2

Hydrofluorocarbon-236fa

HYDROFLUOROCARBON (HFC)-236FA, or 1,1,1,3,3,3-hexafluoropropane, is a gaseous halocarbon that is being considered as a replacement for the refrigerant chlorofluorocarbon (CFC)-114, which is used in centrifugal chillers aboard U.S. Navy submarines. To protect submariners from large accidental releases or low-level slow leaks of HFC-236fa, emergency exposure guidance levels (EEGLs) and continuous exposure guidance levels (CEGLs) are needed to avoid adverse health effects from short-term or prolonged exposures to HFC-236fa and to avoid degradation in crew performance. This chapter presents the available toxicity information on HFC-236fa and the subcommittee's evaluation of the Navy's proposed 1-hr and 24-hr EEGLs and 90-day CEGL.

CHEMICAL AND PHYSICAL PROPERTIES



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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a 2 Hydrofluorocarbon-236fa HYDROFLUOROCARBON (HFC)-236FA, or 1,1,1,3,3,3-hexafluoropropane, is a gaseous halocarbon that is being considered as a replacement for the refrigerant chlorofluorocarbon (CFC)-114, which is used in centrifugal chillers aboard U.S. Navy submarines. To protect submariners from large accidental releases or low-level slow leaks of HFC-236fa, emergency exposure guidance levels (EEGLs) and continuous exposure guidance levels (CEGLs) are needed to avoid adverse health effects from short-term or prolonged exposures to HFC-236fa and to avoid degradation in crew performance. This chapter presents the available toxicity information on HFC-236fa and the subcommittee's evaluation of the Navy's proposed 1-hr and 24-hr EEGLs and 90-day CEGL. CHEMICAL AND PHYSICAL PROPERTIES

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a Common name: HFC-236fa Chemical name: 1,1,1,3,3,3-hexafluoropropane Synonyms: Hexafluoropropane; 2,2-Dihydrohexafluoropropane CAS number: 690-39-1 Structural formula: CF3CH2CF3 Description: Colorless gas Molecular weight: 152.01 Boiling point: -0.7°C Melting point: -93.6°C Density and specific gravity: 1.370 g/cc Vapor pressure: 36 psia at 25°C (calculated) Conversion factors: 1 mg/m3= 0.16 ppm; 1 ppm = 6.22 mg/m3 TOXICOKINETICS Using tissues obtained from male rats, Vinegar et al. (1995) determined tissue and air partition coefficients for HCF-236fa by vial equilibration. Coefficients were determined for blood/air, liver/air, fat/air, gut/air, rapidly perfused tissue/air, and slowly perfused tissue/air in incubations of 3 hr at 37°C with 800 parts per million (ppm) of HFC-236fa. The partition coefficients (mean ± standard deviation of 12 determinations) were found to be 0.49 ± 0.04 (blood/air), 0.56 ± 0.06 (liver/air), 3.69 ± 0.56 (fat/air), 0.56 ± 0.06 (gut/air), 0.56 ± 0.06 (rapidly perfused tissues/air), and 0.87 ± 0.08 (slowly perfused tissues/air). Gas-uptake experiments were performed by Vinegar et al. (1995) by exposing three male rats for 6 hr to HFC-236fa via inhalation at concentrations of 100, 530, 2350, 7300, and 18,000 ppm. Loss runs, tests performed without rats to determine the loss rate of HFC-236fa from the chamber, showed percent losses of 0.38% ± 0.07% to 2.85% ± 1.40% per hr, and loss runs with animals in the chamber ranged from 1.57% to 11.77%. For both situations, loss of HFC-236fa from exposure chambers was greatest at lower concentrations. Humidity levels, initially thought to be affecting loss rates, were found to have no appreciable effect on the loss of the test material. The role of carbon dioxide in the inexplicable loss of test material was considered but not investigated. Inhalation uptake of HFC-236fa by rats was

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a biphasic with a rapid equilibration phase of up to 30 min followed by a slow linear uptake phase. The partition-coefficient data and the data obtained from the gas-uptake experiments were used in a physiologically based pharmacokinetic (PB-PK) model in an attempt to describe mathematically the disposition and metabolism of HFC-236fa. The PB-PK model was unable to describe adequately the loss of the test material from the animal chamber. Data from the gas-uptake experiments were inconsistent with metabolism-mediated disappearance of HFC-236fa. Samples of blood, urine, or feces were collected from rats exposed to HFC-236fa after 6 and 24 hr of exposure (Vinegar et al. 1995). The samples were extracted with hexane or cyclohexane and analyzed by gas chromatography and mass spectrometry (GC-MS); some samples were methylated before GC-MS analysis to detect organic acids. Although HFC-236fa was detected in samples of blood, urine, or feces, no fluorocarbon metabolites of HFC-236fa were detected by GC-MS, either in the total-ion-current mode or in the single-ion-monitoring mode. Moreover, GC-MS analysis revealed no compounds with retention times consistent with seven fluorocarbons proposed as possible metabolites of HFC-236fa. Valentine (1995) found no fluoride ions in the urine of rats exposed to HFC-236fa concentrations as high as 50,000 ppm for 6 hr per day, 5 days per week for 2 weeks, thereby indicating no significant metabolism of the compound. TOXICITY INFORMATION Acute Toxicity Currently available data indicate that HFC-236fa has low acute toxicity by the inhalation route. Keller (1994) exposed young male rats to concentrations of HFC-236fa at 150,000 or 200,000 ppm (purity 99.06%) for 4 hr. Actual mean concentrations were approximately 134,000 and 189,000 ppm, respectively. During the whole-body exposure, the oxygen concentration was maintained at 21% ± 3% and air flow was approximately 2 liters (L) per min with a total chamber volume of 13 L. No rats died during exposure or during an additional day of observation following the exposure. Exposure to HFC-236fa at 134,000 ppm produced no observable effects, but rats exposed at 189,000 ppm exhibited narcosis (nonresponsive to sound) that persisted for approximately 30 min after cessation of exposure. No additional effects were observed during the 1-day post-exposure period, and no patho-

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a logical evaluations were conducted. Under the conditions of this study, the 4-hr no-observed-adverse-effect level (NOAEL) for narcosis in rats is at or above 134,000 ppm, and the 4-hr lowest-observed-adverse-effect level (LOAEL) for narcosis is at or below 189,000 ppm. In an acute inhalation study by Ulrich (1996), a group of five male and five female young adult rats was exposed (whole body) to HFC-236fa (purity >99.5%) at a nominal concentration of 471,000 ppm (actual mean concentration was 457,000 ppm) for 4 hr. Chamber oxygen was maintained at 21.5% ± 5.33% with an air flow of 18.7 L/min. Although chamber temperature ranged from 19.7 to 30.8°C, there was no apparent effect on the test animals. Shortly after initial exposure, the rats exhibited a brief period of hyperactivity before becoming prostrate. No toxicologically significant effects were observed 1 hr after cessation of exposure or during the 14-day post-exposure observation period. A transient loss of body weight was observed in two female rats (3 and 9 g, respectively, during the first 3 days after exposure), but terminal weights exceeded those of day 0. Necropsy revealed dark red lungs in one male and three females, renal cysts in two females, and an enlarged pituitary in one female. The pathological findings were not considered to be exposure related. On the basis of the results of this study, 457,000 ppm is considered a 4-hr NOAEL for HFC-236fa inhalation exposure in rats. Cardiac Sensitization Huntington Research Centre (HRC 1994) examined the cardiac sensitization potential of HFC-236fa in six young adult male beagle dogs. The specific epinephrine dose to elicit a minimal response, as determined by altered electrocardiogram (ECG) with a few ectopic beats, was determined for each dog and found to range from 2 to 12 µg/kg. Dogs were exposed by face mask to HFC-236fa at concentrations of 50,000, 100,000, 150,000, 200,000, 250,000, or 300,000 ppm. An epinephrine challenge injection was administered after 5 min of exposure, and ECG monitoring was continued for another 5 min after the challenge. Evidence for cardiac sensitization to epinephrine challenge was observed in two of six dogs following exposure to HFC-236fa at 150,000 ppm as shown by multifocal ventricular ectopic activity in one dog and a fatal ventricular fibrillation in another. Following a 5-min exposure of six dogs to 200,000 ppm, two of the dogs (one of which also exhibited a positive response at 150,000 ppm) exhibited multifocal ventricular ectopic activity. At higher concentrations, excitation or narcosis in

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a 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

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a 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

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a 20,000 and 50,000-ppm groups. Although considered exposure related, these changes are not considered to be of toxicological significance. Decreases in total protein and albumin and alterations in blood urea nitrogen (BUN) concentration were also detected but were not dose related. Changes in some serum electrolyte concentrations were not considered to be biologically relevant. Urinalysis revealed no biologically relevant findings. There was no definitive evidence for induction of hepatic peroxisomes in rats following discontinuous subchronic exposure to HFC-236fa at concentrations as high as 50,000 ppm. Reproductive Toxicity There are no reports of reproductive toxicity studies in animals for HFC-236fa. Developmental Toxicity Two developmental toxicity studies (one in rats and one in rabbits) were conducted in animals to examine the developmental effects of HFC-236fa. The highest concentration tested in these studies—50,000 ppm—was the highest that could be attained without supplementing chamber oxygen. Munley (1995) administered HFC-236fa by inhalation to pregnant rats at concentrations of 0, 5,000, 20,000 and 50,000 ppm for 6 hr per day from days 7 to 16 of gestation. The study was terminated on day 22 of gestation. At 20,000 and 50,000 ppm, there were significant dose-related decreases in maternal body-weight gain over the first 2 days of inhalation exposures. At 50,000 ppm, that was accompanied by significant reduction in food consumption and diminished alerting responses during the inhalation exposures. No evidence of maternal toxicity was detected at 5,000 ppm. There was no evidence of developmental toxicity in the fetuses at any exposure concentration tested. Munley (1996) exposed pregnant New Zealand rabbits (20 per group) to HFC-236fa by inhalation at daily (6 hr per day) exposure concentrations of 0, 5,000, 20,000, or 50,000 ppm on days 7 to 19 of gestation. Does were killed on day 29, and fetuses were weighed and examined for external, internal, and skeletal abnormalities. There was no evidence of any maternal or developmental toxicity at any exposure concentration tested. There were no compound-related effects on maternal body weight, weight change,

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a or food consumption or in clinical observations or post-mortem findings. There were no compound-related developmental effects. The end points evaluated were mean fetal weight, mean litter size, pre- and post-implantation embryo lethality, and fetal malformations and variations. Genotoxicity Bentley (1995a) evaluated HFC-236fa (concentrations ranging from 200,000 to 1,000,000 ppm) for clastogenic activity in human lymphocytes in vitro following 3-hr exposures with and without metabolic activations (S9). No increases in the percent of chromosomally abnormal cells occurred at any HFC-236fa concentration evaluated, and no concentration-related trends in chromosomal-aberration induction were observed. An inhalation micronucleus study was conducted in male and female mice exposed to HFC-236fa at 0, 5,000, 20,000, or 50,000 ppm for 6 hr per day for 2 consecutive days. Bone-marrow smears were prepared approximately 24 and 48 hr after the second exposure (Bentley 1995b). No statistically significant increases in micronucleated polychromatic erythrocytes were observed in any animal at any concentration tested. HFC-236fa was also evaluated for mutagenicity in Salmonella typhimurium strains TA100, TA1535, TA97, and TA98 and in Escherichia coli WPSuvrA-(pKM101) with and without an exogenous metabolic activation system (S9) (Bentley 1995c). At concentrations tested between 0 and 1,000,000 ppm, no evidence of mutagenic activity was detected in either of two independent trials. On the basis of the available data, the subcommittee concludes that HFC-236fa is not genotoxic and is unlikely to induce heritable effects in humans Carcinogenicity No chronic carcinogenicity exposure studies of HFC-236fa are currently available. SUMMARY Studies on the metabolism and disposition of HFC-236fa indicate that HFC-236fa is not metabolized to any significant extent. PB-PK modeling us-

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a ing data from gas-uptake studies did not adequately describe the rapid disappearance of HFC-236fa from exposure chambers. Inhalation uptake of HFC-236fa by rats was biphasic with a rapid equilibration phase of up to 30 min followed by a slow linear uptake phase. The pattern of loss was inconsistent with either first-order or saturable metabolism. Experiments have revealed that HFC-236fa has low blood/tissue partition coefficients. Acute and subchronic inhalation studies in rats have shown HFC-236fa to be of low toxicity. The principal effects of HFC-236fa appear to be attenuation of alerting response, narcosis, and cardiac sensitization. There is some evidence suggesting accommodation to decrements in alerting response resulting from HFC-236fa exposure. Exposure-related alterations in some clinical chemistry measurements have been shown following acute and subchronic exposure of rats to high concentrations of HFC-236fa, but the changes are of questionable biological or toxicological relevance. Reductions in hepatic β-oxidation were observed in rats following 2-week discontinuous exposure to 50,000 ppm, but there were no histopathological correlates to confirm peroxisome proliferation. There was no evidence of peroxisome proliferation in rats following 90-day discontinuous exposure to HFC-236fa at concentrations as high as 50,000 ppm. Studies in dogs indicate that HFC-236fa might have the potential for cardiac sensitization at high exposure concentrations (i.e., ≥150,000 ppm). There have been no studies assessing the carcinogenic potential of HFC-236fa. NOAEL and LOAEL values for noncancer end points are summarized in Table 2-1. Results of developmental toxicity studies in rats and rabbits suggest that HFC-236fa at concentrations as high as 50,000 ppm is not a developmental toxicant. Signs of maternal toxicity were evident at concentrations of 20,000 and 50,000 ppm in rats but not in rabbits. Genotoxicity studies of HFC-236fa are negative. There are no currently available reproductive toxicity or carcinogenicity studies of HFC-236fa. EXPOSURE GUIDANCE LEVELS The Navy proposes to use the same exposure guidance levels for HFC-236fa that were set for chlorofluorocarbons CFC-12 and CFC-114 (1-hr EEGL of 2,000 ppm, 24-hr EEGL of 1,000 ppm, and 90-day CEGL of 100 ppm), but did not provide an adequate rationale for doing this. To evaluate the validity the Navy's proposed guidance levels, the subcommittee reviewed the available toxicity data on HFC-236fa to determine what levels would be ade-

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a TABLE 2-1 Summary of Noncancer Toxicity Information for HFC-236fa Species Exposure Frequency and Duration End Point NOAEL, ppm LOAEL, ppm Reference Acute Toxicity           Dog 5 min Cardiac sensitization 100,000 150,000 HRC 1994 Rat 4 hr Narcosis ≥134,000 ≤189,000 Keller 1994 Rat 4 hr Narcosis ND 457,000 Ulrich 1996 Subchronic Toxicity           Rat 6 hr/d, 5 d No significant effect 50,000 ND Smith et al. 1997 Rat 6 hr/d, 5 d/wk for 2 wk Alerting response decrement 5,000 20,000 Valentine 1995 Rat 6 hr/d, 5 d/wk for 14 wk Alerting response decrement 20,000 50,000a Valentine 1996 Rat 6 hr/d, gestation Developmental toxicity 50,000 ND Munley 1995   d 7-16 Maternal toxicity 5,000 20,000b   Rabbit 6 hr/d, gestation Developmental toxicity 50,000 ND Munley 1996   d 7-19 Maternal toxicity 50,000 ND   aAccommodation to alerting-response decrement occurred by day 18; exposure-related clinical-chemistry changes were also observed but were not considered to be biologically or toxicologically relevant. bDecreased body-weight gain in dams over first 2 days of exposure; diminished alerting response during exposure. Abbreviation: ND, not determined.

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a quately protective of submariner health. A comparison of those results is presented below. Submarine Exposure Guidance Levels for HFC-236fa Exposure Level NRC's Calculated Values Navy's Proposed Values 1-hr EEGL 10,000 ppm 2,000 ppm 24-hr EEGL 2,000 ppm 1,000 ppm 90-day CEGL 350 ppm 100 ppm The subcommittee evaluated the Navy's proposed 1-hr EEGL of 2,000 ppm for HFC-236fa by considering an acute toxicity study in rats (Keller 1994) and a cardiac sensitization study in dogs (HRC 1994). In the study by Keller (1994), the NOAEL for a 4-hr exposure was 134,000 ppm based on the end point of narcosis in rats. In the HRC (1994) study, the NOAEL for a 5-min exposure was 100,000 ppm based on cardiac sensitization in dogs. The subcommittee divided those NOAELs by an uncertainty factor of 10 to account for interspecies differences, yielding values of 13,400 ppm based on the Keller (1994) study and 10,000 ppm based on the HRC (1994) study. The Navy's proposed 1-hr EEGL of 2,000 ppm is well below those values, and, therefore, the subcommittee concludes that it is adequately protective of submariner health. To evaluate the Navy's proposed 24-hr EEGL of 1,000 ppm for HFC-236fa, the subcommittee considered a 2-week toxicity study (Valentine 1995) and a 14-week toxicity study (Valentine 1996) conducted in rats. The 2-week study involved a cumulative exposure of 60 hr and reported a LOAEL of 20,000 ppm and a NOAEL of 5,000 ppm based on alerting response. In contrast, the 14-week study reported a NOAEL of 20,000 ppm based on the same end point. The subcommittee questioned the use of alerting response for determining a NOAEL, because the effects were transient in both studies. In addition, alerting responses are subjectively analyzed and vary among strains and individual animals, and it is unclear how or if such effects are applicable to humans. The subcommittee considered using a NOAEL of 5,000 ppm found in the 2-week study (Valentine 1995) but decided that that value was probably too conservative. Having no data on HFC-236fa at concentrations between 5,000 ppm and 20,000 ppm, the subcommittee believed that 20,000 ppm was a better choice for a NOAEL. The subcommittee

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a divided that value by an uncertainty factor of 10 to account for interspecies differences, yielding a value of 2,000 ppm. The Navy 's proposed 24-hr EEGL of 1,000 ppm is half this value and is thus an adequate exposure guidance level. In its evaluation of the Navy's proposed 90-day CEGL of 100 ppm for HFC-236fa, the subcommittee used the 14-week study in rats (Valentine 1996). On the basis of transient decrements in alerting response, a NOAEL of 20,000 ppm was determined. The subcommittee divided that value by a factor of 10 to account for interspecies differences to yield a value of 2,000 ppm. Because the study involved a discontinuous exposure regimen, the subcommittee multiplied that value by 1/4 (to account for exposure for 6 hr per day) and by 5/7 (to account for exposure five times per week), which yielded a value of about 350 ppm. The Navy's proposed 90-day CEGL of 100 ppm is below that value, and, therefore, the subcommittee concludes that the Navy's CEGL is adequately protective of health for prolonged exposures. The subcommittee noted that a developmental toxicity study in rats (Munley 1995) reported reduced weight gain and decrements in alerting response in the dams at 20,000 ppm, the same concentration as the NOAEL identified in the 14-week toxicity study. Because the purpose of this project was to establish exposure guidance levels for use on submarines, vessels that have no female crew members, the subcommittee did not use the developmental toxicity study as the basis for calculating the 24-hr EEGL or 90-day CEGL. However, if HFC-236fa is considered for use on vessels with female personnel, those values might have to be reconsidered on the basis of maternal toxicity. RECOMMENDATIONS Uncertainties exist with regard to the effects that HFC-236fa might have on human performance. End points of narcosis and decrements in alerting response have been observed in laboratory animals, but it is unclear whether human performance would be affected similarly. Because HFC-236fa was relatively nontoxic in laboratory studies and because human studies have been conducted with other HFCs, such as HFC-23 and HFC-134a, the subcommittee recommends that tests be conducted with humans to determine whether HFC-236fa affects performance skills, such as motor coordination and alertness.

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a REFERENCES Bentley, K.S. 1995a. In Vitro Assay of HFC-236fa for Chromosome Aberrations in Human Lymphocytes . Haskell Laboratory Report No. 604-94. Haskell Laboratory, Wilmington, DE. Bentley, K.S. 1995b. Mouse Bone Marrow Micronucleus Assay of HFC-236fa by Inhalation. Haskell Laboratory. Report No. 602-94. Haskell Laboratory, Wilmington, DE. Bentley, K.S. 1995c. Mutagenicity Testing of HFC-236fa in the Salmonella Typhimurium and Escherichia Coli Plate Incorporation Assay. Haskell Laboratory Report No. 647-94. Haskell Laboratory, Wilmington, DE. HRC (Huntington Research Centre). 1994. HFC 236fa. Assessment of Cardiac Sensitization Potential in Dogs. Report No. DPT 293/931308. Huntington Research Centre, Ltd. Huntington, England. Keller, D.A. 1994. Acute Inhalation Toxicity of HFC-236fa and HFC-236ea in the Rat. Report No. 761-93. Haskell Laboratory for Toxicology and Industrial Medicine. Newark, DE. Munley, S.M. 1996. Inhalation Developmental Toxicity of HFC-236fa in Rabbits. Haskell Laboratory Report No. 417-96. Haskell Laboratory, Wilmington, DE. Munley, S.M. 1995. Inhalation Developmental Toxicity Study of HFC-236fa in Rats. Haskell Laboratory. Report No. 66-95. Haskell Laboratory, Wilmington, DE. Smith, N.D., T.G. Brna, C.L. Gage, and R.V. Hendriks. 1997. New Chemical Alternative for Ozone-Depleting Substances: HFC-236fa. EPA-600/R-97-065. U.S. Environmental Protection Agency, National Risk Management Research Laboratory, Air Pollution Prevention and Control Division, Research Triangle Park, N.C. Ulrich, C.E. 1996. Acute Inhalation Toxicity Study of HFC-236fa in Albino Rats. WIL Research Laboratories, Inc. WIL-189022. DuPont Report No. HLO 74-96. Ashland, OH. Valentine, R. 1996. 90-Day Inhalation Toxicity Study with HFC-236fa in Rats. Haskell Laboratory Report No. 211-95; DuPont HLR 211-95. Haskell Laboratory for Toxicology and Industrial Medicine. Newark, DE. Valentine, R. 1995. Two-week Inhalation Toxicity Study with HFC-236fa in Rats. Haskell Laboratory for Toxicology and Industrial Medicine. Report. No. 596-94; DuPont HLR 596-94, Newark, DE. Vinegar, A., G.W. Buttler, M.C. Caracci, and J.D. McCafferty. 1995. Gas Uptake Kinetics of 1,1,1,3,3,3-hexafluoropropane (HFC-236fa) and Identification of Its Potential Metabolites. Armstrong Laboratory, Occupational and Environmental Health Directorate, Toxicology Division, Human Systems Center, Air Force Materiel Command . Wright-Patterson A.F.B., OH. AL/OE-TR-1995-0177, NMRI-95-46.