3

Hydrofluorocarbon-23

HYDROFLUOROCARBON (HFC)-23, or trifluoromethane, is a combustion product of HFC-236fa. It belongs to the class of halocarbons. As discussed in Chapter 2, HFC-236fa is under consideration for use in centrifugal chillers aboard naval submarines. If HFC-236fa is accidentally leaked, it will pass through the submarine's carbon-monoxide-hydrogen burner system, which operates at 500°F. Under these conditions, less than 0.1 parts per million (ppm) of HFC-23 is formed per 100 ppm of HFC-236fa. Assuming a worst-case scenario of an HFC-236fa leak at concentrations approaching 100 ppm and no HFC-23 being removed from the air, concentrations of HFC-23 within a submarine could rise by 0.5 ppm per day (Naval Surface Warfare Center 1997).

Emergency exposure guidance levels (EEGLs) and continuous exposure guidance levels (CEGLs) are needed to avoid adverse health effects in submariners from short-term or prolonged exposures to HFC-23 and to avoid degradation in crew performance. This chapter presents the available toxicity information on HFC-23 and the subcommittee's evaluation of the U.S. 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 3 Hydrofluorocarbon-23 HYDROFLUOROCARBON (HFC)-23, or trifluoromethane, is a combustion product of HFC-236fa. It belongs to the class of halocarbons. As discussed in Chapter 2, HFC-236fa is under consideration for use in centrifugal chillers aboard naval submarines. If HFC-236fa is accidentally leaked, it will pass through the submarine's carbon-monoxide-hydrogen burner system, which operates at 500°F. Under these conditions, less than 0.1 parts per million (ppm) of HFC-23 is formed per 100 ppm of HFC-236fa. Assuming a worst-case scenario of an HFC-236fa leak at concentrations approaching 100 ppm and no HFC-23 being removed from the air, concentrations of HFC-23 within a submarine could rise by 0.5 ppm per day (Naval Surface Warfare Center 1997). Emergency exposure guidance levels (EEGLs) and continuous exposure guidance levels (CEGLs) are needed to avoid adverse health effects in submariners from short-term or prolonged exposures to HFC-23 and to avoid degradation in crew performance. This chapter presents the available toxicity information on HFC-23 and the subcommittee's evaluation of the U.S. 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-23 Chemical name: Trifluromethane Synonyms: Freon 23, Genetron 23, fluoroform, HC-23, fluoryl, Arcton 1, carbon trifluoride, halocarbon 23, methyl trifluoride, R 23, FE-13 CAS number: 75-46-7 Structural formula: HCF3 Description: Colorless gas Molecular weight: 70.01 Boiling point: -82.03°C at 760 mm Hg Melting point: -155.2°C Density and specific gravity: 0.670 g/mL at 25°C Vapor pressure: 686 psig at 25°C (77°F) Vapor density: 2.4 (Air = 1.0) Flash point and flammability: Nonflammable Solubility: 0.10 wt% in water Autoignition: 765°C (1409°F) Octanol and water partition coefficient: Kow = 0.64 Conversion factors: 1 mg/m3= 0.35; 1 ppm = 2.86 mg/m3> TOXICOKINETICS Ewing et al. (1990) studied the use of HFC-23 in nuclear magnetic resonance spectroscopy as a gaseous indicator of cerebral blood flow in cats. HFC-23 at a concentration of 600,000 ppm was rapidly absorbed from the lungs and the arterial blood concentration reached a plateau within 3 or 4 min after initiation of the exposure. Likewise, HFC-23 was rapidly eliminated from the blood upon termination of the exposure. It was also rapidly taken up by the brain, with the brain uptake lagging the arterial blood uptake by about 2 min. Similar findings were demonstrated with 670,000 ppm by Detre et al. (1990) in the rat.

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a No published information is available on the distribution, metabolism, or pharmacokinetics for HFC-23. TOXICITY INFORMATION Human Studies Fagan et al. (1995) conducted a human exposure study to assess the feasibility of using HFC-23 as an indicator for the measurement of human cerebral blood flow in nuclear magnetic resonance spectroscopy. Five subjects were exposed in a blinded fashion to HFC-23 at concentrations ranging from 100,000 to 600,000 ppm. Up to eight pulsed exposures lasting 3 min each, interspersed with 2 min of air exposure between pulses, constituted the exposure regimen. The subjects underwent extensive physiological and neurobehavioral monitoring throughout the study. The maximum tolerated concentration was considered to be 300,000 ppm. Effects such as lightheadedness, tingling and numbness of the extremities, and hyperacusis (abnormal acuteness of hearing) were noted at concentrations of 300,000 ppm and above. These effects were seen in only one subject at 300,000 ppm, and no effects were observed at concentrations of 100,000 ppm and 200,000 ppm. No clinically significant physiological effects (e.g., heart rate and rhythm, respiratory rate, and oxygenation) were noted, nor were abnormal clinical laboratory or neurobehavioral effects observed. A small but statistically significant retention of carbon dioxide occurred at 300,000 ppm. The effects of HFC-23 were very short in duration and all subjects were back to baseline at the 30-day evaluation. Acute Toxicity HFC-23 has low acute toxicity by the inhalation route. Its approximate lethal concentration (ALC) in rats is greater than 663,000 ppm after a 4-hr inhalation exposure. Kennedy and Nash (1980) exposed groups of six male albino rats to HFC-23 for a single 4-hr period at concentrations of 18,900 ppm, 186,000 ppm, and 663,000 ppm. Oxygen concentrations were maintained at about 20%. Clinical signs observed during exposure to the two higher concentrations included reduced response to sound, gasping, labored breathing, sluggishness, and gnawing. Mild weight loss was observed 24-48 hr after exposure, but normal weight gain was achieved thereafter.

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a Clayton et al. (1960) reported an ALC of greater than 200,000 ppm in guinea pigs after a 2-hr exposure to HFC-23. Twelve male albino guinea pigs were exposed at that concentration for 2 hr, and no clinical signs or pathological changes were attributable to HFC-23. Fleming (1945) exposed two male albino guinea pigs to HFC-23 at a concentration of approximately 30,000 ppm for 6 hr. No effects on respiration or weight gain were observed, and no gross or microscopic pathological effects were found when the animals were sacrificed 1 week after exposure. Cardiac Sensitization On the basis of studies in three species that are discussed in this section, HFC-23 has an extremely low cardiac-sensitization potential. These studies were done using a standard epinephrine challenge test similar to that reported by Reinhardt et al. (1971). In all the cardiac-sensitization studies discussed below, supplemental oxygen was given at HFC-23 concentrations of 500,000 ppm and above. Hopkins and Krantz (1968) exposed female mongrel dogs to HFC-23 at 800,000 ppm and found no effect on cardiac automaticity after an intravenous injection of epinephrine. A control injection of epinephrine at 10 µg/kg body weight was given before exposure to HFC-23, and a challenge injection (same dose) was given after a 5- to 10-min exposure period. An electrocardiogram (ECG) was recorded at the beginning of the injection and for at least 60 sec after each epinephrine injection. A formula for measuring the intensity of a myocardial-sensitization response in terms of relative incidence of multifocal ventricular ectopic contractions (RIMVEC) was used to quantitate the electrocardiographic response. The average RIMVEC response following the challenge injection of epinephrine after exposure to HFC-23 was essentially the same as that following the control injection of epinephrine in the five dogs tested. Hardy and Kieran (1993) exposed male beagle dogs to HFC-23 at concentrations ranging from 100,000 to 500,000 ppm and found no evidence of cardiac sensitization after an intravenous injection of epinephrine. A control injection of epinephrine was given before exposure, and a challenge injection (same dose) was given after 5 min of exposure; the exposure continued for an additional 5 min. The dose of epinephrine was calibrated for each dog to produce an acceptable number (about 10) of ectopic ventricular beats. A dose of 12 µg/kg was the maximum dose used. One dog was test-

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a ed at each of the six concentrations used. No positive responses were observed in any of the dogs. Branch et al. (1994) evaluated the acute cardiac and central-nervous-system effects of HFC-23 in eight anesthetized baboons. An intravenous injection of 1 µg/kg epinephrine was given after 3 min of exposure to HFC-23 at concentrations of 600,000 ppm or 700,000 ppm. The effects of a control injection of epinephrine had been previously evaluated. Premature ventricular activity totaling four beats was observed in one animal 1 min after the epinephrine injection during inhalation of HFC-23 at 700,000 ppm. No other arrhythmic activity was observed during this study. Ewing et al. (1990) exposed anesthetized cats to HFC-23 at a concentration of 700,000 ppm for 10 min and observed cardiac sensitization in three of five cats after an intravenous injection of epinephrine. Two of the three sensitized cats received 1 µg/kg and the other one received 10 µg/kg. Two other cats that given epinephrine at 0.1 µg/kg did not develop any cardiac arrhythmias. Branch et al. (1990) exposed anesthetized cats to HFC-23 at a concentration of 700,000 ppm for 10 min and observed cardiac sensitization in three of seven cats after an intravenous injection of epinephrine. All seven cats received 1 µg/kg. Two other cats that received epinephrine at 0.1 µg/kg did not develop any cardiac arrhythmias. In both of these studies, the epinephrine was given immediately after exposure. Subchronic Toxicity Leuschner et al. (1983) exposed groups of 20 male and 20 female rats to HFC-23 at 10,000 ppm for 6 hr per day for 90 consecutive days. Likewise, they exposed groups of three male and three female beagle dogs to HFC-23 at 5,000 ppm for 6 hr per day for 90 consecutive days. Clinical signs, food and water consumption, changes in body weight, clinical chemistry, gross and microscopic pathology, and ECGs on the dogs were evaluated. No abnormalities attributable to the test compound were observed and no premature deaths occurred. The investigators concluded that HFC-23 did not produce any adverse effects in the rats or dogs under the test conditions used. Reproductive Toxicity No reproductive toxicity studies of HFC-23 are currently available.

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a Developmental Toxicity Munley (1997) exposed groups of 25 mated female rats to HFC-23 at concentrations of 5,000 ppm, 20,000 ppm, or 50,000 ppm on days 7 to 21 of gestation for 6 hr per day. No evidence of any maternal or developmental toxicity was observed at any exposure concentration tested. No compound-related effects were observed on maternal body weights, weight changes, food consumption, clinical observations, or post-mortem findings. No compound-related developmental effects were observed. The end points evaluated were mean fetal weight, mean litter size, measures of pre- and post-implantation embryo lethality, and the incidences of fetal malformations and variations. Thus, the no-observed-adverse-effect level (NOAEL) is 50,000 ppm for developmental and maternal effects. Therefore, the results of this study indicate that HFC-23 is not toxic to the rat conceptus. Genotoxicity Foltz and Fuerst (1974) exposed Drosophila melanogaster to a presumably high, but unknown, concentration of HFC-23 for 10 min to assess its mutagenic potential. HFC-23 was found to significantly increase mutation rates in Drosophila progeny over the control rates. However, the investigators state that an undetermined part of the observed mutagenic effects of the gas might be due to anoxia and warrants further investigation. Lee et al. (1983) in a report of the U.S. Environmental Protection Agency gene-tox program reviewed a large number of studies on the sex-linked recessive lethal (SLRL) test for mutagenesis in D. melanogaster, including the study by Foltz and Fuerst (1974) cited above. The report categorized HFC-23 as a compound that could not be classified as positive or negative for mutagenic activity in the Drosophila SLRL test because of inadequate sample size. Andrews (1996a) conducted an Ames Salmonella typhimurium reverse mutation assay on HFC-23 by exposing five strains of the bacteria to concentrations ranging from 100,000 to 1,000,000 ppm for 24 hr. The results indicate a negative mutagenic response in all five strains both in the presence and in the absence of metabolic activation. Longstaff et al. (1984) also conducted an Ames Salmonella reverse mutation assay on HFC-23 at concentrations up to 500,000 ppm and obtained negative results in four strains of the bacteria, with and without metabolic activation.

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a Tice (1996a) conducted a mouse bone-marrow micronucleus assay on HFC-23 by exposing groups of five B6C3F1 mice per sex to concentrations ranging from 130,000 to 500,000 ppm for 6 hr per day for three consecutive days. That exposure was followed by a single sample time 24 hr after the final exposure. Positive and negative controls were included in the study. The results indicate that HFC-23 did not significantly increase the frequency of micronucleated polychromatic erythrocytes (PCEs) in the bone marrow of male or female mice or significantly affect the percentage of PCEs in either sex. Andrews (1996b) evaluated the ability of HFC-23 to induce gene mutations in the guanine phosphoribosyl-transferase (gpt) locus of cultured AS52 Chinese hamster ovary (CHO) cells in the presence or absence of metabolic activation. The cells were exposed to HFC-23 in concentrations ranging from 500,000 to 1,000,000 ppm for 5 hr. Positive and negative controls were included in the study. The results indicate that HFC-23, in either the presence or the absence of metabolic activation, did not induce a significant increase in the mutant frequency at the gpt locus in cultured AS52 cells. Tice (1996b) evaluated the potential of HFC-23 to induce structural chromosomal damage in cultured CHO cells in both the absence and the presence of metabolic activation. The cells were exposed to HFC-23 in concentrations ranging from 500,000 to 1,000,000 ppm for 4 hr. Positive and negative controls were included in the study. HFC-23 induced a significant increase in clastogenic damage at concentrations in air ranging from 800,000 to 1,000,000 ppm in the absence of metabolic activation. Under those same conditions, 100% nitrogen induced a significant increase in chromosomal damage to the same magnitude, suggesting the possibility that the response might reflect changes in oxygen concentrations rather than HFC-23 specifically. In the presence of metabolic activation, HFC-23 and 100% nitrogen induced an increase in chromosomal damage that was not statistically significant. On the basis of the available data, the subcommittee concludes that HFC-23 is not genotoxic and is unlikely to induce heritable effects in humans. Carcinogenicity No chronic exposure or carcinogenicity studies of HFC-23 are currently available.

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a SUMMARY Toxicokinetic studies indicate that HFC-23 is readily absorbed by the lungs and that blood concentrations reach a plateau within minutes. HFC-23 is rapidly eliminated from the blood upon termination of exposure. Table 3-1 summarizes the studies on HFC-23 for cardiac sensitization and Table 3-2 summarizes all the noncancer toxicity studies on HFC-23. The animal toxicity information and human exposure data indicate that HFC-23 has low toxicity. The only significant observations were reduced response to sound in rats exposed at 186,000 ppm and lightheadedness, tingling and numbness of the extremities, and hyperacusis in humans after exposure at 300,000 ppm and above. Cardiac-sensitization studies conducted in three species indicate that HFC-23 has the potential to cause cardiac sensitization at high concentrations. Evidence of such sensitization was observed in baboons and cats exposed at 700,000 ppm, but no evidence was observed in dogs exposed at concentrations as high as 800,000 ppm. A developmental toxicity study in rats exposed to HFC-23 at a concentration of 50,000 ppm reported no evidence of maternal or fetal toxicity or teratogenicity. There is no evidence that HFC-23 is genotoxic. There are no available long-term toxicity studies or carcinogenicity bioassays of HFC-23. TABLE 3-1 Summary of Cardiac Sensitization Studies with HFC-23 Species Concentration, ppm Ventricular Arrhythmia Reference Mongrel dogs 800,000 0/5 Hopkins and Krantz 1968 Beagle dogs 100,000-500,000 0/6 Hardy and Kieran 1993 Baboons 600,000 0/8 Branch et al. 1994 Baboons 700,000 1/8 Branch et al. 1994 Cats 700,000 3/5 Ewing et al. 1990 Cats 700,000 3/7 Branch et al. 1990

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a TABLE 3-2 Summary of Noncancer Toxicity Information for HFC-23 Species Exposure Frequency and Duration End Point NOAEL, ppm LOAEL, ppm Reference Acute Toxicity           Human 3 min, air 2 min, 8 pulses Central nervous system effects 200,000 300,000 Fagan et al. 1995 Rat 4 hr Central nervous system effects 18,900 186,000 Kennedy and Nash 1980 Guinea pig 2 hr No significant effect 200,000 ND Clayton et al. 1960 Guinea pig 6 hr No significant effect 30,000 ND Fleming 1945 Dog 5-10 min Cardiac sensitization 800,000 ND Hopkins and Krantz 1968 Dog 10 min Cardiac sensitization 500,000 ND Hardy and Kieran 1993 Baboon 3 min Cardiac sensitization 600,000 700,000 Branch et al. 1994 Cat 10 min Cardiac sensitization ND 700,000 Ewing et al. 1990 Cat 10 min Cardiac sensitization ND 700,000 Branch et al. 1990 Subchronic Toxicity           Rat 6 hr/d, 90 consecutive d No significant effect 10,000 ND Leuschner et al. 1983 Dog 6 hr/d, 90 consecutive d No significant effect 5,000 ND Leuschner et al. 1983 Developmental Toxicity           Rat 6 hr/d, gestation d 7-21 Maternal toxicity 50,000 ND Munley 1997     Fetal toxicity 50,000 ND   Abbreviation: ND, not determined.

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a EXPOSURE GUIDANCE LEVELS The Navy proposes to use the same exposure guidance levels for HFC-23 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 of the proposed guidance levels, the subcommittee reviewed the available toxicity data on HFC-23 to determine what levels would be adequately protective of submariner health. A comparison of those results is presented below. 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. Submarine Exposure Guidance Levels for HFC-23 Exposure Level NRC's Calculated Levels Navy's Proposed Levels 1-hr EEGL 20,000 ppm 2,000 ppm 24-hr EEGL 5,000 ppm 1,000 ppm 90-day CEGL 500 ppm 100 ppm To evaluate the proposed 1-hr EEGL of 2,000 ppm for HFC-23, the subcommittee considered the human exposure study by Fagan et al. (1995). In that study, eight exposures of 3 min each, interspersed with 2 min of air, did not produce any effects at a concentration of 200,000 ppm, and only one of five subjects was affected at 300,000 ppm. Although the cumulative exposure in the study was 24 min, the subcommittee used the NOAEL of 200,000 ppm without time extrapolation 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). However, it was necessary to account for the uncertainty associated with the discontinuous exposure by dividing the NOAEL by an uncertainty factor of 10 to yield a value of 20,000 ppm. Because that value is 10-fold higher than the 1-hr EEGL of 2,000 ppm proposed by the Navy, the subcommittee concludes that the Navy's value is adequately protective of health. In its evaluation of the Navy's proposed 24-hr EEGL, the subcommittee used a developmental toxicity study in rats (Munley 1997). Although developmental toxicity is not necessarily the most appropriate end point for de-

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a riving an EEGL for use aboard submarines (vessels with no female crew members) this study has the most relevant exposure duration (total of 90 hr) of all the available studies, and no maternal or developmental toxicity was observed. Thus, the highest concentration tested of 50,000 ppm was considered to be the NOAEL. Because the available human data on HFC-23 are inadequate to determine the magnitude of difference between rats and humans, the subcommittee divided the NOAEL by an uncertainty factor of 10 to account for interspecies variability to yield a value of 5,000 ppm. The Navy's proposed 24-hr EEGL of 1,000 ppm is five times lower than that value and is therefore an adequate guidance level. To evaluate the Navy's proposed 90-day CEGL, the subcommittee used the 90-day toxicity studies in rats and dogs (Leuschner et al. 1983). For rats, the NOAEL was 10,000 ppm for 6 hr per day for 90 consecutive days, and for dogs, the NOAEL was 5,000 ppm for the same duration. The NOAELs in these studies were the only concentrations tested. The subcommittee believes that they are probably lower than the true NOAEL for HFC-23 because NOAELs reported in 90-day studies of similar HFCs were higher; for example, the NOAEL was 40,000 ppm for HFC-143a (Brock et al. 1996) and 50,000 ppm for HFC-125 (Nakayama et al. 1993 as cited in Kawano et al. 1995) and HFC-134a (Hext 1989; Collins et al. 1995). Furthermore, HFC-23 had no maternal or fetal effects in a developmental toxicity study at a concentration of 50,000 ppm. Given this, an uncertainty factor to adjust for the 6 hr per day exposures was not used. However, an uncertainty factor of 10 was applied to the NOAELs to account for interspecies variability, giving values of 1,000 ppm and 500 ppm, respectively. Because the Navy's proposed 90-day CEGL of 100 ppm is 5-fold lower than 500 ppm, the subcommittee finds the Navy 's exposure guidance levels to be adequately protective of health for prolonged exposures. REFERENCES Andrews, P.W. 1996a. Salmonella Typhimuriam Microsome Reverse Mutation Assay. Proj. No. ILS A073-001. Integrated Laboratory Systems, Durham, N.C. Andrews, P.W. 1996b. AS52/GPT Mammalian Mutagenesis Assay. Proj. No. ILS A073-003. Integrated Laboratory Systems, Durham, N.C. 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. Branch, C.A., D.A. Goldberg, J.R. Ewing, S.C. Fagan, S.S. Butt, and J. Gayner. 1994. Evaluation of the acute cardiac and central nervous system effects of the fluoro-

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a carbon trifluoromethane in baboons. J. Toxicol. Environ. Health 43:25-35. Branch, C.A., J.R. Ewing, S.C. Fagan, D.A. Goldberg, and K.M.A. Welch. 1990. Acute toxicity of a nuclear magnetic resonance cerebral blood flow indicator in cats. Stroke 21:1172-1177. 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. Clayton, J.W., Jr., D.B. Hood, and J.W. Williams. 1960. Acute Testing. Rep. No. 25-60. Haskell Laboratory, Newark, DE. 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. Detre, J.A., C.J. Eskey, and A.P Koretsky. 1990. Measurement of cerebral blood flow in rat brain by 19F-NMR detection of trifluoromethane washout. Magn. Reson. Med. 15:45-57. Ewing, J.R., C.A. Branch, S.C. Fagan, J.A. Helpern, R.T. Simkins, S.M. Butt, and K.M.A. Welch. 1990. Fluorocarbon-23 measure of cat cerebral blood flow by nuclear magnetic resonance. Stroke 21:100-106. Fagan, S.C., A.A. Rahill, G. Balakrishnan, J.R. Ewing, C.A. Branch, and G.G. Brown. 1995. Neurobehavioral and physiologic effects of trifluoromethane in humans . J. Toxicol. Environ. Health 45:221-229. Fleming, A.J. 1945. Kitchen Tests on “Freon” Refrigerants. Rep. No. 0023-45. Haskell Laboratory, Newark, DE. Foltz, V.C., and R. Fuerst. 1974. Mutation studies with Drosophila melanogaster exposed to four fluorinated hydrocarbon gases. Environ. Res. 7:275-285. Hardy, C.J., and P.C Kieran. 1993. Halon 13B1, Freon 23, Mixture of Freon 23 and HFC 125, Assessment of Cardiac Sensitisation Potential in Dogs. DPT 273/921009. Huntingdon Research Centre Ltd., Huntingdon, Cambridgeshire, England. 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. Hopkins, R.M., and J.C. Krantz. 1968. Relative effects of haloforms and epinephrine on cardiac automaticity . Anesth. Analg. 47:56-67. Kennedy, G.L., and S.D. Nash. 1980. Inhalation Approximate Lethal Concentration. Rep. No. 641-80. Haskell Laboratory, Newark, DE. Lee, W.R., S. Abrahamson, R. Valencia, E.S. von Halle, F.E. Wurgler, and S. Zimmering. 1983. The Sex-linked recessive lethal test for mutagenesis in Drosophila melanogaster, a report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation Res. 123:183-279. Leuschner, F., B.W. Neumann, and F. Hubscher. 1983. Report on subacute toxicological studies with several fluorocarbons in rats and dogs by inhalation. Arzneim.-Forsch. 33:1475-1476.

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a Longstaff, E., M. Robinson, C. Bradbrock, 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. 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. Munley, S.M. 1997. HFC-23: Inhalation Developmental Toxicity Study in Rats. Rep. No. 995-96. Haskell Laboratory, Newark, DE. Naval Surface Warfare Center. 1997. Subject: Refrigerant decomposition in submarine CO-H2 burners. Letter to Commander, Naval Sea Systems Command, from Commander, Carderock Division, Naval Surface Warfare Center, Philadelphia, PA., dated June 24, 1997. Reinhardt, C.F., A. Azar, M.E. Maxfield, P.E. Smith, Jr., and L.S. Mullin. 1971. Cardiac arrhythmias and aerosol “sniffing.” Arch. Environ. Health 22:265-279. Tice, R.R. 1996a. Repeated Inhalation Exposure of FE-13 in Mice, Mus musculus (Bone Marrow Micronucleus Assay). Proj. No. ILS A073-002. Integrated Laboratory Systems, Durham, N.C. Tice, R.R. 1996b. In Vitro Chromosome Aberrations Study in Chinese Hamster Ovary (CHO) Cells. Proj. No. ILS A073-004. Integrated Laboratory Systems, Durham, N.C. 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.