFLUOROCARBON-404A 66 134a-exposed group. However, the significance of these results is uncertain because the study did not involve lifetime exposure. The NRC also evaluated an inhalation study by Hext and Parr-Dobrzanski (1993), which was subsequently published by Collins et al. (1995). In that study, rats (85 of each sex per group) were exposed (whole body) to HFC-134a at concentrations of 0, 2,500, 10,000, or 50,000 ppm for 6 hr per day, 5 days per week for 104 weeks. The only exposure-related effect of toxicological importance was an increased incidence of Leydig-cell hyperplasia and Leydig- cell adenoma in male rats in the 50,000-ppm group. The tumors were benign and not life threatening. The survival rate was similar in all groups. In 1996, the NRC concluded that Leydig-cell tumors were not applicable to humans and thus were not considered an adverse effect. Two additional studies have been published. Alexander et al. (1995) exposed (nose-only) mice (60 of each sex per group) to HFC-134a at concentrations of 2,500, 15,000, or 75,000 ppm for 1 hr per day for at least 104 weeks. There were two air-only (control) exposure groups. Clinical observations, behavioral observations (Modified Irwin Screen), body weights, hematology, and microscopic tissue pathology were monitored. There were no exposure-related effects in any of the measurements. In another study, rats (60 of each sex per group) were exposed (nose only) to HFC-134 at concentrations of 2,500, 10,000, or 50,000 ppm for 1 hr per day for at least 108 weeks (Alexander et al. 1995). HFC-134a vapor was delivered using a metered-dose inhaler. An air-only (control) exposure group consisted of 120 rats of each sex. Clinical observations, behavioral observations (Modified Irwin Screen), body weights, hematology, and microscopic tissue pathology were monitored. A statistically significant increase in subacute and chronic laryngitis occurred in female rats only in the 50,000-ppm group. The severity of laryngitis was slight, and the observation was considered to be of no toxicological significance. There were no exposure-related effects in any of the other measurements. Exposure Guidance Levels for HFC-134a In 1996, the NRC reviewed the available toxicity data on HFC-134a and proposed a 1-hr EEGL of 4,000 ppm, a 24-EEGL of 1,000 ppm, and a 90-day CEGL of 900 ppm. The Navy chose to set lower values for the 1-hr EEGL and 90-day CEGL because of the lack of experience with HFCs, but it did adopt the NRC's proposed 24-EEGL. Since the 1996 review, additional data on HFC-134a have become avail
HYDROFLUOROCARBON-404A 67 able. An updated summary of the noncancer toxicity studies on HFC-134a are presented in Table 4-4. The subcommittee used the new studies to reevaluate the exposure guidance levels proposed by the NRC in 1996 and those currently used by the Navy (see below). Because the submariner population is all male, young, and healthier than the general public, the committee did not use an uncertainty factor for intraspecies variability in its calculations. Exposure Guidance Levels for HFC-134a Exposure Level NRC's Calculated NRC's (1996) Navy's Levels Levels Calculated Levels 1-hr EEGL 8,000 ppm 4,000 ppm 2,000 ppm 24-hr EEGL 5,000 ppm 1,000 ppm 1,000 ppm 90-day CEGL 900 ppm 900 ppm 100 ppm One of the new studies was an ascending-concentration safety study in humans. The subjects were exposed to HFC-134a at concentrations up to 8,000 ppm for 1 hr with no adverse effects (Emmen and Hoogendijk 1999). The subcommittee believes that this study should be used to determine the 1-hr EEGL rather than the cardiac-sensitization study in dogs (Hardy et al. 1991) used by the NRC (1996) in its earlier evaluation of HFC-134a. Although the human subjects were not challenged with epinephrine as in the dog study, the subcommittee notes that the human NOAEL of 8,000 ppm is five-fold lower than the NOAEL of 40,000 ppm for dogs. Thus, the subcommittee believes that a 1-hr EEGL of 8,000 ppm can be justified. That value is four-fold greater than that currently used by the Navy. The subcommittee considered a 13-week toxicity study in rats (Hext 1989; Collins et al. 1995) to be the most appropriate for deriving the 24-hr EEGL for HFC-134a. In this study, the highest concentration of 50,000 ppm was the NOAEL. Because the available data on HFC-134a were inadequate to determine the magnitude of difference between rats and humans, the NOAEL was divided by an uncertainty factor of 10 to account for interspecies variability, which yielded a 24-hr EEGL of 5,000 ppm. This exposure level is higher than the 1,000-ppm guidance level used by the Navy and proposed by the NRC in 1996. The reason for the difference is that in 1996 the NRC was determining exposure levels for use aboard Navy ships with female crew members and, therefore, based the NOAEL of 10,000 ppm on a devel
TABLE 4-4 Updated Summary of Noncancer Toxicity Information for HFC-134a Species Exposure Frequency and End Point NOAEL, ppm LOAEL, ppm Reference Duration Acute Toxicity Dog 10 min Cardiac sensitization 50,000 75,000 Mullin and Hartgrove 1979 Dog 10 min Cardiac sensitization 40,000 80,000 Hardy et al. 1991 Mice 1 hr No significant effect 810,000 ND Alexander and Libretto 1995 Rat 1 hr No significant effect 810,000 ND Alexander and Libretto 1995 Rat 4 hr Lethality ND 567,000a Silber and Kennedy 1979a HYDROFLUOROCARBON-404A Dog 1 hr Salivation, head shaking, and 80,000 160,000 Alexander and Libretto struggling 1995 Subchronic Toxicity Rat 6 hr/d, 5 d/wk for 14 d Increased respiratory rate ND 100,000 Silber and Kennedy 1979b Rat 6 hr/d, 5 d/wk for 4 wk Slight focal interstitial 10,000 50,000b Riley et al. 1979 pneumonia Rat 6 hr/d, 5 d/wk for 13 wk No significant effect 50,000 ND Hext 1989; Collins et al. 1995 Rat 1 hr/d, 7 d/wk for 50 wk No significant effect 50,000 ND Alexander and Libretto 1995 68
Mice 1 hr/d, 7 d/wk for 90 d No significant effect 50,000 ND Alexander and Libretto 1995 Dogs 1 hr/d, 7 d/wk for 1 yr No significant effect 120,000 ND Alexander and Libretto 1995 Dogs Twice a day using a metered No significant effect 2.25 g ND Alexander and Libretto 1995; dose inhaler via Alexander et al. 1995 oropharyngeal tube for 1 yr Human 1 hr, 1 d/wk for 8 wk No significant effect 8,000 ND Emmen and Hoogendijk 1999 Developmental and Reproductive Toxicity Rat 6 hr/d, gestation days 6-15 Maternal toxicity 30,000 100,000 Lu and Staples 1981 Fetal toxicity 100,000 300,000 Rat 6 hr/d, gestation days 6-15 Maternal toxicity 50,000 ND Hodge et at. 1979a HYDROFLUOROCARBON-404A Fetal toxicity 10,000 50,000 Rabbit 6 hr/d, gestation days 6-18 Maternal toxicity 2,500 10,000 Wickramaratne 1989a,b Fetal toxicity 10,000 ND Rabbit 6 hr/d, gestation days 7-19 Maternal toxicity 2,500 10,000 Collins et al. 1995 Fetal toxicity 40,000 ND Rat 1 hr/d, 10 wk (F0 male) or 3 Maternal toxicity (F0) 50,000 ND Alexander et al. 1996 / 69 wk (F0 female) before mating, during mating, and on days 1-21 postpartum for females Paternal toxicity (F0) 50,000 ND Fetal toxicity (F1 and F2) 50,000 ND 69
Rat 1 hr/d on gestation days 17-20 and on days 1-21 Maternal toxicity (F0) 64,400 ND Alexander et al. 1996 postpartum (F0 generation) Fetal toxicity (F1 and F2) 64,400 ND Male rat 6 hr/d for 18 wk Testicular endocrine functionc 30,000 100,000 Barton et al. 1994 Rat 1 hr/d, 10 wk (F0 male) or 3 wk (F0 female) before mating, Fertility (F0 and F1) 50,000 ND Alexander et al. 1996 during mating, and on days 1-21 postpartum for females 1 hr/d on gestation days 17-20 and on days 1-21 Fertility (F0 and F1) 64,400 ND postpartum (F0 generation) aApproximate lethal concentration. bThis effect was not observed in subsequent studies. cIncrease in testosterone secretion and biosynthesis and a concomitant increase in progesterone secretion when the testis was incubated with human chorionic HYDROFLUOROCARBON-404A gonadotrophin. Abbreviation: ND, not determined. 70
