B1 Bromotrifluoromethane (Halon 1301)

Chiu-Wing Lam, Ph.D.

Johnson Space Center Toxicology Group

Biomedical Operations and Research Branch

National Aeronautics and Space Administration

Houston, Texas

PHYSICAL AND CHEMICAL PROPERTIES

Synonyms:

Trifluorobromomethane,

Freon 1301, Freon 13B1,

Fluorocarbon 1301

CAS number:

75-63-8

Formula:

CBrF3

Molecular weight:

148.9

Melting point:

-167.7°C

Boiling point:

-57.8°C

Vapor pressure:

Exists as a gas at ambient temperature

Concentration conversion at 25°C:

1 ppm = 6.1 mg/m3; 1 mg/m3 = 0.16 ppm

OCCURRENCE AND USE

Bromotrifluoromethane, a gaseous fluorocarbon, is commonly known as Halon 1301. It is widely used as a fire-extinguishing agent, especially in computer and high-technology facilities (Holness and House, 1992). Because it is effective and residue-free, Halon 1301 is used in the space-shuttle fire-suppression system. Three fixed fire extinguishers



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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 B1 Bromotrifluoromethane (Halon 1301) Chiu-Wing Lam, Ph.D. Johnson Space Center Toxicology Group Biomedical Operations and Research Branch National Aeronautics and Space Administration Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Synonyms: Trifluorobromomethane, Freon 1301, Freon 13B1, Fluorocarbon 1301 CAS number: 75-63-8 Formula: CBrF3 Molecular weight: 148.9 Melting point: -167.7°C Boiling point: -57.8°C Vapor pressure: Exists as a gas at ambient temperature Concentration conversion at 25°C: 1 ppm = 6.1 mg/m3; 1 mg/m3 = 0.16 ppm OCCURRENCE AND USE Bromotrifluoromethane, a gaseous fluorocarbon, is commonly known as Halon 1301. It is widely used as a fire-extinguishing agent, especially in computer and high-technology facilities (Holness and House, 1992). Because it is effective and residue-free, Halon 1301 is used in the space-shuttle fire-suppression system. Three fixed fire extinguishers

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 are positioned in the avionic bays, and three portable extinguishers are located in the crew module; the fixed and portable extinguisher tanks each contain 1.73 and 1.25 kg of Halon 1301, respectively (M. Hoy, NASA Fire Detection and Suppression Branch, Crew and Thermal Systems Division, personal commun., 1993). Halon 1301 has been detected, probably from small leaks in the tanks, in the in-flight air samples in about two-thirds of the shuttle missions flown to date. Detected concentrations ranged from 2.3 to 77 mg/m3 for the first 24 missions (Coleman, 1988); in more recent missions (STS-26 to 52, missions after the Challenger accident), concentrations were generally below 10 mg/m3, and half of those were below 1 mg/m3. None of the extinguisher tanks has ever been discharged during a mission. However, in the event of a fire or a false alarm in the avionics bay, all three tanks could be discharged, resulting in a cabin concentration of Halon 1301 at 1% (10,000 ppm, 61,000 mg/m3). This low concentration of halogenated methane cannot be removed effectively by activated charcoal and would remain in the confined environment of the spacecraft. The crew could be exposed to Halon 1301 for up to 24 h before the shuttle could return safely to earth. Current environmental policy in the United States calls for phasing out chlorofluorocarbons (CFCs). Although the National Aeronautics and Space Administration (NASA) is phasing out noncritical uses of CFCs, Halon 1301 will continue to be used in the shuttle fire-suppression system. It will not be used in the space station, because the air-revitalization system planned for the station could not remove this compound efficiently (M. Hoy, NASA Fire Detection and Suppression Branch, Crew and Thermal Systems Division, personal commun., 1993). However, if Halon 1301 is discharged in the shuttle while it is docked with the station, the gas could diffuse into the station, and crews could be exposed to low concentrations of Halon 1301 for extended periods during their tours of duty. TOXICOKINETICS AND METABOLISM Toxicokinetics An inhalation study sponsored by NASA was conducted with eight pairs of human subjects exposed to 1% (10,000 ppm) Halon 1301 for

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 24 h; toxicokinetics were studied. Blood concentrations of Halon 1301 increased rapidly and approached a steady state within 2 h of starting the exposure; the steady-state concentration was approximately 3-4.5 µg/mL (Lam et al., 1993). Postexposure elimination of the compound was biphasic with average half-lives of 4.5 min for richly perfused tissues and 200 min for poorly perfused tissues (chiefly fat). Six hours after the cessation of exposure, the blood concentration was about 10% of the steady-state concentration. The end-tidal-breath, blood, tissue, and fat partition coefficients were estimated to be 17, 1, 0.5, and 33, respectively. Blood concentrations of Halon 1301 were also determined in humans by Harrison et al. (1982) in six volunteers exposed at 7% for 3 h. The mean venous concentrations determined at 30 min, 90 min, and 3 h were 25-29 µg/mL and did not seem to depend on exposure duration. In a study of dogs exposed at 5.0%, 7.6%, and 10% for 20-40 min, venous blood Halon 1301 concentrations were roughly proportional to the inhalation concentrations; the corresponding blood concentrations were 14.6, 28.4, and 32.1 µg/mL (Mullin et al., 1979). Five minutes after the exposure was terminated, blood concentrations decreased to about one-third of the plateau value. When rabbits were exposed to 5% Halon 1301 for 30 min, blood concentrations of Halon 1301, measured 10-30 min after exposure, generally varied from 10 to 15 µg/mL (Griffin et al., 1972). These data show that regardless of the species, the blood at the steady state took up Halon 1301 at about 3-4 µg/mL for each 1% airborne Halon 1301 exposure. Griffin et al. (1972) further concluded that Halon 1301 in the blood was not cumulative in rats exposed for 23 h/d for 30 d. Tissue concentrations and uptake and elimination kinetics of Halon 1301 in the heart and brain (two major target organs) were investigated in rats exposed to 71-76% Halon 1301 for 5 min (Van Stee and Back, 1971a). The Halon 1301 concentration in the brain was found to be approximately 50% greater than that in the blood; the concentrations in the heart and the blood were about the same. The uptake and elimination kinetics of Halon 1301 in the heart and brain, both richly perfused organs, was similar to that in the blood. Metabolism Many halogenated hydrocarbons are known to be biotransformed to

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 toxic metabolites, which might include free radicals, by mixed-function oxidases in the liver. It is generally agreed that metabolic activation of these compounds is required for producing hepatotoxicity or carcinogenicity (Andrews and Snyder, 1991). Halon 1301, a trifluorinated bromomethane, on the other hand, is metabolically inert. No reports have indicated that Halon 1301, per se, is hepatotoxic in animals exposed to even very high concentrations. Bromide, a potential product of Halon 1301 metabolism, was not detected in serum from human subjects exposed to 7% Halon 1301 (70,000 ppm) for 3 h (Harrison et al., 1982). Liver functions and enzymes of these subjects were not altered. No changes in serum liver enzymes were also observed in another study of eight human subjects exposed to 1% Halon 1301 for 24 h (Calkins et al., 1993). In animal studies, liver morphology and enzymes were found to be normal in monkeys exposed to 5-20% Halon 1301 for 2 h. Van Stee and Back (1971b) exposed 30 mice to 80% Halon 1301 for 5 h/d for 3 consecutive days. The hexabarbital sleeping times and zoxazolamine paralysis times determined in these exposed mice were found to be no different from those in controls. When rats were exposed to 5% Halon 1301 for 30 d (23 h/d), there was no increase in the rate of excretion of fluoride ion in the urine (Griffin et al., 1972). These studies indicate that Halon 1301 is not metabolized in the body or that the metabolism is insignificant. TOXICITY SUMMARY Owing to its inertness, Halon 1301 is low in toxicity (Reinhardt and Reinke, 1972). The toxicity of Halon 1301 has been extensively reviewed (DuPont, 1971; NAS, 1972; Haskell Laboratory, 1974, 1978; Van Stee, 1974; NRC, 1978, 1984; Graham, 1981). At relatively high concentrations, Halon 1301 exerts toxic effects primarily on the central nervous system (CNS) and the cardiovascular system (NRC, 1984) at relatively high concentrations. A number of studies have been conducted on human subjects exposed to Halon 1301 at concentrations ranging from 0.1% to 17% (NRC, 1984). The major CNS symptoms, observed mainly at concentrations of a few percent or higher, were light-headedness, dizziness, and/or disturbances in motor coordination (Hine et al., 1968; Call, 1973; Harrison et al., 1982; D. G. Clark, ICI Ltd., unpublished data, 1970, cited in Graham, 1981). Cardiovascular effects, seen

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 in controlled exposures only at concentrations of 10% or more, included increased heart rate, depressed T wave, and/or premature ventricular contraction (Hine et al., 1968). The cardiovascular effects probably are due in part to the sensitization of the heart to epinephrine, a phenomenon that can be induced by exposures to high concentrations of hydrocarbons and halogenated hydrocarbons (Van Stee and Back, 1969; Hanig and Herman, 1991). Acute and Short-Term Exposures Human Exposures CNS Effects An accidental discharge of 1200 lb of Halon 1301 for 30 s was triggered by a fire alarm in a hospital facility. The system was designed to provide a Halon 1301 concentration of 5% at equilibrium. Of the 22 workers present at the scene, 12 left after the incident and 10 remained. Some of these workers could have been exposed briefly to concentrations much higher than 5% if they were near the discharge source. Halon 1301 was exhausted with high-volume ventilation equipment after the firemen arrived. No information is available on how long it took to remove Halon 1301 after it was discharged or how long the workers were exposed to it. The CNS symptoms reported by these 22 workers were light-headedness (77%), headache (45%), and disorientation (36%) (Holness and House, 1992). Fatigue, numbness, and anxiety were also reported; however, these symptoms might have been due to the apprehension of the accident itself rather than to the effect of Halon 1301. Some subjects also showed signs of cardiovascular toxicity, which is discussed below in the section on cardiac toxicity. In a controlled study by D. G. Clark (ICI Ltd., unpublished data, 1970, cited in Graham, 1981), human subjects were exposed to 10%, 12%, or 15% Halon 1301 for 1 min. Severe dizziness and marked paresthesia were observed in subjects exposed to 15%. These symptoms were concentration-dependent. At 10%, slight dizziness and mild paresthesia were reported by half of the test subjects. In another study, dizziness, faintness, or drowsiness was also observed in six of eight human subjects exposed to 7% Halon 1301 (Call,

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 1973). Behavioral tests conducted during and after the exposures showed that reaction time was significantly increased when these subjects performed a complex reaction-time task; however, maze-tracking tasks were not affected by Halon 1301. Subjects exposed to 4% Halon 1301 also showed performance decrements, although to a lesser degree. The effect of Halon 1301 on sensory-motor test performance was also evaluated in groups of four or six subjects exposed to 1.25%, 2.5%, 5%, and 10% Halon 1301 for 22 min in an inhalation chamber (Hine et al., 1968, 1969). The subjects were aware of their exposure to Halon 1301 but did not know the exposure concentration; no control (air only) exposure was included. Slight performance decrements, as compared with pre-exposure results, were observed at 1.25% and 2.5% but not at 5 %. Marked decrements were observed when subjects were exposed to 10% Halon 1301. Two of the four subjects exposed to 1.25% and all six subjects exposed to 10% indicated a feeling of light-headedness after 3 to 5 min of exposure; one subject experienced a buzzing in his ears in addition to tingling of extremities. In the same study, 10 subjects were exposed to Halon 1301 at concentrations of 5-16% by masks (exposure length was not specified). Three subjects breathing 14.4-16.9% felt impending unconsciousness; most of the subjects inhaling 15 % felt markedly confused. All subjects recovered from their CNS symptoms within 20 min of the exposure. Headache occurred in two subjects during exposures and persisted for 12 h thereafter. In a well-controlled study, six human subjects were exposed in a single-blinded fashion for 3 h to 7% Halon 1301 or 7% sulfur hexafluoride (as heavy gas control) on different days; O2 was added to achieve an O2 concentration of 20% in the chamber (Harrison et al., 1982). Subjects were also given two 3-h air-only exposures. When exposed to Halon 1301, the subjects experienced mainly transient light-headedness and mild euphoria. Visual and vestibular functions were not impaired. Psychological performance tests showed that reaction time, scores, and number correct were significantly affected; the results on 18 of the 20 tests showed impairment. The authors equated the effects of Halon 1301 with awakening at 3:00 to 5:00 in the morning and a blood alcohol concentration of 90 mg/100 mL. The subjects were aware of the dense gas but could not distinguish between Halon 1301 and sulfur hexafluoride. A similar study was conducted on subjects who were all exposed to

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 1% and 2% Halon 1301 for 6 h (Strong, 1987). In two of the four tests, subjects were affected by Halon 1301 exposure; performance decrements, which were only detected at one of the three test points during the 6-h exposure, were about 4%. Statistically, only one of these decrements is significant. This transitory decrement was considered mild and physiologically insignificant. Strong also noted performance fluctuations of 11.6%, 9.5%, and 7.5% from subject variation, daily variation, and diurnal variation alone, respectively. Because no studies had been conducted in which humans were exposed to Halon 1301 for more than several hours, NASA sponsored a double-blind human inhalation study in which four pairs of subjects were each exposed for 24 h to Halon 1301 or air (NASA, 1989; Calkins et al., 1993). Six cognitive performance assessments and a motor function test, which produced 13 measurements of accuracy and reaction time, were administered before, during, and after the inhalation exposures. Of the 13 measurements, only two (from the same cognitive test) showed a statistically significant decrement with a magnitude of about 4% of the baseline values. Performance decrement was not dependent on the duration of exposure. No symptoms (such as headache, light-headedness, or irritation) were observed. The subjects were unable to tell whether they had been exposed to Halon 1301 or air. Cardiac Effects Cardiac effects could result from exposures to high concentrations of halogenated hydrocarbons, which are known to sensitize the heart to epinephrine (Hanig and Herman, 1991). Thus, in the NASA-sponsored inhalation study, electrocardiograms (EKGs) were continuously monitored throughout the 24-h study; no EKG abnormality was observed even during the 15-min light exercise to stimulate the release of epinephrine. Negative EKG results were also observed in human subjects exposed to 7% Halon 1301 for 3 h or to 1% or 2% Halon 1301 for 6 h (Harrison et al., 1982; Strong, 1987). Call (1973) also reported no EKG changes during and after exposure in eight human subjects exposed to either 4% or 7% Halon 1301 for 3 min. No effects on cardiac rhythm were observed in three men exposed to 1%, 3%, 5%, or 10% Halon 1301 for 3.5 min (Reinhardt and Stopps, 1966). Hine et al. (1968, 1969) reported that exposing human volunteers to

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 5% or 10% Halon 1301 for up to 20 min produced no cardiac effects. However, one subject did develop a spontaneous cardiac arrhythmia after inhaling 14% Halon 1301 for 5 min. The symptoms disappeared within 2 min of discontinuation of inhalation. D. G. Clark (ICI Ltd., unpublished data, 1970, cited in Graham, 1981) observed increased heart rates and T-wave depression in subjects exposed to 10%, 12%, or 15% Halon 1301 for 1 min. Recovery was rapid and complete within 5 min of the exposure. Cardiac effects have not been detected in subjects exposed at lower concentrations. The cardiovascular toxic signs and incidence reported by hospital workers exposed to a nominal concentration of 5% Halon 1301 during an accidental discharge were shortness of breath (36%), chest tightness (36%), chest pain (9%), and fast heart rate (45%) (Holness and House, 1992). At the concentrations to which these workers were exposed, cardiac effects would not be expected unless the workers were apprehensive during the accident. In fact, it was reported that a majority of these workers were anxious. Anxiety or fright is known to trigger epinephrine release. Halon 1301 has been shown to sensitize the heart to epinephrine (Van Stee and Back, 1969; Mullin et al., 1979; Clark and Tinston, 1982). Irritation In the accidental discharge of Halon 1301 (Holness and House, 1992), all 22 workers complained of throat irritation, and more than half reported eye and nose irritation. The authors attributed the irritation to possible contaminants in the Halon 1301 discharge system. Hine et al. (1968, 1969) reported that two subjects experienced slight eye irritation at exposure concentrations of 5% and 10%; another subject reported moderate eye irritation at 10%, and one reported severe nasal irritation at 10%. The subjects also reported a ''bromine odor.'' The authors noted that a space heater was located near the area where the Halon 1301 was released and that the odor and irritation could be attributed to the thermal decomposition products of Halon 1301. In two well-controlled studies, irritation was not detected by six subjects exposed to 7% for 3 h (Harrison et al., 1982) or by eight subjects exposed to 1% for 24 h (Calkins et al., 1993). It seems that the irritation reported in those two studies was not due to Halon 1301 itself.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Animal Exposures CNS Effects According to Carter et al. (1970), monkeys became depressed, tranquilized, and lethargic and shiver when exposed to Halon 1301 at concentrations of 20% or higher. In operant-trained monkeys exposed to 10.5-42% Halon 1301, 20-25% caused performance decrements and higher concentrations caused a complete disintegration of operant behavior. No performance decrements were detected at exposure concentrations less than 20%. Beagles became anxious and agitated and developed generalized tremors within 1-3 min of exposure to 20% Halon 1301 or more (Van Stee and Back, 1969). The severity of symptoms increased with increased concentrations; when the concentration reached 50% or higher, some dogs developed epileptiform convulsions. Anesthetized dogs and monkeys showed electroencephalographic changes 2-3 min after exposure to 70-80% Halon 1301 (Van Stee et al., 1970). Similar results in unanesthetized dogs were observed by Hine et al. (1968, 1969). Exposing eight dogs to 40% Halon 1301 for 55 min resulted in tremors, howling, dyspnea, and salivation. Eight dogs exposed to 20% Halon 1301 showed tremors but no other toxic signs. All animals returned to normal approximately 20 min after exposure. Dogs exposed to 10% Halon 1301 showed no toxic signs (Hine et al., 1968; Van Stee and Back, 1969). CNS effects were also observed in rats exposed to 30-53% Halon 1301 for 10 min (Clark and Tinston, 1982). The EC50 for inducing tremors of the limbs, ataxia, or loss of righting reflex was 42%. However, tremors were not observed by McHale (1972) in 10 rats exposed for 1 h to either 77% or 56% Halon 1301. The animals did exhibit initial hyperactivity and subsequent hypoactivity, increased rate of respiration, abdominal breathing, slight-to-moderate ataxia, and a slight bluish tint to the skin. All animals appeared normal during the 14-d postexposure observation period. Cardiac Effects Halon 1301 sensitizes the heart to epinephrine. Mullin et al. (1979)

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 exposed anesthetized dogs to 5%, 7.5%, 10%, and 20% Halon 1301 and gave them intravenous injections of epinephrine at concentrations of 8-10 µg/kg; the incidences of marked cardiac arrhythmias were 0, 5.5%, 11.5%, 28.6%, and 61.5%, respectively. Clark and Tinston (1982) reported similar findings. The EC50 for cardiac sensitization in dogs exposed to Halon 1301 and given epinephrine was 20%. Effects on the cardiovascular system could also be produced in dogs not treated with epinephrine, but these animals were exposed at higher concentrations of Halon 1301. Van Stee and Back (1969) observed an increase in heart rates in dogs exposed to 20-30% Halon 1301 or more. Increases in concentrations beyond 40% caused T-wave alterations and unifocal and multifocal ventricular arrhythmias. Spontaneous arrhythmias developed in all dogs within 5 to 40 s of exposures to 20-80% Halon 1301 (Van Stee and Back, 1969). Further study (Van Stee and Back, 1971c) of anesthetized monkeys exposed to 30% Halon 1301 yielded similar results; spontaneous arrhythmias followed moderate hypotension, all of which might occur during the first 5 min of exposure. Histopathology and Mortality An extensive toxicity study of a commercial-grade Halon 1301 (purity 98.8%) was conducted by Treon et al. (1957a) using groups of 31 animals per dose (10 mice, 10 rats, 6 guinea pigs, 4 rabbits, and 1 cat). No compound-related deaths were observed when these animals were exposed for 7 h once or twice at 4.4-4.7% Halon 1301; however, five daily exposures (7 h/d) to the same concentration (4.4%) killed one mouse. No animals died when they were exposed only once for 7 h to 8.8% Halon 1301, but one animal died after two daily exposures, and six died after five daily exposures. Concentrations around 18% killed one animal after one 7-h exposure and seven after two 7-h exposures. Concentrations at 35.9-37.4% killed 0, 5, or 23 animals after exposures of 1.3, 3.5, or 7 h, respectively. The lethality of this commercial product seemed to depend on concentration and exposure length. The causes of death attributed to Halon 1301 exposures were acute hemorrhagic pneumonitis, acute pulmonary edema, and degenerative change of the liver and kidneys. Several animals died from extraneous causes, such as generalized or localized infection (pneumonia, peritonitis, or parasitic infection). Apparently, no control animals were included in the study.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 The impurities in this commercial-grade Halon 1301, determined by infrared spectrometric analysis of fluorine, included trifluoromethane, dichlorodifluoromethane, dibromodifluoromethane, bromodifluoromethane, and 1-bromo, -, -, 2-, 2-, 2-pentafluoroethane. No information was presented on whether there were nonfluorinated impurities. In a similar study by Treon et al. (1957b), no deaths occurred from one 7-h exposure and two 7-h exposures to purified Halon 1301 (purity greater than 99.85%) at concentrations of 32% and 17%. According to DuPont (1971), the purity of Halon 1301 marketed since 1958 is superior to that of the sample used by Treon et al. (1957a). The current DuPont specification (DuPont, 1971) and the U.S. military specification on Halon 1301 (MIL-M-12218C of 1981) set a purity minimum of 99.6% for Halon 1301 (Batt, 1988). To find out whether the impurities caused animal deaths, DuPont investigated the toxic effects of impurities in Halon 1301 on six groups of rats (10 per group) exposed for 4 h to either one of the four samples containing 80% Halon 1301. One sample was highly purified; the other three contained "maximal permissible concentrations" (allowed by product specifications) of one or more of the impurities that might be present in the commercial product, which was the same product used by Treon et al. (1957a). Animals showed toxic signs, but none died. An additional study of 10 other rats exposed to an 80% Halon 1301 containing all possible impurities produced three deaths from marked pulmonary congestion and edema (Waritz, 1968). It appeared that the impurities could be the main cause of the animal death. The toxicity of Halon 1301 (probably the purified product) was also evaluated by Paulet (1962) in large groups of animals in acute-and repeated-exposure studies. Exposing groups of 10 mice to 30%, 40%, 50%, and 60% Halon 1301 and 30 mice to 80% Halon 1301 for 2 h produced no deaths. A similar study with four groups of rats exposed to either 30%, 40%, or 80% (two groups) Halon 1301 also had no deaths. All eight rabbits survived a 2-h exposure to either 50% or 80% Halon 1301. Clinical signs, including drowsiness, tremors, or short convulsions, were observed mainly in animals exposed to 80% Halon 1301. Deaths of exposed mice and guinea pigs occurred when the Halon 1301 concentration was increased to 85% (O2 15% or less). In a repeated-exposure study, 20 mice, 10 rats, and 10 guinea pigs were exposed to 50% Halon 1301 2 h daily for 15 consecutive days; one mouse and one guinea pig died. Paulet (1962) stated that these two

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 TABLE 1-5 Exposure Limits Set or Recommended by Other Organizations Agency or Organization Exposure Limit, ppm Reference ACGIH's TLV 1000 ACGIH, 1991 OSHA's PEL 1000 NIOSH, 1990 NRC's 30-min EEL 40,000 NRC, 1984 NRC's 60-min EEL 25,000 NRC, 1984 NRC's 90-d CEL 100 NRC, 1984 TLV, Threshold Limit Value; PEL, permissible exposure limit; EEL, emergency exposure limit; CEL, continuous exposure limit. TABLE 1-6 Spacecraft Maximum Allowable Concentrations Exposure Duration Concentration, ppm Concentration, mg/m3 Target Toxicity 1 h 3500 21,350 Cardiovascular effects 24 h 3500 21,350 Cardiovascular effects 7 d 1800 11,000 CNS effects 30 d 1800 11,000 CNS effects 180 d 1800 11,000 CNS effects RATIONALE FOR ACCEPTABLE CONCENTRATIONS The general approach to prepare a SMAC document and the safety factors used to derive the acceptable concentrations (ACs) are outlined in Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants (NRC, 1992). Studies Not Considered in Setting ACs Studies on ''Impure'' Halon 1301 A study using the commercial grade of Halon 1301 available at that

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 time (purity 98.3%) revealed that, at exposure concentrations as low as 4.5%, Halon 1301 caused acute hemorrhagic pneumonitis, acute fatty degenerative changes of the liver and kidneys, and death (Treon et al., 1957a). A subsequent study by Treon et al. (1957b) using purified Halon 1301 (purity 99.8%) showed no such toxicity. The commercial grade of Halon 1301 marketed after 1957 was purified. Results from extensive studies conducted thereafter showed no evidence of lung, kidney, and liver damage even at very high exposure concentrations. Well-controlled exposures of humans to 7% Halon 1301 for 3 h or 1% for 24 h produced no signs of pulmonary irritation and no changes in kidney and liver enzymes to reveal organ injury (Harrison et al., 1982; Calkins et al., 1993). Toxicity seen in the early study of Treon et al. (1957a) seems to be due to the impurities in Halon 1301. Therefore, results from this study are not used to set an exposure limit. Studies on Irritation As discussed above, Holness and House (1992) attributed the sensory irritation experienced by the hospital workers to contaminants in the Halon 1301 discharge system. Hine et al. (1968) suggested that the eye and nasal irritation reported by some of their human subjects in their study was due to Halon 1301 thermal decomposition products. Two well-controlled studies conducted with 14 subjects exposed to 1% or 7% Halon 1301 revealed no sensory irritation (Harrison et al., 1982; Calkins et al., 1993). Therefore, sensory irritation as a toxicity end point is not considered in setting the SMACs. Studies on Short-Term Exposures of Animals Halon 1301 produces CNS and cardiovascular effects in humans and animals. Since many short-term human studies have been conducted to evaluate these effects and toxicity data reveal that animals are not as sensitive to those toxicity end points as humans, short-term animal studies are not considered in setting SMACs. However no human Halon 1301 exposures were tested beyond 24 h; therefore, data obtained from the Griffin el al. (1972) long-term animal pathology study is considered in setting SMACs.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Studies Considered in Setting ACs Studies on CNS Effects in Humans Harrison et al. (1982) reported that exposing six human subjects to 7% Halon 1301 for 3 h produced transient light-headedness, mild euphoria, and considerable performance decrements. Further unpublished studies by the same group (Strong, 1987) in subjects exposed to 1% for 6 h produced no overt CNS symptoms and only a very slight cognitive performance decrement. Similar findings were reported by Calkins et al. (1993) on eight subjects exposed to 1% Halon 1301 for 24 h. Because a slight cognitive decrement is acceptable for both 1-h and 24-h exposures in the spacecraft, the AC for CNS effects is set at 1% or 10,000 ppm. The Calkins and Strong groups also found the effects of Halon 1301 to be noncumulative; these observations are strengthened by toxicokinetic data. Lam et al. (1993) reported that Halon 1301 concentrations in blood in humans increased rapidly and approached a steady state within 2 h of exposure; the half-life (t1/2) of uptake for the fast-perfusion tissues was estimated to be 5 min. Van Stee and Back (1971b) reported that the uptake and elimination kinetics of Halon 1301 in the brain of rats were similar to those in blood. Therefore, prolonged exposure to Halon 1301 is not likely to increase the amount of Halon 1301 in the brain. It is reasonable to assume that the CNS effects of such a stable inert gas depends on its concentration in the brain. From the results of these cognitive tests and toxicokinetic studies, it can be concluded that the CNS effects of Halon 1301 in subjects exposed for 24 h or longer would be similar. The possible mild cognitive decrement acceptable for a 24-h exposure is not acceptable for longer exposures in the spacecraft. Since the CNS effects observed at 10,000 ppm of Halon 1301 were very mild, a factor of 2 is used to extrapolate from the lowest-observed-adverse-effect level (LOAEL) to a no-observed-adverse-effect level (NOAEL). The ACs for 7-d, 30-d, and 180-d exposures thus are set at 1800 ppm, based on the calculation below: The number 13 in the above equation is the total number of test sub-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 jects in the Strong and Calkins studies. (Cognitive test results were available from only seven subjects in the latter study.) According to the National Research Council guidelines (NRC, 1992), a factor equal to the square root of the number of subjects divided by 100 (i.e., √(n/100) or (√n)/10)) is used to account for the small sample size (n) for estimating a true NOAEL from an experimental NOAEL observed in a human study. The rationale for combining the number of subjects in the Strong and Calkins studies is that both studies measured reaction time and scoring accuracy, even though the cognitive tests used by these two groups were different. Studies on Cardiovascular Effects in Humans Hine et al. (1968, 1969) reported that an exposure of humans to 5% or 10% Halon 1301 for up to 20 min produced no cardiac effects. D. G. Clark (ICI Ltd., unpublished data, 1970, cited in Graham, 1981) observed increased heart rates and T-wave depression in subjects exposed to 15%, 12%, and 10% Halon 1301 for 1 min. Harrison et al. (1982) and Calkins et al. (1993) recorded no cardiac changes in humans exposed to 7% Halon 1301 for 3 h or 1% Halon 1301 for 24 h, respectively. It may be concluded that 7% is close to the highest NOAEL for the heart. As discussed above, Van Stee and Back (1971a) reported that uptake and elimination kinetics of Halon 1301 in hearts of rats were rapid and similar to those in blood. Also as noted above, onset and abolition of cardiac effects, upon initiation and termination of exposure to Halon 1301, were also rapid (within a few minutes) (Hine et al., 1968; D. G. Clark, ICI Ltd., unpublished data, 1970, cited in Graham, 1981). These observations support the contention that the cardiac effects of this inert fluorocarbon gas depend on its concentration in the blood or heart. Lam et al. (1993) observed that Halon 1301 blood concentrations in exposed human subjects increased rapidly and approached a steady state within 2 h of starting the exposure; thus, the cardiac effects would be expected to be relatively independent of exposure time shortly after the initiation of exposure. Therefore, 7% Halon 1301, a NOAEL for a 3-h exposure in the Harrison et al. (1982) study, could be considered a NOAEL for longer exposure times. The ACs for 1-h, 24-h, 7-d, 30-d and 180-d exposures are set at the same value (see below). Because

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 spaceflight is known to have deleterious effects on heart rhythm, a safety factor of 5 has been included in calculating the safe exposure concentration. The value 6 in the following equation is the number of subjects in the Harrison et al. (1982) study: The safe exposure level is rounded from 3430 ppm. Studies on Subchronic Exposures in Animals Comstock et al. (1953) observed moderate diffuse congestion in the respiratory tracts of rats exposed to 2.3% Halon 1301 for 30 d. As discussed above, the Halon 1301 products used before 1957 might have contained toxic impurities, and thus these data are not used to set ACs. The study by Geller et al. (1981) on four baboons exposed to 2.8% Halon 1301 for 30 d (23 h/d) showed that two baboons reacted more slowly but two performed significantly better in a memory test. Ammonia was noted by the authors to be present in the chamber during the exposure. This study does not provide data useful for setting long-duration ACs. Exposing rats to 5% Halon 1301 continuously (24 or 23 h/d) for 10 d or 30 d produced no observable clinical signs of toxicity, gross pathological changes, or hematological changes (McHale, 1972; Griffin et al., 1972). McHale further reported that microscopic examination of selected organs revealed no lesions. Griffin et al. indicated that a thorough histopathological examination was under way; however, no findings have ever been published. It is reasonable to conclude that 5% Halon 1301 is the NOAEL in rats. An animal-to-human species safety factor of 10 is used to extrapolate a NOAEL to humans. The 30-d and 180-d ACs are set at 0.5% (5000 ppm).

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 TABLE 1-7 Acceptable Concentrations     Uncertainty Factors       To     Space- Acceptable Concentrations, ppm Effect, Data, Reference Species NOAEL Species Time flight 1 h 24 h 7 d 30 d 180 d CNS effects Human - - 1 1 10,000 10,000       LOAEL = 10,000 ppm   2 × √(13/100)a - 1 1     1800 1800 1800 (24-h inhalation) (Strong, 1987; Calkins et al., 1993) Cardiac effects   NOAEL = 70,000 ppm Human √ (6/100)a - 1 5 3500 3500 3500 3500 3500 (3-h inhalation)                     (Harrison et al., 1982)                     Histopathology                     NOAEL = 50,000 Rat 1 10 1 1 - - 5000 5000 5000 (23-h, 30-d inhalation)                     (Griffin et al., 1972)                     SMACs           3500 3500 1800 1800 1800 a Factor 2 for extrapolating from LOAEL to NOAEL; √ (n/100) is used to account for small sample size, n. —, Data not considered applicable to the exposure time.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 ACKNOWLEDGMENT The author is grateful to Dr. Henry Trochimowicz, of Haskell Laboratory, E.I. du Pont de Nemours & Co., Newark, Del., for kindly providing several of the reports listed in the references. REFERENCES ACGIH. 1991. Documentation of the Threshold Limit Values and Biological Exposure Indices, 6th Ed. American Conference of Governmental Industrial Hygienists, Cincinnati, Ohio. Andrews, L. S., and R. Snyder. 1991. Toxic effects of solvents and vapors. P. 692 in Casarett and Doull's Toxicology: The Basic Science of Poisons, 4th Ed., M. O. Amdur, J. Doull, and C. D. Klaassen, eds. New York: Pergamon. Batt, J. M. 1988. Letter (dated 6/1/88) from Atochem (Glen Rock, N.J.) to K. King, of Baylor College of Medicine (Houston, Tex.). Calkins, D.S., J. J. Degioanni, M. N. Tan, J. R. Davis, and D. L. Pierson. 1993. Effects of inhalation of 1% bromotrifluoromethane (Halon 1301) on human performance and physiology. Fundam. Appl. Toxicol. 20:249-247. Call, D. 1973. A study of Halon 1301 (CBrF3) toxicity under simulated flight conditions. Clin. Aviation Aerospace Med. 44:202-204. Carter, V. L., K. C. Back, and D. N. Farrer. 1970. The effect of bromotrifluoromethane on operant behavior in monkeys. Toxicol. Appl. Pharmacol. 17:648-655. Clark, D. G., and D. J. Tinston. 1982. Correlation of the cardiac-sensitizing potential of halogenated hydrocarbons with their physicochemical properties. Br. J. Pharmacol. 49:355-357. Coleman, M. E. 1988. Toxicological Requirements and Support Plan for the Space Station. JSC Doc. 32016. Medical Sciences Division, Space and Life Sciences Directorate, NASA Johnson Space Center, Houston, Tex. Comstock, C. C., J. Kerschner, and F. W. Oberst. 1953. Toxicology of Inhaled Trifluorobromomethane and Difluorodibromomethane Vapors from Subacute and Chronic Exposures of Rats and Dogs. Chemical Corps Medical Laboratories Research Report No. 180, U.S. Army Chemical Center, Md.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 DuPont. 1971. Toxicology of DuPont Halon 1301 Fire Extinguishant. Technical Information S-35A. E.I. du Pont de Nemours & Co., Wilmington, Del. Geller, I., C. Garcia, C. Gleiser, R. Haines, M. Hamilton, R. Hartmann, V. Mendez, A. Samuels, and M. San Miguel. 1981. Report on Evaluation of the CNS and Cardiovascular Effects of Prolonged Exposure to Bromotrifluoromethane (CBrF3). Southwest Foundation for Research and Education, San Antonio, Tex. Graham, R. C. 1981. Toxicity Review on Halon 1301. Haskell Laboratory, E.I. du Pont de Nemours & Co., Newark, Del. Griffin, T. B., J. L. Byard, and F. Coulston. 1972. Toxicological responses to halogenated hydrocarbons. Pp. 136-147 in An Appraisal of Halogenated Fire Extinguishing Agents . Washington, D.C.: National Academy of Sciences. Hanig, J. P., and E. H. Herman. 1991. Toxic responses of the heart and vascular systems. P. 442 in Casarett and Doull's Toxicology: The Basic Science of Poisons, 4th Ed., M. O. Amdur, J. Doull, and C. D. Klaassen, eds. New York: Pergamon. Harrison, J. N., D. J. Smith, R. Strong, M. Scott, M. Davey, and C. Morgan. 1982. The use of Halon 1301 for fire fighting in confined spaces. J. Soc. Occup. Med. 32:37-43. Haskell Laboratory. 1974. Toxicity of Bromotrifluoromethane. Report No. 577-74. E.I. du Pont de Nemours & Co., Newark, Del. Haskell Laboratory. 1978. Literature Review on Bromotrifluoromethane. E.I. du Pont de Nemours & Co., Newark, Del. Hine, C. H., H. W. Elliott, M.D. Harrah, J. W. Kaufman, and S. Leung. 1968. Clinical Toxicologic Studies on "Freon" FE 1301. Report prepared for Boeing Co. and E.I. du Pont de Nemours & Co. by Hine Laboratories, Inc., San Francisco, Calif. Hine, C. H., H. W. Elliott, J. W. Kaufman, and S. Leung. 1969. Clinical Toxicologic Studies on Freon, FE 1301. Pp. 8-1 to 8-4 in Space, Technology, and Society, Proceedings, Vol. 2. Canaveral Council of Technical Societies, Cocoa Beach, Fla. Holness D. L., and R. House. 1992. Health effects of Halon 1301 exposure. J. Occup. Med. 34:722-725. Lam, C.-W., F. W. Weir, K. Williams-Cavender, M. N. Tan, T. J. Galen, and D. L. Pierson. 1993. Toxicokinetics of inhaled bromotrifluoromethane (Halon 1301) in human subjects. Fundam. Appl. Toxicol. 20:231-239.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 MacFarland, H. N. 1967. Acute Inhalation Exposure—Monkey, Rabbits, Guinea Pigs, and Rats—Freon FE 1301. Final Report. Hazleton Laboratories, Falls Church, Va. McHale, E. T. 1972. Final Technical Report on Habitable Atmospheres Which Do Not Support Combustion. Prepared for U.S. Army Research Office, Arlington, Va., by Atlantic Research Corp., Alexandria, Va. 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. 40:653-658. NAS. 1972. Symposium: An Appraisal of Halogenated Fire Extinguishing Agents. National Academy of Sciences, Washington, D.C. NASA. 1989. Halon 1301 Human Inhalation Study, Final Report, JSC Document 23845. Medical Sciences Division, Space and Life Sciences Directorate, NASA Johnson Space Center, Houston, Tex. NIOSH. 1990. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publ. No. 90-117. U.S. Department of Health and Human Services, National Institute for Occupational Safety and Health, Cincinnati, Ohio. NRC. 1978. Bromotrifluoromethane: A Literature Review. Washington, D.C.: National Academy Press. NRC. 1984. Emergency and Continuous Exposure Limits for Selected Airborne Contaminants. Vol. 3, Bromotrifluoromethane. Washington, D.C.: National Academy Press. NRC. 1992. Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants. Washington, D.C.: National Academy Press. NTP. 1986. Toxicology and Carcinogenesis Study of Ephedrine Sulfate in F344/N Rats and B6C3F1 Mice. Tech. Rep. Ser. No. 307. National Institutes of Health, National Toxicology Program, Research Triangle Park, N.C. NTP. 1990. Toxicology and Carcinogenesis Studies of l-Epinephrine Hydrochloride in F344/N Rats and B6C3F1 Mice . Tech. Rep. Ser. No. 380. National Institutes of Health, National Toxicology Program, Research Triangle Park, N.C. Paulet, G. 1962. Toxicology and physiopathologic study of mono-bromotrifluoromethane (CF3Br). Arch. Mal. Prof. 23:341. Reinhardt, C., and R. Reinke. 1972. Toxicology of Halogenated Fire

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Extinguishing Agent Halon 1301. E.I. du Pont de Nemours & Co., Wilmington, Del. Reinhardt, C., and G. J. Stopps. 1966. Human Exposures to Bromotrifluoromethane. Rep. 230-66. E.I. du Pont de Nemours & Co., Wilmington, Del. Strong, R. 1987. Letter (dated June 12, 1987) from R.. Strong of the Institute of Naval Medicine (Gosport, England) to Dr. R. Malone (Houston, Tex.). Treon, J. F., F. P. Cleveland, E. E. Larson, and J. Cappel. 1957a. The Toxicity of Undecomposed Monobromotrifluoromethane ("Freon 13B1") and That of the Mixtures of Materials Which Are Obtained in Passing the Compound through an Inconel Tube Heated to a Temperature of Nine Hundred, Eleven Hundred, or Thirteen Hundred Degree Fahrenheit. Kettering Laboratory, University of Cincinnati, Cincinnati, Ohio. Treon, J. F., F. P. Cleveland, E. E. Larson, and J. Cappel. 1957b. The Toxicity of a Purified Batch of Monobromotrifluoromethane ("Freon 13B1"), and That of the Products of Its Partial, Thermal Decomposition, When Breathed by Experimental Animals. Kettering Laboratory, University of Cincinnati, Cincinnati, Ohio. Van Stee, E. W. 1974. A Review of the Toxicology of Halogenated Fire Extinguishing Agents. Aerospace Medical Research Laboratory. Report AMRL-TR-74-143. Wright-Patterson Air Force Base, Dayton, Ohio. Van Stee, E. W., and K. C. Back. 1969. Short-term inhaltion exposure to bromotrifluoromethane. Toxicol. Appl. Pharmacol. 15: 164-174. Van Stee, E. W., and K. C. Back. 1971a. Brain and Heart Accumulation of Bromotrifluoromethane. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Dayton, Ohio. Van Stee, E. W., and K. C. Back. 1971b. Hypotension During Bromotrifluoromethane Exposure. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Dayton, Ohio. Van Stee, E. W., and K. C. Back. 1971c. Spontaneous Cardiac Arrhythmias Induced by Bromotrifluoromethane. Aerospace Medical Research Laboratory. Report AMRL-TR-68-188. Wright-Patterson Air Force Base, Dayton, Ohio. Van Stee, W., K. C. Back, and R. B. Prynn. 1970. Alteration of electroencephalogram during bromotrifluoromethane exposure. Toxicol. Appl. Pharmacol. 16:779-785.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Waritz, R. S. 1968. Acute Inhalation Toxicity of Bromotrifluoromethane (Freon 13B1) . Rep. No. 46-68. Haskell Laboratory, E.I. du Pont de Nemours & Co., Newark, Del.