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
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
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
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
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,
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
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
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.
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)
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.
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
deaths were "not significant," but the possible cause of death was not revealed. Unfortunately, no controls were included in the Paulet (1962) study.
No deaths were observed when three groups of animals, each group consisting of 2 monkeys, 4 rabbits, 6 guinea pigs, and 10 rats, were exposed to Halon 1301 at 10%, 15%, or 20% for 2 h. Results of blood-chemistry tests, including assays for liver enzymes (determined only in the monkeys), and gross necropsy and microscopic examination of major organs including the liver were found to be unremarkable. Eye irritation was observed in one monkey in each exposure group (MacFarland, 1967).
Subchronic Exposures
No human studies and only a few animal studies have been conducted to examine the toxicity of Halon 1301 in exposures lasting longer than 1 w. McHale (1972) exposed 20 rats (10 males and 10 females) and 20 guinea pigs (10 males and 10 females) to 5% Halon 1301 continuously (24 h daily) for 10 d and studied clinical toxic signs, clinical chemistry, gross pathological changes of all organs, and microscopic histopathological changes of selected organs (lungs, liver, heart, kidneys, and spleen) of these animals. The findings showed that Halon 1301 caused no signs of toxicity, except for a statistically significant elevation of white-blood-cell counts in female guinea pigs when compared with air-exposed animals. McHale (1972) stated that some animals had pneumonitis, which could easily account for the elevated leukocyte counts. The results also showed that the mean weights of adrenal glands from Halon-exposed male and female rats were reduced by 83% and 88% compared with those of male and female controls, respectively (Table 1-1).
The reported adrenal-gland weights of the air-exposed control rats (Sprague-Dawley) in McHale's (1972) study were about 4 times greater than those of control rats (Fischer 344) of equal size in two National Toxicology Program studies (NTP, 1986, 1990) (Table 1-1). Adrenal glands, which secrete epinephrine, norepinephrine, and corticosteroid hormones, control many vital functions, such as mood, activity, metabolism, and renal function. If the adrenal glands in Halon-exposed animals had undergone such drastic atrophic changes (> 80% weight re-
TABLE 1-1 Comparison of Rat Adrenal Weights Reported by McHale and NTP
|
Male Rats |
Female Rats |
|||||
|
Body Wt, |
Organ Wt, |
Organ/Body |
Body Wt, |
Organ Wt, |
Organ/Body |
|
Study |
g |
mg |
Wt, % |
g |
mg |
Wt, % |
Rat Strain |
Controls (McHale, 1972) |
330 ± 5 |
180 ± 38 |
0.060 |
243 ± 3 |
170 |
0.70 |
SD |
Halon exposure (McHale, 1972) |
321 ± 4 |
30 ± 4a |
0.010 |
243 ± 3 |
20a |
0.10 |
SD |
Controls (NTP, 1986) |
359 ± 16 |
39.9 ± 1.31 |
0.011 |
201 ± 10 |
51.3 ± 0.44 |
0.23 |
F344 |
Controls (NTP, 1990) |
357 ± 6 |
42.7 ± 1.31 |
0.012 |
208 ± 5 |
52.9 ± 0.46 |
0.25 |
F344 |
a The author reported the organ weight in grams only up to two decimal places. SD, Sprague-Dawley; F344, Fischer 344. |
duction) in 10 d, toxic signs would certainly have been manifested. However, no clinical signs were observed in the Halon-exposed animals. Moreover, McHale (1972) also observed that adrenal weights in Halon 1301-exposed guinea pigs were not statistically different from those of air-exposed guinea pigs. Therefore, the effects of Halon 1301 on the adrenal glands in rats are questionable, and these results would not be considered in setting the exposure limit.
Griffin et al. (1972) also observed no signs of toxicity, hematological changes, and gross pathological changes in rats exposed to 5% Halon 1301 continuously (23 h/d) for 30 d. The authors indicated that a thorough histological examination was under way at the time of the report. However, no further results have been found on this NASA-sponsored animal study.
Comstock et al. (1953) found no clinical signs in rats and dogs exposed to 2.3% Halon 1301 for 18 w (6 h/d, 5 d/w). Necropsy revealed moderate diffuse congestion of the entire respiratory tract but no other significant pathological changes. It is noteworthy that the Halon 1301 used in this study was not the highly purified grade manufactured after 1958.
Four baboons were exposed to 2.3% Halon 1301 for 30 d (23 h/d), and a match-to-sample discrimination task (a test of memory) was administered (Geller et al., 1981). Reaction time was significantly longer in two baboons during the exposures; however, the number of correct responses was greater during exposures than before, which the authors attributed to learning. They also noticed the presence of ammonia in the chamber during Halon 1301 exposure. Geller et al. (1981) also assessed the long-term effects of Halon 1301 on the hearts of monkeys exposed to 2.8% Halon 1301 for 30 d while confined in restraining chairs. Arterial and venous catheters were implanted in the right common carotid artery and the right internal jugular vein of four of the six cynomolgus monkeys. Available EKG results obtained from chest-wall-implanted EKG leads showed no abnormalities. Pathological results were difficult to interpret because of severe stress, fatal emboli, animal deaths, incomplete result documentation, and no control animals in the study.
Developmental Toxicity
Three groups of 27 pregnant rats were exposed to Halon 1301 at concentrations of 0.1%, 1%, or 5% for 6 h daily on days 6-15 of gestation. The number of implantation sites, resorptions, and live fetuses was not significantly different from that of the control animals. No compound-related clinical signs of toxicity or behavioral changes were observed. Exposure did not affect fetal development as measured by fetal weight and crown-rump length. Three fetuses were found malformed; all three were from dams exposed at 1%. These effects were not considered compound-related. Halon 1301 was not considered a developmental toxicant under these test conditions (NRC, 1984; Haskell Laboratory, unpublished data, cited in NRC, 1984, and Graham, 1981).
Mutagenicity
Halon 1301 was tested in Salmonella typhimurium strains TA 1538, TA 1537, TA 1535, TA 100, and TA 98 at concentrations up to 40%. The gas was not mutagenic regardless of whether a rat liver microsomal system was present (Haskell Laboratory, unpublished data, cited in NRC, 1984, and Graham, 1981).
Carcinogenicity
No chronic-exposure studies have been conducted to evaluate the carcinogenic potential of this compound; no evidence of carcinogenic potential has been found (NRC, 1984). Because of its biochemical inertness, Halon 1301 is likely to be noncarcinogenic.
TABLE 1-2 Toxicity Summary of Human Studies
Concentration, % |
Exposure Duration |
Number of Subjects |
Cardiovascular Effects |
CNS and Other Effects |
Reference |
1, 3, 5 |
3 min |
3 |
None observed |
Not reported |
Reinhardt and Stopps, 1996 |
1 |
24 h |
8 |
None observed |
Slight decrement in 2 of 13 cognitive tests |
Calkins et al., 1993 |
1-2 |
3 h |
6 |
Not detected |
No CNS syndromes, minimal decrement in mental performance |
Strong, 1987 |
1.25 |
22 min |
4 |
Not determined |
Slight performance decrement, light-headedness |
Hine et al., 1969 |
2.5 |
22 min |
4 or 6 |
Not determined |
Slight performance decrement |
Hine et al., 1969 |
5 or more |
Probably several min or more |
22 |
Shortness of breath, chest tightness, chest pain, fast heart rate |
Light-headedness, headache, disorientation, eye and throat irritation |
Holness and House, 1992 |
4 or 7 |
3 min |
8 |
No changes in EKG |
Increased behavioral reaction time |
Call, 1973 |
5 |
22 min |
4 or 6 |
Not determined |
Light-headedness, no performance decrement, slight eye irritation |
Hine et al., 1969 |
7 |
3 h |
6 |
Not detected |
Transient light-headedness, mild euphoria, impairment of mental performance, no irritation perceived |
Harrison et al., 1982 |
10 |
22 min |
6 |
Not determined |
Light-headedness, performance decrement, moderate/severe eye irritation |
Hine et al., 1969 |
14-16 |
Unspecified |
10 |
Not determined |
Feeling impending unconsciousness |
Hine et al., 1969 |
Concentration, % |
Exposure Duration |
Number of Subjects |
Cardiovascular Effects |
CNS and other Effects |
Reference |
10-17 |
15-25 min |
Unspecified |
Flattening of T wave, premature ventricular contractions, tachycardia |
Not reported |
Hine et al., 1969 |
TABLE 1-3 Toxicity Summary of Studies of Animals Exposed to Impure Halon 1301
Concentration, % |
Exposure Duration |
Species |
Effects |
Reference |
Short-Term Studies |
||||
4.4 |
1 × 7 h |
1 cat, 4 rabbits, 6 guinea pigs, 10 rats, 10 mice |
Mortality: None (1 rabbit died of extraneous causes) |
Treon et al., 1957a |
4.8 |
2 × 7 h |
1 cat, 4 rabbits, 6 guinea pigs, 10 rats, 10 mice |
Mortality: None (2 rats and 1 mouse died of extraneous causes) |
Treon et al., 1957a |
4.4 |
5 × 7 h |
1 cat, 4 rabbits, 6 guinea pigs, 10 rats, 10 mice |
Mortality: 1 mouse (3 rabbits died of extraneous causes) |
Treon et al., 1957a |
8.8 |
1 × 7 h |
1 cat, 4 rabbits, 6 guinea pigs, 10 rats, 10 mice |
Mortality: None (1 rat died of extraneous causes) |
Treon et al., 1957a |
9.1 |
2 × 7 h |
1 cat, 4 rabbits, 6 guinea pigs, 10 rats, 10 mice |
Motality: 1 guinea pig |
Treon et al., 1957a |
8.7 |
5 × 7 h |
1 cat, 4 rabbits, 6 guinea pigs, 10 rats, 10 mice |
Mortality: 4 guinea pigs, 1 rat, 1 mouse |
Treon et al., 1957a |
18.3 |
1 × 7 h |
1 cat, 4 rabbits, 6 guinea pigs, 10 rats, 10 mice |
Mortality: 1 of 3 rabbits |
Treon et al., 1957a |
17.3 |
2 × 7 h |
1 cat, 4 rabbits, 6 guinea pigs, 10 rats, 10 mice |
Mortality: 1 rabbit, 6 guinea pigs |
Treon et al., 1957a |
Concentration, % |
Exposure Duration |
Species |
Effects |
Reference |
Short Term Studies |
||||
35.9 |
1 × 1.3 h |
1 cat, 4 rabbits, 6 guinea pigs, 10 rats, 10 mice |
Mortality: None |
Treon et al., 1957a |
36.0 |
1 × 3.5 h |
1 cat, 4 rabbits, 6 guinea pigs, 10 rats, 10 mice |
Mortality: 5 guinea pigs |
Treon et al., 1957a |
37.4 |
1 × 7 h |
1 cat, 4 rabbits, 6 guinea pigs, 10 rats, 10 mice |
Mortality: 1 cat, 4 rabbits, 6 guinea pigs, 4 rats, 8 mice |
Treon et al., 1957a |
Long-Term Studies |
||||
2.3 |
18 w (6 h/d, 5 d/w) |
Rat, dog |
Moderate diffuse congestion of the entire respiratory tract; no other toxic signs |
Comstock et al., 1953 |
TABLE 1-4 Toxicity Summary of Studies of Animals Exposed to Purified Halon 1301
Concentration, % |
Exposure Duration |
Species |
Effects |
Reference |
Acute Toxicity Studies |
||||
0.7 |
1 × 0.3 h |
1 cat, 4 rabbits, 6 guinea pigs, 10 rats, 10 mice |
Mortality: None |
Treon et al., 1957b |
1.8 |
1 × 0.3 h |
1 cat, 4 rabbits, 6 guinea pigs, 10 rats, 10 mice |
Mortality: None |
Treon et al., 1957b |
17.3 |
2 × 7 h |
1 cat, 4 rabbits, 6 guinea pigs, 10 rats, 10 mice |
Mortality: 1 guinea pig died 39 d later |
Treon et al., 1957b |
Concentration, % |
Exposure Duration |
Species |
Effects |
Reference |
32.7 |
1 × 7 h |
1 cat, 4 rabbits, 6 guinea pigs, 10 rats, 10 mice |
Mortality: 1 rabbit died 4 d later |
Treon et al., 1957b |
5-20 + iv epinephrine |
60 min |
Dog |
Incidence of cardiac arrhythmias at 5% (0), 7.5% (5.5%), 10% (11.5%), 15% (28.6%), and 20% (61.5%) Halon 1301 |
Mullin et al., 1979 |
10 |
55 min |
Dog |
No toxic signs |
Hine et al., 1968 |
20 + iv epinephrine |
5 min |
Monkey |
EC50 for cardiac sensitization was 20% Halon 1301 |
Clark and Tinston, 1982 |
10.5-20 |
15 min |
Monkey |
No performance degradations detected |
Carter et al., 1970 |
20 |
55 min |
Dog |
Tremors |
Hine et al., 1968 |
20 |
Unspecified |
Dog |
Anxious, agitated, and tremors |
Van Stee and Back, 1969 |
20-25 |
15 min |
Monkey |
Significant performance decrements |
Carter et al., 1970 |
20-30 |
Unspecified |
Dog |
Increase in heart rate |
Van Stee and Back, 1969 |
20-80 |
Unspecified |
Monkey, baboon |
Spontaneous cardiac arrhythmias developed in monkeys and baboons within 5-40 s of exposures; monkeys were depressed, tranquilized, shivering, lethargic |
Van Stee and Back, 1969 |
25-42 |
15 min |
Monkey |
Performance greatly impaired in some animals |
Carter et al., 1970 |
30 |
5 min or more |
Monkey |
Hypotension, spontaneous arrhythmias |
Van Stee and Back, 1971c |
30 |
2 h |
Mouse, rat, guinea pig |
None observed |
Paulet, 1962 |
40 |
2 h |
Mouse |
None observed |
Paulet, 1962 |
Concentration, % |
Exposure Duration |
Species |
Effects |
Reference |
40 |
55 min |
Dog |
Dyspnea, salivation, howling, and tremors |
Hine et al., 1968 |
42 |
10 min |
Rat |
EC50 for CNS effects (tremors of the limbs, ataxia and loss of righting reflex) |
Clark and Tinston, 1982 |
40-60 |
Unspecified |
Dog |
Increased heart rate, spontaneous cardiac arrhythmias in most dogs |
Van Stee and Back, 1969 |
50 |
Unspecified |
Dog |
Anxious, agitated, tremors |
Van Stee and Back, 1969 |
50 |
2 h/d, 15 d |
Mouse, rat, guinea pig |
Mortality: 1/20 mice, 0/10 rats, 1/10 guinea pigs |
Paulet, 1962 |
50 |
2 h/d, 15 d |
Mouse, rat, guinea pig |
Mortality: 1/20 mice, 0/10 rats, 1/10 guinea pigs |
Paulet, 1962 |
50 |
2 h |
Mouse, rat, guinea pig, rabbit |
Slight behavioral changes rats, guinea pigs, and rabbits; no deaths in 32 animals |
Paulet, 1962 |
60 |
2h |
Mouse |
Slight behavioral changes |
Paulet, 1962 |
56 or 77 |
1 h |
Rat |
Initial hyperactivity and subsequent hypoactivity, increased abdominal breathing, slight to moderate ataxia, and slight bluish tint to skin; no animal deaths |
McHale, 1972 |
70-80 |
>2 min |
Dog |
Electroencephalographic changes 2-3 min after exposure |
Van Stee et al., 1970 |
Concentration, % |
Exposure |
Species |
Effects |
Reference |
80 |
2 h |
Mouse, rat, guinea pig, rabbit |
Mice: decreased activity, dyspnea, depression, terminal tremors, abnormal gait, and disequilibrium Rats: drowsiness, slight abnormal gait Guinea pigs: drowsiness, terminal tremors, weak limbs Rabbits: Ataxia, dyspnea, depression, tremors, short convulsion No deaths in 44 animals |
Paulet, 1962 |
80 |
15 min |
Rat |
LC50 > 80% |
Clark and Tinston, 1982 |
85 |
2 h |
Mouse, guinea pig |
Marked depression, tremors. Mortality: 8/10 mice (Note: 02 was 15% or less) |
Paulet, 1962 |
Subchronic Toxicity Studies |
||||
2.8 |
23 h/d, 30 d |
Baboon |
Increased reaction time or accuracy during exposure |
Geller et al., 1981 |
5 |
24 h/d, 10 d |
Rat, guinea pig |
No clinical signs, no changes in clinical chemistry, no gross pathology, and no microscopic histopathological changes |
McHale, 1972 |
5 |
23 h/d, 30 d |
Rat |
No histological and hematological changes |
Griffin et al., 1972 |
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
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.
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-
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
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).
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. |
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.
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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.
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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.