4

Hydrofluorocarbon-404a

HYDROFLUOROCARBON (HFC)-404a is a gaseous mixture of three halocarbons—52% HFC-143a, 44% HFC-125, and 4% HFC-134a. It is used as a refrigerant in ice-cream machines. The U.S. Navy is considering installing a single ice-cream machine aboard each of its submarines. The Navy does not intend to perform servicing of this equipment when its submarines are under way, so the only HFC-404a aboard will be in the ice cream machine (i.e, there will be no cylinders of HFC-404a aboard). The refrigerant systems of the machines are sealed and operate in a manner similar to that of a household refrigerator.

To protect submariners from large accidental releases or low-level slow releases of HFC-404a, 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-404a and to avoid degradation in crew performance. No toxicity studies on HFC-404a were available, so the subcommittee reviewed the available data on its three components—HFC-143a, HFC-125, and HFC-134a. The subcommittee used these data to determine 1-hr and 24-hr EEGLs and 90-day CEGLs for each of the components, and then those values were used to calculate exposure guidance levels for HFC-404a on the basis of percent composition of the individual components. The calculated EEGLs and CEGL for HFC-404a were used to evaluate the Navy's proposed exposure guidance levels for HFC-404a.



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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a 4 Hydrofluorocarbon-404a HYDROFLUOROCARBON (HFC)-404a is a gaseous mixture of three halocarbons—52% HFC-143a, 44% HFC-125, and 4% HFC-134a. It is used as a refrigerant in ice-cream machines. The U.S. Navy is considering installing a single ice-cream machine aboard each of its submarines. The Navy does not intend to perform servicing of this equipment when its submarines are under way, so the only HFC-404a aboard will be in the ice cream machine (i.e, there will be no cylinders of HFC-404a aboard). The refrigerant systems of the machines are sealed and operate in a manner similar to that of a household refrigerator. To protect submariners from large accidental releases or low-level slow releases of HFC-404a, 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-404a and to avoid degradation in crew performance. No toxicity studies on HFC-404a were available, so the subcommittee reviewed the available data on its three components—HFC-143a, HFC-125, and HFC-134a. The subcommittee used these data to determine 1-hr and 24-hr EEGLs and 90-day CEGLs for each of the components, and then those values were used to calculate exposure guidance levels for HFC-404a on the basis of percent composition of the individual components. The calculated EEGLs and CEGL for HFC-404a were used to evaluate the Navy's proposed exposure guidance levels for HFC-404a.

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a HFC-143a Chemical and Physical Properties Common name: HFC-143a Chemical name: 1,1,1-Trifluoroethane Synonyms: FC-143a; hydrofluorocarbon 143a CAS number: 420-46-6 Structural formula: CH3CF3 Description: Colorless gas Molecular weight: 84.04 Boiling point: -47.3°C at 760 mm Hg Melting point: -111.3°C Flash point and flammability: -90°C Solubility: Soluble in chloroform and ether Auto-ignition: 750°C Conversion factors: 1 ppm = 3.40 mg/m3; 1 mg/m3 = 0.29 ppm Toxicokinetics In a study of rats exposed by inhalation to HFC-143a at 4,800 ppm for 4-5 hr, 2,2,2-trifluoroethanol was the only metabolite detected. Nuclear magnetic resonance showed that HFC-143a was metabolized slowly, primarily through an oxidative route (DuPont 1994, as cited in AIHA 1996).

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a Toxicity Information Acute Toxicity Groups of six male rats were exposed for 4 hr (nose only) to HFC-143a at concentrations of 97,000 or 540,000 parts per million (ppm) (Brock et al. 1996). No deaths occurred during exposure or during the 14-day post-exposure observation period. No clinical signs attributed to HFC-143a were observed. Slight-to-moderate body-weight losses were observed in both exposure groups on the day following exposure, but normal weight gains were observed through the remainder of the study. Thus, the 4-hr LC50 (concentration causing death in 50% of test animals) for rats is considered to be greater than 540,000 ppm. The LC50 value of HFC-143a in mice is reported to be greater than 500,000 ppm (Nikijenko and Tolgskaya 1965, as cited in AIHA 1996). Cardiac Sensitization Brock et al. (1996) evaluated the cardiac-sensitization potential of HFC-143a in an epinephrine challenge test. An intravenous control injection of epinephrine (2-12 µg/kg) was administered to groups of six beagle dogs that were subsequently exposed for 10 min to HFC-143a at concentrations ranging from 50,000 to 300,000 ppm via single-pass-through face mask. Five minutes after initiating vapor exposure, a challenge concentration of epinephrine (same as the pre-test concentration) was administered. Evidence of cardiac sensitization was determined if multiple ectopic beats (more than five beats) or ventricular fibrillation, which could be fatal, was evident. No cardiac-sensitization responses were observed at HFC-143a concentrations of 50,000 to 250,000 ppm. At 300,000 ppm, two of five dogs were considered to have exhibited cardiac sensitization. Subchronic Toxicity Four groups of rats (10 of each sex) were exposed nose-only for 6 hr per day, 5 days per week for 4 weeks to HFC-143a at 0, 2,000, 10,000, or 40,000 ppm (Brock et al. 1996). Clinical signs, body weights, food consumption, clinical pathology, organ weights, and tissue histopathology were evaluated. Premature deaths in three rats from different exposure groups were consid-

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a ered incidental. The only remarkable finding was degenerative changes in the testes of male rats in all exposure groups. No evidence of toxicity was observed in female rats. Excessive temperature conditions and problems with the proper fit of the nose-only restraint system on the animals were reported. To investigate whether the testicular changes might have been an artifact of the excessive temperature conditions, which are known to adversely affect the testes of rats and humans (Van Demark and Fre 1970), or the stress of the restraint system, another 4-week study was conducted in male rats using the same HFC-143a concentrations under normal chamber temperature conditions and without restraint (i.e., whole-body exposure system) (Brock et al. 1996). No adverse testicular effects or adverse clinical signs were observed at any exposure concentration in the study. Because of the absence of testicular changes in this study as well as in a 90-day study (discussed below), the subcommittee believes that the testicular changes observed in the first 4-week study were not caused by exposure to HFC-143a. Four groups of rats (20 of each sex) were exposed (whole body) for 6 hr per day, 5 days per week for 90 days to 0, 2,000, 10,000, or 40,000 ppm (Brock et al. 1996). Clinical signs, body weights, food consumption, clinical pathology, organ weights, and tissue histopathology were evaluated. Liver β-oxidation activity, an indicator of peroxisomal proliferation, was also measured. There were no HFC-143a-related adverse effects at any exposure level. Reproductive Toxicity No reproductive toxicity studies of HFC-143a are currently available. Developmental Toxicity Two inhalation studies, one in rats and one in rabbits, were conducted to evaluate the developmental toxicity of HFC-143a. Brock et al. (1996) exposed groups of 25 pregnant rats to HFC-143a at concentrations of 0, 2,000, 10,000, or 40,000 ppm for 6 hr per day on days 6 to 15 of gestation. There were no signs of maternal toxicity during or after exposure, nor were there any significant changes in body weight, body-weight gains, or food consumption throughout the study. The number of corpora lutea and implants and the incidence of malformations and develop-

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a mental variations in the fetuses were not statistically significant. However, there was a significant increase in the mean percentage per litter of visceral variations due to retarded development in all the test groups. When these anomalies were combined for visceral, skeletal, and external variations, a statistically significant increase was found only at the highest concentration. However, the increase appeared to be a reflection of an unusually low incidence (1.6%) of variations in the control group (the range in historical controls was 6.8% to 16.2%). Because of that, the investigators did not consider the observed anomalies to be compound related. No external variations were observed in any group. In a study with rabbits, groups of 24 pregnant animals were exposed to HFC-143a at concentrations of 0, 2,000, 10,000, or 40,000 ppm for 6 hr per day on days 6 to 18 of gestation (Brock et al. 1996). There were no signs of maternal toxicity during or after exposure, nor were there any significant changes in body weight, body-weight gains, or food consumption throughout the study. However, there was a slight increase in the incidence of combined malformations, expressed as mean percentage per litter, in the litters of the 2,000-ppm and 40,000-ppm groups. The increase appeared to be primarily due to increases in skeletal malformations (expressed as percentage incidence per litter); increases of 1.5%, 7.5%, 3.4%, and 6.3% were found in the control, 2,000-ppm, 10,000-ppm, and 40,000-ppm groups, respectively. Because no clear concentration response was found, however, in either the types or the numbers of malformations and the incidence was within the range of historical controls (0-12.9%), the investigators did not consider the malformations to be compound related. No statistically significant increase in the incidence of soft tissue or external malformation was found compared with controls. Genotoxicity Ames Salmonella reverse mutation assays were conducted in three independent laboratories using a modified experimental design for testing HFC-143a gas (Longstaff et al. 1984; Brock et al. 1996). In one laboratory, HFC-143a was mutagenic in two of four Salmonella strains tested (TA1535 and TA100). HFC-143a was not mutagenic in tests performed at the other two laboratories that used four to five Salmonella strains, including TA1535 and TA100. It was also negative in an Escherichia coli strain (WP2uvrA) assay system which detects DNA damage and repair. HFC-143a was negative in a cell-transformation (Styles) assay using BHK21

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a cultures (Longstaff et al. 1984). HFC-143a was not clastogenic in in vitro tests with cultured human lymphocytes at exposure concentrations up to 35,000 ppm (Brock et al. 1996). There was no statistically significant increase in micronuclei in bone-marrow cells of male and female mice exposed to concentrations of up to 40,000 ppm for 6 hr per day for 2 consecutive days (Brock et al. 1996). On the basis of the available data, the subcommittee concludes that HFC-143a is not genotoxic and is unlikely to induce heritable effects in humans. Carcinogenicity HFC-143a was one of five fluorocarbons tested for carcinogenicity in rats (36 of each sex) using a limited bioassay design (Longstaff et al. 1984). Each fluorocarbon was dissolved in corn oil and a dose of 300 mg/kg was administered by gavage for 5 days per week for 52 weeks. Control groups consisted of an undosed group (32 per sex) and two vehicle dosed groups (36-40 per sex). Clinical signs, body weights, gross abnormalities, and tissue (lungs, liver, spleen, kidneys, and brain) histopathology were evaluated. The study was terminated at week 125. Male rats receiving HFC-143a had lower mean body weights from weeks 28 to 88. Mortality in the exposed group was similar to that in the control groups. There was no significant increase in incidence of neoplasms in any organ in the HFC-143a exposure group. Exposure Guidance Levels for HFC-143a A summary of the noncancer toxicity studies on HFC-143a is presented in Table 4-1. On the basis of those data, the subcommittee calculated 1-hr and 24-hr EEGLs and a 90-day CEGL for HFC-143a. Because the submariner population is all male, young, and healthier than the general population, the subcommittee did not use an uncertainty factor to account for intraspecies differences in its calculations. For a 1-hr EEGL, a cardiac-sensitization study in dogs (Brock et al. 1996) was found to be the most appropriate for determining a NOAEL of 250,000 ppm. Because absorption of hydrofluorocarbons via the inhalation route is rapid, reaching maximal concentrations in the blood within 5 min of exposure and equilibrium within the next 15 min (Azar et al. 1973; Trochimowicz et al. 1974; Mullin et al. 1979), the NOAEL identified for cardiac sensitization following a 10-min exposure can be used without time extrapolation.

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a TABLE 4-1 Summary of Noncancer Toxicity Information for HFC-143a Species Exposure Frequency and Duration End Point NOAEL, ppm LOAEL, ppm Reference Acute Toxicity           Rat 4 hr No significant effect 540,000 ND Brock et al. 1996 Dogs 10 min Cardiac sensitization 250,000 300,000 Brock et al. 1996 Subchronic Toxicity           Rat 6 hr/d, 5 d/wk for 4wk Testicular changes ND 2,000a Brock et al. 1996 Rat 6 hr/d, 5 d/wk for 4wk No significant effect 40,000 ND Brock et al. 1996 Rat 6 hr/d, 5 d/wk for 90 d No significant effect 40,000 ND Brock et al. 1996 Developmental Toxicity           Rat 6 hr/d, gestation Maternal toxicity 40,000 ND Brock et al. 1996   d 6-15 Fetal toxicity 40,000 ND   Rabbit 6 hr/d, gestation Maternal toxicity 40,000 ND Brock et al. 1996   d 6-18 Fetal toxicity 40,000 ND   aEnd point considered to be an artifact of exposure system (nose-only exposure and excessive temperature conditions), because repeated study under normal exposure (whole body) and temperature conditions did not cause similar effects. Abbreviation: ND, not determined.

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a The subcommittee divided the NOAEL by an uncertainty factor of 10 to account for interspecies variability, because there are no human data on HFC-143a, for a 1-hr EEGL of 25,000 ppm. For determining a 24-hr EEGL, the subcommittee used a 4-week toxicity study in rats, in which the highest tested concentration of 40,000 ppm was the NOAEL (Brock et al. 1996). The NOAEL was divided by an uncertainty factor of 10 to account for interspecies variability for a 24-hr EEGL for HFC-143a of 4,000 ppm. A 90-day toxicity study (Brock et al. 1996) in rats was used to calculate the 90-day CEGL for HFC-143a. In that study, the highest tested concentration of 40,000 ppm was the NOAEL. The subcommittee divided that value by a factor of 10 to account for interspecies variability and then multiplied that value by 1/4 (to account for exposure for 6 hr per day) and by 5/7 (to account for exposure 5 days per week), which yielded a value of about 700 ppm. HFC-125 Chemical and Physical Properties Common name: 1,1,1,2,2-Pentafluoroethane Chemical name: 1,1,1,2,2-Pentafluoroethane Synonyms: Pentafluoroethane; HFC-125; fluorocarbon 125 CAS number: 354-33-6 Structural formula: CF3CHF2 Description: Colorless gas Molecular weight: 120.0 Boiling point: -48.5°C Density and specific gravity: 1.35 g/cc at 21°C Vapor pressure: 1,381 psia at 25°C Vapor density: 4 (air = 1) Flash point and flammability: Nonflammable Solubility: 0.97 g/L in water at 25°C Autoignition: No applicable

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a Octanol and water partition coefficient: log Pow = 1.48 Conversion factors: 1 ppm = 4.90 mg/m3; 1 mg/m3 = 0.20 ppm Toxicokinetics In a study of male rats exposed to HFC-125 at 10,000 ppm for 6 hr, Harris et al. (1992) demonstrated that HFC-125 is slowly metabolized to trifluoroacetic acid. The rate of metabolism of HFC-125 was shown to be much slower than that of hydrochlorofluorocarbon (HCFC)-124 (2-chloro-1,1,1,2-tetrafluoroethane) or HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane). That finding is consistent with preliminary data (PAFT 1989), as reported by ECETOC (1994), showing that HFC-125 undergoes little uptake and metabolism at exposure concentrations ranging from 1,000 to 50,000 ppm. Another study (Nakayama et al. 1993, as cited in Kawano et al. 1995) reported no detectable increases in plasma or urine fluoride concentrations in rats exposed to HFC-125 at concentrations up to 50,000 ppm for 4 or 13 weeks, which also suggests that metabolism of HFC-125 is low. Wang et al. (1993) reported that HFC-125 stimulates oxygen consumption and the defluorination of 2-chloro-1,1-difluoroethane in hepatic microsomes from phenobarbital treated rabbits. As in the other studies, no metabolism of HFC-125 was detected under the incubation conditions used. Toxicity Information Summaries of the toxicology of HFC-125 have been published by the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC 1994) and Kawano et al. (1995). Acute Toxicity Groups of five male rats were exposed for 4 hr to HFC-125 at concentrations of 504,000 or 710,000 ppm (Panepinto 1990, as cited in ECETOC 1994). There was no mortality or clinical signs, but transient body-weight loss was observed. In another study, rats (five of each sex) were exposed

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a (whole body) to HFC-125 at 800,000 ppm for 4 hr (Nakayama et al. 1992a, as cited in Kawano et al. 1995). Oxygen was maintained at 200,000 ppm. No deaths occurred during exposure or during the 14-day post-exposure observation period. Clinical signs observed during exposure included ataxia, decreased locomotor activity, dyspnea, and decreased auditory response. These signs disappeared within 1 hr after exposure. Thus, the 4-hr LC50 value for HFC-125 is considered to be greater than 800,000 ppm. Cardiac Sensitization Male beagle dogs were exposed to HFC-125 at concentrations of 0, 75,000, 100,000, 150,000, 200,000, 250,000, or 300,000 ppm for 10 min. An intravenous injection of epinephrine was administered before and during exposure to HFC-125 (Hardy 1992, as cited in Kawano et al. 1995). If a life-threatening arrhythmia occurred after the challenge injection, the material was considered a cardiac sensitizer at that inhaled concentration. A known cardiac sensitizer (CFC-11) was used as a positive control to validate the system, and Halon 1301 (CF 3 Br), also a known cardiac sensitizer, was used to provide comparative data. Positive evidence of cardiac sensitization was seen at 100,000 ppm and greater but not at 75,000 ppm. Therefore, the no-observed-adverse-effect level (NOAEL) for cardiac sensitization was determined to be 75,000 ppm and the lowest-observed-adverse-effect level (LOAEL) was 100,000 ppm. HFC-125 was less potent than CFC-11 but more potent than Halon 1301. Vinegar and Jepson (1995) proposed a quantitative approach for relating blood-concentration time courses to cardiac-sensitization thresholds during inhalation of HFC-125. A physiologically based pharmacokinetic model was used to simulate blood concentrations of HFC-125 in humans during inhalation exposure. The target concentration of HFC-125 in blood was established by simulating a 5-min inhalation exposure at the LOAEL for cardiac sensitization (100,000 ppm). Although the chemical concentration in venous blood does not achieve a steady-state value after 5 min, that exposure period is used in most cardiac-sensitization protocols prior to epinephrine challenge. The blood concentration achieved after 5 min was used as the concentration at which cardiac sensitization was likely to occur. The exposure time required to produce that target level at various concentrations was estimated for resting- and moderate-activity conditions. Results of this study showed that some exposures will not produce the target chemical concentrations in blood no matter how long the exposure occurs, that expo-

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a sure concentrations well above the NOAEL can reach the target chemical concentrations in blood within min, and that exposure concentrations below the LOAEL can reach target chemical concentrations in blood if exposure continues long enough. Subchronic Toxicity Nakayama et al. (1992b, as cited in Kawano et al. 1995) exposed (whole body) rats (10 of each sex per group) to HFC-125 for 6 hr per day, 5 days per week for 4 weeks at concentrations of 0, 5,000, 15,600, or 50,000 ppm. In addition, 10 rats per sex were assigned to the control and high-exposure groups for assessment of a 2-week post-exposure recovery. Clinical observations, body weight, food consumption, clinical pathology, organ weight, and tissue histopathology were evaluated. Liver β-oxidation activity was also measured. There were no HFC-125-related adverse effects at any exposure concentration. In another study using the same test concentrations as above (5,000, 15,600, and 50,000 ppm), groups of rats (20 per sex) were exposed for 13 weeks, and the same biological end points measured in the 4-week study were evaluated (Nakayama et al. 1993, as cited in Kawano et al. 1995). No adverse effects were observed. Reproductive Toxicity No reproductive toxicity studies of HFC-125 are currently available. Developmental Toxicity Two inhalation studies, one in rats and one in rabbits, were conducted to evaluate the developmental toxicity of HFC-125. In the study with rats (Master et al. 1992, as cited in Kawano et al. 1995), groups of 25-29 pregnant rats were exposed (whole body) to HFC-125 at concentrations of 0, 5,000, 15,000, or 50,000 ppm for 6 hr per day on days 6-15 of gestation. The only signs of clinical maternal effects were observed in the group exposed at 50,000 ppm. The rats exhibited unsteady gait during exposure but not after. There were no significant differences between

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a for these subchronic studies are 40,000, 50,000, and 50,000 ppm for HFC-143a, HFC-134a, and HFC-125, respectively. Numerous in vitro and in vivo genotoxicity studies were performed on the three HFCs. Results indicate that none of the components are genotoxic. These genotoxicity results are in agreement with the tumor bioassays that have been performed on two of the three components. Both HFC-143a and HFC-134a showed no significant increase in the incidence of neoplasms in all organs and tissues evaluated. Because HFC-404a is a gaseous mixture of three halocarbons (52% HFC-143a, 44% HFC-125, and 4% HFC-143a), the possibility of toxic interaction should be considered in evaluating the toxic potential of this mixture, in addition to evaluating the potential adverse health effects of the individual components. Combined exposures to multiple chemicals could result in interactions leading to a significant increase or decrease (synergism or antagonism, respectively) in overall toxicity of the mixture compared with the summation of the toxicity of individual components (Krishnan and Brodeur 1991; Mehendale 1994). However, for a large number of chemicals, the overall toxicity of a mixture can be represented by the summation of the effects of the individual components (additive effect). There are three approaches for risk assessment of chemical mixtures (Mumtaz et al. 1994). In two of these approaches, mixtures with stable composition, semi-characterized mixtures, or specially formulated mixtures are treated as a single chemical when data are available on the mixture itself. In cases when testing has been done only on the components of the mixture and not on the mixture itself, the primary method used is the hazard index (HI) approach. The HI approach is based on the principle of dose addition and uses the toxicity data available for the various components of the mixture (EPA 1986; Mumtaz et al. 1994; Teuschler and Hertzberg 1995). It is well established that some chemical components of a mixture have the potential to influence the toxicity of other components of the mixture (Groten et al. 1996). However, the HI approach does not allow the use of available interaction data. To overcome this fundamental shortcoming of the HI approach, a weight-of-evidence (WOE) method has been proposed to integrate available interaction data (Mumtaz and Durkin 1992). Recent experimental studies have shown that the WOE method is useful in assessing the toxicity of low-concentration exposures to chemical mixtures (Mumtaz et al. 1998). Because HFC-404a is an azeotrope composed of similar compounds, it is assumed that the components of the mixture would have additive effects. It is suggested that studies of HFC-404a be conducted to determine if this is a valid assumption.

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a EXPOSURE GUIDANCE LEVELS FOR HFC-404a The Navy proposes to use the same exposure guidance levels for HFC-404a that were set for 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 of the proposed guidance levels, the subcommittee reviewed the available toxicity data on HFC-404a to determine what levels would be adequately protective of submariner health. A comparison of those results is presented below. Submarine Exposure Guidance Levels for HFC-404a Exposure Level NRC's Calculated Levels Navy's Proposed Levels 1-hr EEGL 12,900 ppm 2,000 ppm 24-hr EEGL 4,300 ppm 1,000 ppm 90-day CEGL 800 ppm 100 ppm The subcommittee believes that the most appropriate way to calculate exposure guidance levels for HFC-404a is the method used by the American Conference of Governmental Industrial Hygienists (ACGIH 1999) to calculate Threshold Limit Values (TLVs) for special cases when the exposure of concern is a liquid mixture and the atmospheric composition is assumed to be similar to that of the original material (i.e., on a time-weighted-average exposure basis, all of the liquid mixture eventually evaporates). In that case, when the percent composition by weight of the liquid mixture is known, the exposure guidance levels can be determined using the following equation: The letter f stands for the fraction of each particular component. The component 's corresponding TLV or, for the purposes of this report, exposure guidance level is expressed in units of milligrams per cubic meter (mg/m3) (see Table 4-5). Using this equation, exposure guidance levels for HFC-404a were calculated using the EEGLs and CEGLs that were derived by the subcommittee for HFC-143a, HFC-125, and HFC-134a (see the following pages for calculations).

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a TABLE 4-5 Submarine Exposure Guidance Levels for HFC-404a Components     Calculated Guidance Levels Exposure ppm mg/m3* HFC-143a (molecular weight: 84.04)     1-hr EEGL 25,000 85,930 24-hr EEGL 4,000 13,749 90-d CEGL 700 2,406 HFC-125 (molecular weight: 120.0)     1-hr EEGL 7,500 36,810 24-hr EEGL 5,000 24,540 90-day CEGL 900 4,417 HFC-134a (molecular weight: 102.03)     1-hr EEGL 8,000 33,384 24-hr EEGL 5,000 20,865 90-d CEGL 900 3,756 aThese values were calculated using the following formula: where the value of 24.45 is the molar volume of air in liters at a pressure of 760 mm Hg and a temperature of 25°C. The 1-hr EEGL, 24-hr EEGL, and 90-day CEGL for HFC-404a were calculated to be 12,900 ppm, 4,300 ppm, and 800 ppm, respectively. The Navy proposes to use lower guidance levels of 2,000 ppm for the 1-hr EEGL, 1,000 ppm for the 24-hr EEGL, and 100 ppm for the 90-day CEGL, which the subcommittee concludes are conservative values that are protective of submariner health. CALCULATIONS Calculations Used to Determine EEGLs and CEGL for HFC-404a HFC-404a contains by weight: 52% HFC-143a, 44% HFC-125, and 4% HFC-134a The equation below was used to calculate the 1-hr and 24-hr EEGLs and 90-

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a day CEGL for the mixture HFC-404a; f is the fraction of each component of the mixture and EGL is the component's corresponding exposure guidance level (which must be expressed in terms of milligrams per cubic meter): Using the values in Table 4-5, the EGLs for HFC-404a were calculated as follows: 1-hr EEGL: Of the mixture, 52% or 52,075 mg/m3 × 0.52 = 27,079 mg/m3 is HFC-143a 44% or 52,075 mg/m3 × 0.44 = 22,913 mg/m3 is HFC-125 4% or 52,075 mg/m3 × 0.04 = 2,083 mg/m3 is HFC-134a. These values can be converted to parts per million as follows: HFC-143a: 27,079 mg/m3 × 0.29 = 7,853 ppm HFC-125: 22,913 mg/m3 × 0.20 = 4,583 ppm HFC-134a: 2,083 mg/m3 × 0.24 =500 ppm. The 1-hr EEGL of HFC-404a = 7,853 + 4,583 + 500 ≈ 12,900 ppm. 24-hr EEGL: Of the mixture, 52% or 17,341 mg/m3 × 0.52 = 9,017 mg/m3 is HFC-143a 44% or 17,341 mg/m3 × 0.44 = 7,630 mg/m3 is HFC-125 4% or 17,341 mg/m3 × 0.04 = 694 mg/m3 is HFC-134a.

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a These values can be converted to parts per million as follows: HFC-143a: 9,017 mg/m3× 0.29 = 2,615 ppm HFC-125: 7,630 mg/m3 × 0.20 = 1,526 ppm HFC-134a: 694 mg/m3 × 0.24 = 167 ppm. 24-hr EEGL of HFC-404a = 2,615 + 1,526 + 167 ≈ 4,300 ppm. 90-day CEGL: Of the mixture, 52% or 3,064 mg/m3 × 0.52 = 1,593 mg/m3 is HFC-143a 44% or 3,064 mg/m3 × 0.44 = 1,348 mg/m3 is HFC-125 4% or 3,064 mg/m3 × 0.04 = 123 mg/m3 is HFC-134a. These values can be converted to parts per million as follows: HFC-143a: 1,593 mg/m3 × 0.29 = 462 ppm HFC-125: 1,348 mg/m3 × 0.20 = 270 ppm HFC-134a: 123 mg/m3× 0.24 = 30 ppm. 90-day CEGL of HFC-404a = 462 + 270 + 30 = 800 ppm. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists) . 1999. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents. Biological Exposure Indices. Cincinnati, OH.: American Conference of Governmental Industrial Hygienists. AIHA (American Industrial Hygiene Association). 1991. Workplace Environmental Exposure Level Guide: 1,1,1,2-Tetrafluoroethane . Akron, OH.: American Industrial Hygiene Association. AIHA (American Industrial Hygiene Association). 1996. Workplace Environmental Exposure Level: 1,1,1-Trifluoroethane. Fairfax, Va.: American Industrial Hygiene Association.

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a Alexander, D.J., and S.E. Libretto. 1995. An overview of the toxicology of HFA-134a (1,1,1,2-tetrafuloeoethane) . Human Exper. Toxicol. 14:715-720. Alexander, D.J., E. Mortimer, G.D. Dines, S.E. Libretto, and D.N. Mallett. 1995. One-year study in dogs of the toxicity of HFA-134a by inhalation. Inhalation Toxicol. 7:1153-1162. Alexander, D.J., S.E. Libretto, M.J. Adams, E.W. Hughes, and M. Bannerman. 1996. HFA-134a (1,1,1,2-tetrafluoroethane): effects of inhalation exposure upon reproductive performance, development and maturation of rats . Human Exp. Toxicol. 15:508-517. Anderson, D., and C.R. Richardson. 1979. Arcton 134a: A Cytogenetic Study in the Rat. Study Number SR0002, Report Number CTL/P/444, Central Toxicology Laboratoy, ICI, England. Araki, A. 1991. Report on Reverse Mutation Assay in Bacteria on Tetrafluoroethane . Japan Bioassay Laboratory, Study Nos. 5292 & 5312. Japan Industrial Safety and Health Association. Asakura, M. 1991. Report on a Chromosomal Aberration Test of 1,1,1,2-Tetrafluoroethane in Cultured Mammalian Cells. Japan Bioassay Laboratory, Study Number 5879. Japan Industrial Safety and Health Association . Azar, A., H.J. Trochimowicz, J.B. Terrill, and L.S. Mullin. 1973. Blood levels of fluorocarbon related to cardiac sensitization. Am. Ind. Hyg. Assoc. J. 34:102-109. Barton, S.J., P. McDonald, and J. Sandow. 1994. HFA-134a Study of the Effects on Testicular Endocrine Function After Inhalation Exposure (6 h per day). IRI Project No. 490704. Study prepared by Inveresk Research International, Tranent, Scotland, for International Pharmaceutical Aerosol Consortium for Toxicology Testing, Washington, D.C. Brock, W.J., H.J. Trochimowicz, C.H. Farr, R.J. Millischer, and G.M. Rusch. 1996. Acute, subchronic, and developmental toxicity and genotoxicity of 1,1,1-trifluoroethane (HFC-143a). Fundam. Appl. Toxicol. 31:200-209. Brooker, A.J., P.J. Brown, D.M. John, and D.W. Coombs. 1992. The Effect of HFC 125 on Pregnancy of the Rabbit. Report No. ALS 10/920856. Huntingdon Research Centre, Cambridgeshire, England. Brusick, D.J. 1976. Mutagenicity data of Genetron 134a. Final Report, LBI Report No. 2683, (unpublished data), Litton Bionetics . Callander, R.D., and K.P. Priestley. 1990. HFC 134a. An Evaluation Using the Salmonella Mutagenicity Assay. Report No. CTL/P/2422, Central Toxicology Laboratory,(unpublished data), ICI, England. Collins, M.A. 1984. HFC 134a: Acute Toxicity in Rats to Tetrafluoroethane. Unpublished data from Central Toxicology Laboratory, ICI, England. Collins, M.A., G.M. Rusch, F. Sato, P.M. Hext, and R.J. Millischer. 1995. 1,1,1,2-Tetrafluoroethane: repeat exposure inhalation toxicity in the rat, developmental toxicity in the rabbit, and genotoxicity in vitro and in vivo. Fundam Appl. Toxicol. 25:271-280. Dance, C.A., and G. Hodson-Walker. 1992. In Vitro Assessment of the Clastogenic

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a Activity of HFC 125 in Cultured Chinese Hamster Ovary (CHO) Cells . LSR Report No. 91/PAR006/1015a. Life Science Research Ltd., Eye, Suffolk, England. Dance, C.A., K.E. Beach, and G. Hodson-Walker. 1992. In Vitro Assessment of the Clastogenic Activity of HFC 125 in Cultured Human Lymphocytes. LSR Report No. 91/PAR005/1014a. Life Science Research Ltd., Eye, Suffolk, England. DuPont Company. 1994. Metabolism of HFC-143a in the Rat. Haskell Laboratory Report No. 3-94. (Unpublished data.) Haskell Laboratory, E.I. du Pont de Nemours & Co., Newark, DE. ECETOC (European Centre for Ecotoxicology and Toxicology of Chemicals) . 1994. Joint Assessment of Commodity Chemicals No. 24, Pentafluoroethane (HFC-125), May, 1994. [ISSN-0773-6339-24]. ECETOC (European Centre for Ecotoxicology and Toxicology of Chemicals) . 1995. Joint Assessment of Commodity Chemicals No. 31, 1,1,1,2-Tetrafluoroethane (HFC-134a), February, 1995. [ISSN-0773-6339-31]. Edwards, C.N., G. Hodson-Walker, and S. Cracknell. 1992. HFC 125: Assessment of Clastogenic Action on Bone Marrow Erythrocytes in the Micronucleus Test. LSR Report No. 92/PAR004/0148. Life Science Research Ltd., Eye, Suffolk, England. Ellis, M.K., L.A. Gowans, T. Green, and R.J.N. Tanner. 1993. Metabolic fate and disposition of 1,1,1,2-tetrafluoroethane (HFC134a) in rat following a single exposure by inhalation. Xenobiotica 23:719-729. Emmen, H.H., and E.M.G. Hoogendijk. 1999. Report on an Ascending Dose Safety Study Comparing HFA-134a with CFC-12 and Air, Administered by Whole-Body Exposure to Healthy Volunteers . TNO Report V98.754 – Vol. 1 and 2, Zeist, The Netherlands: TNO Nutrition and Food Research Institute. EPA ( U.S. Environmental Protection Agency). 1986. Guidelines for Health Risk Assessment of Chemical Mixtures. 51 FR 34014. Sept, 24. Finch, J.R., E.J. Dadey, S.L. Smith, L.I. Harrison, and G.A. Digenis. 1995a. Dynamic monitoring of total-body absorption by 19F NMR spectroscopy: one hour ventilation of HFA-134a in male and female rats. Magn. Reson. Med. 33:409-413. Finch, J.R., W.R. Banks, D.R. Hwang, M.R. Satter, B. Ezzidene, J.C. Mantil, and G.A. Digenis. 1995b. Synthesis and in vivo disposition studies of 18F-labeled HFA-134a. Appl. Radiat. Isot. 46:241-248. Groten J.P., E.D. Schoen, P.J. van Bladeren, C.F. Kuper, J.A. van Zorge, and V.J. Feron. 1996. Subacute toxicity of a mixture of nine chemicals in rats: detecting interactive effects with a fractionated two-level factorial design . Fundam. Appl. Toxicol. 36:15-29. Hardy, C.J. 1992. Assessment of Cardiac Sensitization Potential in Dogs: Comparison of HFC-125 and Halon 13B1 Report No. ALS11/920116. Huntingdon Research Centre Ltd., Cambridgeshire, England. Hardy, C.J., I.J. Sharman, and G.C. Clark. 1991. Assessment of Cardiac Sensitization Potential in Dogs. Rep. No. CTL/C/2521. Huntingdon Research Centre, Cambridgeshire, U.K. Harris, J.W., J.P. Jones, J.L. Martin, A.C. La Rosa, M.J. Olson, L.R. Pohl, and M.W. An-

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a ders. 1992. Pentahaloethane-based chlorofluorocarbon substitutes and halothane: correlation of in vivo hepatic protein-trifluoroacetylation and urinary trifluoroacetic acid excretion with calculated enthalpies of activation . Chem. Res. Toxicol. 5:720-725. Harrison, L.I., D. Donnell, J.L. Simmons, B.P. Ekholm, K.M. Cooper, and P.J. Wyld. 1996. Twenty-eight-day double-blind safety study of an HFA-134a inhalation aerosol system in healthy subjects. J. Pharm. Pharmacol. 48:596-600. Hext, P.M. 1989. HFC-134a: 90-Day Inhalation Toxicity Study in the Rat. ICI Rep. No. CTL/P/2466. Central Toxicology Laboratory, Imperial Chemical Industries, Alderley Park, Macclesfield, Cheshire, U.K. Hext, P.M., and R.J. Parr-Dobrzanski. 1993. HFC-134a: A 2-Year Inhalation Toxicity Study in the Rat. ICI Rep. No. CTL/P/3841. Central Toxicology Laboratory, Imperial Chemical Industries, Alderley Park, Macclesfield, Cheshire, U.K. Hodge, M.C.E., M. Kilmartin, R.A. Riley, T.M. Weight, and J. Wilson. 1979a. Arcton 134a: Teratogenicity Study in the Rat. ICI Rep. No. CTL/P/417. Central Toxicology Laboratory, Imperial Chemical Industries, Alderley Park, Macclesfield, Cheshire, U.K. Hodge, M.C.E., D. Anderson, I.P. Bennett, and T.M. Weight. 1979b. Arcton 134a: Dominant Lethal Study in the Mouse. ICI Rep. No. CTL/P/437, Central Toxicology Laboratory, Imperial Chemical Industries, Alderley Park, Macclesfield, Cheshire, U.K. ICI Chemicals & Polymers. 1991. Cardiac Sensitization Study in Dogs. [Personal communication]. I.C.I. Chemicals & Polymers, Attn: Dr. David Farrar. P.O. Box 14, The Heath, Runcorn, Cheshire WA7 4QG, England. Kawano, T., H.J. Trochimowicz, G. Malinverno, and G.M. Rusch. 1995. Toxicological evaluation of 1,1,1,2,2-pentafluororethane (HFC-125) . Fundam. Appl. Toxicol. 28:223-231. Krishnan, K., and J. Brodeur. 1991. Toxicological consequences of combined exposures to environmental pollutants. Arch. Complex Environ. Studies 3:1-106. Longstaff, E., M. Robinson, C. Bradbrook, J.A. Styles, and I.F.H. Purchase. 1984. Genotoxicity and carcinogenicity of fluorocarbons: assessment by short-term in vitro tests and chronic exposure in rats. Toxicol. Appl. Pharmacol. 72:15-31. Lu, M., and R. Staples. 1981. 1,1,1,2-Tetrafluoroethane (FC-134a): Embryo-Fetal Toxicity and Teratogenicity Study by Inhalation in the Rat. Report No. 317-81. Haskell Laboratory, Wilmington, DE. Mackay, J.M. 1990. HFC 134a. An Evaluation in the in Vitro Cytogenetic Assay in Human Lymphocytes. Report Number CTL/P/2977, Central Toxicology Laboratory, ICI, England. Master, R.E., R.J. Brown, D.M. John, and D.W. Coombs. 1992. A Study of the Effect of HFC 125 on Pregnancy of the Rat (Inhalation Exposure). Report No. ALS 9/920434. Huntingdon Research Centre Ltd., Cambridgeshire, England. May, K., D. Watson, and G. Hodson-Walker. 1992. HFC 125 in Gaseous Phase: Assessment of Mutagenic Potential in Amino Acid Auxotrophs of Salmonella

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a Typhimurium and Escherichia Coli (the Ames Test). LSR Report No. 91/PAR003/1152a. Life Science Research Ltd., Eye, Suffolk, England. Mehendale, H.M. 1994. Amplified interactive toxicity of chemicals at nontoxic levels: mechanistic considerations and implications to public health. Environ. Health Perspect. 102 (Suppl. 9):139-149. Mercier, O. 1989. HFA-134a: Test to Determine the Index of Primary Cutaneous Irritation in the Rabbit. Report No. 911422. Hazelton, France. Mercier, O. 1990a. HFA-134a: Test to Evaluate the Ocular Irritation in the Rabbit. Report No. 912349. Hazelton, France. Mercier, O. 1990b. HFA-134a: Test to Evaluate the Sensitising Potential by Topical Applications in the Guinea Pig. The Epicutaneous Maximisation Test. Report No. 001380. Hazelton, France. Monte, S.Y., I. Ismail, D.N. Mallett, C. Matthews, and R.J. Tanner. 1994. The minimal metabolism of inhaled 1,1,1,2-tetrafluoroethane to trifluoroacetic acid in man as determined by high sensitivity 19F nuclear magnetic resonance spectroscopy of urine samples. J. Pharm. Biomed. Anal. 12:1489-1493. Müller, W., and T. Hofmann. 1989. CFC 134a: Micronucleus Test in Male and Female NMRI Mice After Inhalation . Study Number 88.1244. Pharma Research Toxicology and Pathology, Hoechst AG, Federal Republic of Germany. Mullin, L.S., and R.W. Hartgrove. 1979. Cardiac Sensitization. Rep. No. 42-79. Haskell Laboratory, Wilimington, DE. Mullin, L.S., C.F. Reinhardt, and R.E. Hemingway. 1979. Cardiac arrhythmias and blood levels associated with inhalation of Halon 1301. Am. Ind. Hyg. Assoc. J. 40:653-658. Mumtaz, M.M., and P.R. Durkin. 1992. A weight-of-evidence approach for assessing interactions in chemical mixtures. Toxicol. Ind. Health 8:377-406. Mumtaz, M.M., C.T. DeRosa, and P.R. Durkin. 1994. Approaches and challenges in risk assessments of chemical mixtures . Pp. 565-597. In: Toxicology of Chemical Mixtures: Case Studies, Mechanisms, and Novel Approaches, R.S.H. Yang, ed., San Diego, CA.: Academic Press. Mumtaz, M.M., C.T. De Rosa, J. Groten, V.J. Feron, H. Hansen, and P.R. Durkin. 1998. Estimation of toxicity of chemical mixtures through modeling of chemical interactions. Environ Health Perspect. 106( suppl 6.): 1353-1360. NRC (National Research Council). 1996. Toxicity of Alternatives to Chlorofluorocarbons: HFC-134a and HCFC-123 . Washington D.C.: National Academy Press. Nakayama, E., K. Nagano, M. Ohnishi, S. Katagiri, and O. Montegi. 1992a. Acute Inhalation Toxicity Study of 1,1,1,2,2-Pentafluoroethane in Rats. Study No. 0184. Japan Bioassay Laboratory, Hirasawa, Japan. Nakayama, E., K. Nagano, M. Ohnishi, and O. Montegi. 1992b. Four-week Inhalation Study of 1,1,1,2,2-Pentafluoroethane (HFC 125) in Rats. Study No. 0182. Japan Bioassay Laboratory, Hirasawa, Japan. Nakayama, E., K. Nagano, M. Ohnishi, and O. Montegi. 1993. Thirteen-week Inhalation Toxicity Study of 1,1,1,2,2-Pentafluoroethane (HFC 125) in Rats. Study No. 0197, Japan Bioassay Laboratory, Hirasawa, Japan.

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a Nikijenko, T.K., and M.S. Tolgskaya. 1965. On the toxico-pathomorphological changes in animals under the effect of Freons-141, 142, and 143, and the intermediate products of their production. [Russian]. Gig. Tr. Prof. Zabol. 9:37-44. Olson, M.J., and S.E. Surbrook, Jr. 1991. Defluorination of the CFC-substitute 1,1,1,2-tetrafluoroethane: comparison in human, rat and rabbit hepatic microsomes. Toxicol. Lett. 59:89-99. Olson, M.J., C.A. Reidy, and J.T. Johnson. 1990a. Defluorination of 1,1,1,2-tetrafluoroethane (R-134a) by rat hepatocytes . Biochem. Biophys. Res. Commun. 166:1390-1397. Olson, M.J., C.A. Reidy, J.T. Johnson, and T.C. Pederson. 1990b. Oxidative defluorination of 1,1,1,2-tetrafluoroethane (R-134a) by rat liver microsomes. Drug Metab. Dispos. 18:992-998. Olson, M.J., S.G. Kim, C.A. Reidy, J.T. Johnson, and R.F. Novak. 1991. Oxidation of 1,1,1,2-tetrafluoroethane in rat liver microsomes is catalyzed primarily by cytochrome P450IIE1. Drug Metab. Dispos. 19:298-303. PAFT (Programme for Alternative Toxicology Testing). 1989. Toxicology Forum, European Symposium, Toulouse, France. Panepinto, A.S. 1990. Four Hours Inhalation Approximate Lethal Concentrations (ALC) of HFC 125, Haskell Laboratory Report 582-90, Haskell Laboratory, DuPont. Pike, V.W., F.I. Aigbirhio, C.A.J. Freemantle, B.C. Page, C.G. Rhodes, S.L. Waters, T. Jones, P. Olsson, G.P. Ventresca, R.J.N. Tanner, M. Hayes, and J.M.B. Hughes. 1995. Disposition of inhaled 1,1,1,2-tetrafluoroethane (HFA134A) in healthy subjects and in patients with chronic airflow limitation. Measurement by 18F-labeling and whole-body γ-counting. Drug Metab. Dispos. 23:832-839. Riley, R.A., I.P. Bennet, I.S. Chart, C.W. Gore, M. Robinson, and T.M. Weight. 1979. Arcton 134a: Subacute Toxicity to the Rat by Inhalation. ICI Rep. No. CTL/P/463, Central Toxicology Laboratory, Imperial Chemical Industries, Alderley Park, Macclesfield, Cheshire, U.K. Rissolo, S.B., and J.A. Zapp. 1967. Acute Inhalation Toxicity. Rep. No. 190-67, Haskell Laboratory, Wilmington, DE. Silber, L.S., and G.L. Kennedy. 1979a. Acute Inhalation Toxicity of Tetrafluoroethane. Rep. No. 422-79. Haskell Laboratory, Wilmington, DE. Silber, L.S., and G.L. Kennedy. 1979b. Subacute Inhalation Toxicity of Tetrafluoroethane (FC-134a). Rep. No. 228-79. Haskell Laboratory, Wilmington, DE. Surbrook, S.E., Jr., and M.J. Olson. 1992. Dominant role of cytochrome P-450 2E1 in human hepatic microsomal oxidation of the CFC-substitute 1,1,1,2-tetrafluoroethane. Drug Metab. Dispos. 20:518-524. Teuschler, L.K., and R.C. Hertzberg. 1995. Current and future risk assessment guidelines, policy, and methods development for chemical mixtures. Toxicology 105:137-144. Trochimowicz, H.J., A. Azar, J.B. Terrill, and L.S. Mullin. 1974. Blood levels of fluorocarbon related to cardiac sensitization: Part II. Am. Ind. Hyg. Assoc. J. 35:632-639. Trueman, R.W. 1990. HFC 134a: Assessment for the Induction of Unscheduled DNA

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a Synthesis in Rat Hepatocytes in Vivo. Study Number SR0337, Report No. CTL/P/2550, Central Toxicology Laboratory, ICI, England. Van Demark, N.L., and M.J. Fre. 1970. Temperature ffects. Pp. 235-245. In: Testis, A.D. Johnson, W.R. Gores, and N.L. Van Demark, Eds. New York, NY: Academic Press. Vinegar, A., and G.W. Jepson. 1995. Relating Blood Concentration Time Courses to Cardiac Sensitization Thresholds During Inhalation of Halon Replacement Chemicals. Report No. AL/OE-TR-1995-0132. U.S. Air Force, Armstrong Laboratory, Wright-Patterson Air Force Base, OH. Vinegar, A., R.S. Cook, J.D. McCafferty, III, M.C. Caracci, and G.W. Jepson. 1997. Human Inhalation of Halon 1301, HFC-134a and HFC-227ea for Collection of Pharmacokinetic Data. Interim Report No. AL/OE-TR-1997-0116, U.S. Air Force, Armstrong Laboratory, Wright-Patterson Air Force Base, OH. Wang, Y., M.J. Olson, and M.T. Baker. 1993. Interaction of fluoroethane chlorofluorocarbon (CFC) substitutes with microsomal cytochrome P450. Stimulation of P450 activity and chlorodifluoroethene metabolism. Biochem. Pharmacol. 46:87-94. Wickramaratne, G.A. 1989a. HFC-134a: Teratogenicity Inhalation Study in the Rabbit. ICI Rep. No. CTL/P/2504. Central Toxicology Laboratory, Imperial Chemical Industries, Alderley Park, Macclesfield, Cheshire, U.K. Wickramaratne, G.A. 1989b. HFC-134a: Embryotoxicity Inhalation Study in the Rabbit. ICI Rep. No. CTL/P/2380. Central Toxicology Laboratory, Imperial Chemical Industries, Alderley Park, Macclesfiled, Cheshire, U.K.