B9

Chlorodifluoromethane (Freon 22)

Hector D. Garcia, Ph.D.

Johnson Space Center Toxicology Group

Medical Operations Branch

Houston, Texas

PHYSICAL AND CHEMICAL PROPERTIES

Chlorodifluoromethane is a colorless, nearly odorless nonflammable gas at room temperature.

Formula:

CIF2CH

CAS no.:

75-45-6

Chemical name:

Chlorodifluoromethane

Synonyms:

Algeon 22, algofrene type 6, algofrene 22, arcton 4, chlorofluorocarbon 22, CFC-22, eskimon 22, electro-CF 22, FC-22, flugene 22, fluorocarbon 22, forane 22, Freon 22, frigen 22, Genetron 22, HCFC 22, HSDB 143, hydrochlorodifluorocarbon 22, isceon 22, isotron 22, kaltron 22, khladon 22, monochlorodifluoromethane, propellant 22, R 22, refrigerant 22, ucon 22

Molecular weight:

86.46

Boiling point:

-40.8°C

Melting point:

-146°C to -147°C

Specific gravity:

1.4909 g/mL (-69°C)

Solubility:

Soluble in water (0.30% wt/wt at 25°C)

 

Soluble in acetone, chloroform, and ether

Conversion Factors at 25°C, 1 atm:

1 ppm = 3.54 mg/m3

 

1 mg/m3 = 0.282 ppm



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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 B9 Chlorodifluoromethane (Freon 22) Hector D. Garcia, Ph.D. Johnson Space Center Toxicology Group Medical Operations Branch Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Chlorodifluoromethane is a colorless, nearly odorless nonflammable gas at room temperature. Formula: CIF2CH CAS no.: 75-45-6 Chemical name: Chlorodifluoromethane Synonyms: Algeon 22, algofrene type 6, algofrene 22, arcton 4, chlorofluorocarbon 22, CFC-22, eskimon 22, electro-CF 22, FC-22, flugene 22, fluorocarbon 22, forane 22, Freon 22, frigen 22, Genetron 22, HCFC 22, HSDB 143, hydrochlorodifluorocarbon 22, isceon 22, isotron 22, kaltron 22, khladon 22, monochlorodifluoromethane, propellant 22, R 22, refrigerant 22, ucon 22 Molecular weight: 86.46 Boiling point: -40.8°C Melting point: -146°C to -147°C Specific gravity: 1.4909 g/mL (-69°C) Solubility: Soluble in water (0.30% wt/wt at 25°C)   Soluble in acetone, chloroform, and ether Conversion Factors at 25°C, 1 atm: 1 ppm = 3.54 mg/m3   1 mg/m3 = 0.282 ppm

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 OCCURRENCE AND USE Chlorodifluoromethane (HCFC-22) is manufactured for use as an aerosol propellant, a refrigerant, and a low-temperature solvent. The shuttle orbiter uses HCFC-22 in an azeotropic 49:51 mixture of HCFC-22 and Freon 115, called Freon 502, as a refrigerant in refrigerators and freezers used in the mid-deck and the modules. Up to four refrigerator-freezers could be flown on any one mission, each of which could be charged with up to 50 g of FC-502 for a total of up to 100 g of HCFC-22 on any given mission. Low concentrations (≤ 0.03 ppm) of HCFC-22 are seen in the spacecraft atmosphere in about one-fourth of shuttle missions (James et al. 1994). UPTAKE, METABOLISM, AND TOXICOKINETICS Absorption The solubility of inhaled HCFC-22 in blood is greater than that of nitrous oxide but less than ether or acetone (Varene et al. 1989). It has an average blood/gas partition coefficient in humans of 0.77 (Woolen et al. 1992) and a mean Bunsen coefficient of solubility of 0.804 cm3 of blood per atmosphere at 37°C (Varene et al. 1989). It is absorbed from the blood by fatty tissues, where it can persist for up to 1 d. In rabbits exposed by inhalation, blood concentrations of HCFC-22 increased very rapidly, steady state being approached in about 1 min, after which a plateau phase continued throughout a 30-min exposure (Sakata et al. 1981). In male volunteers inhaling HCFC-22 at either 92 or 518 ppm for 4 h, breath concentrations during exposure were similar to exposure concentrations from 0.5 h onward. Within the first hour of exposure, blood concentrations approached a plateau, which was proportional to the dose (Woolen et al. 1992). Distribution No data were found on the distribution of inhaled HCFC-22 in humans or animals except that its fat/blood partition coefficient was estimated to be about 10 (Woolen et al. 1992).

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Excretion Following inhalation by male volunteers, there was a rapid initial decline in blood concentrations followed by a slower decline (Woolen et al. 1992). Breath concentrations declined steadily, following a three-compartment model. Physiologically based pharmacokinetic modeling indicated that >90% of the HCFC-22 absorbed is eliminated within 10 h. Some HCFC-22 was detectable in the urine for up to 22 h in the high-dose exposure group. Woolen et al. (1992) estimated half-lives for three elimination phases in humans to be 0.005, 0.2, and 2.6 h, but stated that some might persist in fatty tissues for up to 1 d. The authors' estimated half-life value of 0.005 h, which equals 18 s, would allow only enough time for about 30% of the blood in the body to pass through the lung. Thus, it cannot represent a true half-life for elimination from the blood, but probably represents clearance of residual unabsorbed compound from within the lung. Following cessation of exposure to 100,000 ppm or 200,000 ppm, blood concentrations of HCFC-22 in rabbits decreased rapidly—up to 50% within 1 min—and after 15-20 min, blood concentrations became 8-9 µL/g in all cases, irrespective of inhaled concentration (Sakata et al. 1981). Metabolism Following inhalation by male volunteers, urinary fluoride concentrations were all within the normal range for unexposed controls, indicating that HCFC-22 is not metabolized to fluoride to any significant extent (Woolen et al. 1992). Measurement of urinary fluoride concentrations, however, would not detect metabolic removal of chlorine atoms, which would occur before removal of fluorine atoms. Thus, extensive metabolism could have occurred undetected. Peter et al. (1986) showed that HCFC-22 administered to rats by either intraperitoneal (ip) injection of 3.08 mL/kg or inhalation at 160 ppm (initial concentration) in a 6.38-L dessicator for 7 h was exhaled almost completely unchanged, even when rats were pretreated with phenobarbital or DDT to enhance liver metabolism. TOXICITY SUMMARY The toxicity of HCFC-22 is reported to be low compared with many other chlorofluorocarbons. Demonstrated effects include sensitization to cardiac arrhythmia, central-nervous-system (CNS) effects at high doses, and minimal genotoxicity. There were reports of small or missing eyes in offspring of rats

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 (at a low incidence), but not of rabbits, exposed at 50,000 ppm during gestation. For exposures of at least 4 mo at 14,000 ppm, pathological changes in the blood and internal organs were also reported (Karpov 1963a). These toxic effects are described in detail below. Acute and Short-Term Exposures Studies of the effects of brief exposures to HCFC-22 have demonstrated that high concentrations affect the nervous system and sensitize the heart to arrhythmias. CNS disturbances have been observed in both human ''sniffing" cases and animals exposed to high doses. Although a number of human "sniffing" deaths have been blamed on HCFC-22-induced arrhythmias, the most reliable data come from animal studies. Lethality Karpov (1963b) reported that the 2-h LC50 (lethal concentration for 50% of the animals), lowest-observed-adverse-effect level (LOAEL), and no-observed-adverse-effect level (NOAEL) for lethality of HCFC-22 in mice were 390,000 ppm, 367,000 ppm, and 316,000 ppm, respectively. Autopsies were performed on two of six fishermen who died from exposure to HCFC-22 in a confined space in a commercial fishing boat accident. The results revealed fine lipid droplets in the cytoplasm of hepatocytes, mainly in the peripheral zone of hepatic lobules, in addition to findings expected for suffocation from oxygen deficiency (i.e., lung congestion and edema) (Morita et al. 1977). Similar fine granular fat droplets were seen in hepatocytes of mice exposed to HCFC-22 at 250,000 ppm (16% oxygen, 59% nitrogen) for 60 min, but not in hepatocytes of control mice (Morita et al. 1977). Cardiac Arrhythmia One study reported HCFC-22-induced cardiac arrhythmias in humans, but its results were questionable due to methodological flaws. In that epidemiological study of medical students during their pathology residency in a Boston hospital, half of those exposed to HCFC-22 during preparation of frozen sections reported heart palpitations. These consisted of mostly premature atrial contractions and episodes of paroxysmal atrial fibrillation, as confirmed by electrocardiography (Speizer et al. 1975). A dose response was found when the frequency of reported episodes of palpitation was compared with the number

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 of frozen sections performed per week. The data and interpretation are not compelling, however. An average exposure of 300 ppm was reported, but much higher peak exposures were likely to have occurred due to the measurement technique used: a 2-min sample was collected from the breathing zone while two 10-s blasts of HCFC-22 were expelled into an open cryostat. In another epidemiological study, no increase was found in HCFC-22-related mortality due to heart or circulatory disorders (ACGIH 1991a). In beagle dogs, cardiac sensitization to induction of arrhythmias by epinephrine was seen experimentally during 5-min exposures to HCFC-22 at 50,000 ppm (2 of 12 exposed dogs) but not at 25,000 ppm (0 of 12 exposed dogs) (Reinhardt et al. 1971). Cardiac sensitization to arrhythmias by all chlorofluorocarbons tested to date appears to be dependent on blood concentrations but independent of exposure duration, once steady state has been achieved. That was demonstrated by Reinhardt using a different Freon, CFC-12 (dichlorodifluoromethane). Exposure for up to 1 h to CFC-12 at 25,000 ppm did not induce arrhythmias, whereas a 5-min exposure at 50,000 ppm produced marked responses in 5 of 12 exposed dogs, and a 0.5-min exposure to 135,000 ppm produced marked responses in 2 of 7 exposed dogs (Reinhardt et al. 1971). FC-22 induced cardiac arrhythmias in anesthetized Swiss mice (three of five exposures) exposed for 6 min at 400,000 ppm only if they received intravenous injections of epinephrine at 6 µg/kg for 2 min after the start of inhalation (Aviado and Belej 1974). The arrhythmias were characterized as second-degree atrioventricular block, ventricular extrasystoles, and ventricular fibrillation. The mice showed no arrhythmias without epinephrine. No sensitization to epinephrine-induced arrhythmias was seen in mice exposed to HCFC-22 at 200,000 ppm (Aviado and Belej 1974) or in monkeys exposed at 200,000 ppm (Belej et al. 1974), although that concentration caused depressed cardiac contractility with a fall in aortic blood pressure in monkeys. One of 14 rabbits exposed to HCFC-22 at 60,000 ppm for 5 h/d, 5 d/w for 8 w, and receiving sodium phenobarbital at 0.5 g/L of drinking water to stimulate drug-metabolizing enzyme systems, developed "well-defined cardiac arrhythmias of probable supraventricular or ventricular origin" (Van Stee and McConnell 1977a). CNS Effects CNS effects (excitation or equilibrium disturbances) were reported in rats and guinea pigs exposed to HCFC-22 for 2 h at 75,000 to 100,000 ppm (Weigland 1971). Narcosis occurred in this study at 200,000 ppm. The following sequence of effects were observed in rabbits exposed to

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 HCFC-22 at concentrations that increased continuously from 0% to about 40% (vol/vol) at various rates, with effects beginning at about 8% HCFC-22: (1) reeling, (2) weakness of the forelegs, (3) falling down, (4) flow of mucous fluid from mouth and nose, dilation of the pupils, and lacrymation, (5) violent movement of body and extremities, i.e., running, (6) cyanosis, and (7) death (Sakata et al. 1981). Death occurred at exposure concentrations of 29% to 42% (vol/vol), depending on the rate of increase of the concentration of HCFC-22 (0.5%/min and 2.0%/min, respectively). At fixed concentrations for 30-min exposures, symptoms appeared in the same order, 5% HCFC-22 being a NOAEL and death occurring in 15 min at 30% and in 10 min at 40% (Sakata et al. 1981). In guinea pigs exposed for 5 min, 30 min, 1 h, or 2 h to HCFC-22, 10,000 ppm was found to be a NOAEL for all exposure times (Nuckolls 1940). Exposure at 24,000-27,000 ppm induced somewhat rapid breathing at 5 min and slight lacrymation with partially closed eyes at 2 h. Exposure at 51,000-54,000 ppm induced deep breathing and slight lacrymation at 5 min and irregular breathing, rubbing of their noses, and shaking their heads at 2 h. Exposure at 95,000-117,000 ppm induced rapid breathing, slight lacrymation, head shaking, nose rubbing, and sniffing at 5 min, labored breathing, slight lacrymation, weakness of the rear legs and occasional tremors at 30 min, stupor, occasional gross tremors, loss of equilibrium, weakness of rear legs, and difficulty standing at 60 min, and at 2 h, stupor, difficulty standing, weakness of rear legs and partially closed eyes. Recovery was rapid after all these exposures up to 117,000 ppm. Exposure at 180,000-226,000 ppm for 5 min caused rapid breathing, convulsive tremors, inability to stand or walk, lacrymation and nasal discharge. Exposure for 30 min induced stupor, inability to stand, convulsive leg movements and tremors, labored breathing, and nasal discharge. Exposure for 60 or 120 min induced audible breathing, lacrymation, nasal discharge, convulsive leg movements, inability to stand, and the animals lay on their backs. Complete recovery after exposures at 180,000-226,000 ppm took 1 d (Nuckolls 1940). Karpov (1963b) reported that 40,000 ppm was a 40-min LOAEL for an increased reflex response time and a decreased reflex response strength in rabbits. Subchronic and Chronic Exposures Subchronic or chronic studies of the effect of HCFC-22 exposure on animals were reported by Karpov (1963a), Tinston et al. (1981 a,b), and Maltoni (1988). The Tinston and Maltoni studies focused on the carcinogenic potential of HCFC-22. The Karpov study examined the systemic toxicity of HCFC-22,

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 reporting that some effects began to be noticeable only around the fourth to sixth month of exposure. In a 1977 study by Van Stee, liver histopathology and cardiac arrhythmias were seen in rabbits exposed to HCFC-22 at 60,000 ppm beginning at 4 w of intermittent exposure and increasing until deaths were seen at 9 w (Van Stee et al. 1977b). In another study, no adverse effects were seen in rats after 2 mo of exposures to HCFC-22 for 5 h/d at 50,000 ppm (Lee and Suzuki 1981). Endurance and Oxygen Consumption Karpov (1963a) reported that mice exposed to HCFC-22 at 14,000 ppm for 6 h/d, 6 d/w. for 10 mo could swim for only 25-110 min compared with control mice, which swam for 55-170 min. Starting with the fourth through sixth month of exposure, Karpov found a progressive decrease in oxygen consumption in rats exposed at 14,000 ppm (6 h/d, 6 d/w for 10 mo) compared to control rats. The swim times of mice and oxygen consumption of rats exposed similarly at 2000 ppm were not different from controls (Karpov 1963a). Decreased Weight Gain Karpov (1963a) reported that mice exposed to HCFC-22 at 14,000 ppm for 6 h/d, 6 d/w for 10 mo weighed 26 ± 1.5 g compared with controls, which weighed 34 ± 1.8 g, with decreased weight gains noticeable beginning around the fourth to sixth month of exposure. Mice exposed similarly to HCFC-22 at 2000 ppm were unaffected (Karpov 1963a) Histopathological Effects An NIEHS study (Van Stee and McConnell 1977a) found that the livers of New Zealand White rabbits exposed 5 h/d, 5 d/w for 10 w to HCFC-22 at 60,000 ppm were pale, and there was a modest increase in the activities of some serum enzymes beginning the 4th w of exposure. Effects were more pronounced in females and in animals treated concomitantly with sodium phenobarbital (NaPB) at 0.5 g/L of drinking water. One female rabbit on NaPB became clinically ill by the end of the 9th w of exposure. This rabbit also developed cardiac arrhythmias during w 6-8. In another NIEHS study, Lee and Suzuki (1981) found no signs of histopathology, hematological toxicity, decreased fertility, dominant lethality, teratoge-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 nicity, or exposure-related changes in organ weights in Sprague-Dawley rats exposed to HCFC-22 at 50,000 ppm for 5 h/d for 8 w except for biologically insignificant reductions in the weights of the prostatic and coagulating glands. Karpov (1963a) reported pathological changes upon histopathological examination of the internal organs of rabbits, rats, and mice exposed at 14,000 ppm (6 h/d, 6 d/w, 10 mo). These changes included dilation of blood-vessel walls; emphysema, atelectasis, and enlarged and torn alveolae in lungs; edema and nerve-cell death in the brain and spinal cord and macrophage proliferation in liver and kidneys; and degeneration of the spleen, beginning anywhere from the first months to the eighth month of exposure. Mice and rats exposed similarly at 2000 ppm were unaffected (Karpov 1963a). Karpov's descriptions of histopathology are often vague and nonquantitative, making it difficult to judge the true significance of the reported effects. In a study by Tinston et al. (1981 a), no exposure-related non-neoplastic organ pathology was observed in rats and mice exposed to HCFC-22 for 5 h/d, 5 d/w at 0, 1000, 10,000, or 50,000 ppm for the rodents' lifetimes except for the following mild effects seen at the highest dose: a decrease in body-weight gain in male rats up to w 80; increased liver, kidney, adrenal, and pituitary absolute weights in female rats; and hyperactivity in mice. A clear no-effect level was seen at 10,000 ppm. Effects on Reflexes Karpov (1963a) reported that mice exposed to HCFC-22 at 14,000 ppm for 6 h/d, 6 d/w for 10 mo were slower in establishing conditioned reflexes than control mice. Beginning around the fourth to sixth month of exposure, rats exposed at 14,000 ppm for 6 h/d, 6 d/w showed a decreased ability to sum subthreshold electrical stimuli for reflex activity (Karpov 1963a). Mice and rats exposed similarly at 2000 ppm were unaffected. Carcinogenicity Tinston et al. (1981a) reported no differences in the total number of animals bearing tumors (without regard to site or type of tumor) in male and female Alderly Park (Wistar-derived) rats exposed to HCFC-22 for a lifetime (5 h/d, 5 d/w) at 0, 1000, 10,000, or 50,000 ppm. Of the tumor-bearing animals, however, an increase in the incidence of subcutaneous fibrosarcomas (most consistently at the salivary gland) was seen only in male rats exposed at 50,000 ppm (18 of 80), compared with the incidence in two rat control groups (5 of 80

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 and 7 of 80), in rats exposed at 1000 ppm (8 of 80), and in rats exposed at 10,000 ppm (5 of 80). In a review of the studies, Litchfield and Longstaff (1984) discounted the biological significance of the salivary-gland tumors, because they were increased only in males and only at 50,000 ppm. Because spontaneously occurring fibrosarcomas are not uncommon in aging male rats, they concluded that the apparent increase in the spontaneous-tumor incidence was possibly due to a nonspecific action, such as stress at the high exposure concentration or a weak promotional effect (Litchfield and Longstaff 1984). There was also a slightly increased incidence of Zymbal-gland carcinomas in the 50,000-ppm male group (4 of 80 vs. 0 of 80 in all other exposure groups) (Tinston et al. 1981a). Again, Litchfield and Longstaff discounted the biological significance of these tumors. Effects similar to those seen in the male rats were not observed in the female rats, nor were they seen in male or female mice in a parallel study (Tinston et al. 1981b) or in Alderly Park rats receiving HCFC-22 orally in corn oil at 300 mg/kg/d, 5 d/w for 52 w (Longstaff et al. 1984). Litchfield and Longstaff's conclusion that the observed tumors were not exposure related is based in part on their finding that no non-neoplastic histopathological changes were seen in either salivary glands or Zymbal glands (i.e., the exposure did not produce any organ-specific non-neoplastic toxicity (H. Trochimowicz, Haskell Laboratory, E.I. du Pont de Nemours, Wilmington, Del., personal commun., March 25, 1998). In another study, Sprague-Dawley rats exposed to HCFC-22 at 5000 or 1000 ppm for 4 h/d, 5 d/w for 104 w and Swiss mice exposed for 4 h/d, 5 d/w for 78 w had no increase in tumor incidence compared with controls (Maltoni et al. 1988). Epidemiological studies (e.g., studies of refrigeration workers) have been inconclusive because of the difficulty of finding sufficiently large study populations with well-defined exposures to HCFC-22 and without confounding exposures (Axelson 1985). Genotoxicity HCFC-22 was found to be weakly to moderately mutagenic only at high levels when tested at concentrations up to 50% in the Ames Salmonella bacterial mutation assay using tester strains TA1535 and TA100 for exposures lasting 24 h to 3 d (Longstaff et al. 1984). HCFC-22 was negative for mutagenicity in Schizosaccharomyces pombe and Saccharomyces cerevisiae and in a host-mediated assay with those two yeast strains (Loprieno and Abbondandolo 1980). It did not induce cell transformation when tested as a gas or liquid in BHK21 cells in vitro in the presence of S-9 mix (Longstaff et al. 1984).

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Loprieno and Abbondandolo (1980) found HCFC-22 to be negative in unscheduled DNA synthesis assays in the human heteroploid EUE cell line and in V-79 and CHO Chinese hamster cells. Reproductive and Developmental Toxicity Exposure of rats to HCFC-22 at 50,000 ppm for 5 h/d for 8 w did not affect male fertility or induce dominant dominant lethality (Lee and Suzuki 1981). Female rats exposed at 50,000 ppm for 6 h/d on d 6 to 15 of pregnancy produced a low incidence of micropthalmia (small eyes) and anopthalmia (missing eyes) in the offspring (Palmer et al. 1978a); those effects were not seen in rabbits (Palmer et al. 1978b). Spaceflight Effects Spaceflight, on rare occasions, has been accompanied by non-life-threatening cardiac dysrhythmias (but no life-threatening arrhythmias) at a higher frequency than observed for the affected individuals in tests on earth (Charles et al. 1994). Such a putative spaceflight-induced predisposition to cardiac dysrhythmias might enhance the arrhythmogenic effects of HCFC-22 in a manner similar to the sensitization seen in animals upon injection of epinephrine. Synergistic Effects Although its effects might not be strictly termed synergistic, epinephrine predisposes the heart to arrhythmia. Dogs (Reinhardt et al. 1971) and mice (Aviado and Belej 1974) administered epinephrine developed cardiac arrhythmia when exposed to HCFC-22 at 50,000 and 400,000 ppm, respectively. That effect was not seen at concentrations of HCFC-22 near 25,000 ppm in dogs and 200,000 ppm in mice, even with injection of epinephrine. More data would be required to establish whether those concentrations could be considered thresholds for cardiac arrhythmia. A summary of the toxicity data on HCFC-22 is presented in Table 9-1.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 TABLE 9-1 Toxicity Summary Concentration, ppm Exposure Duration Species Effects Reference 300 Occupational Human Cardiac arrhythmias Speizer et al. 1975 Unknown, high A few min (industrial accident) Human (n = 2) Fine lipid droplets in the cytoplasm of hepatocytes; death due to suffocation Morita et al. 1977 2000 6 h/d, 6 d/w, 10 mo Rat, mouse, rabbit NOAEL for decreased swim time, decreased weight gain, decreased oxygen consumption, toxicity and histopathological changes in internal organs, slowed formation of conditioned reflexes, and decreased ability to sum sub-threshold stimuli Karpov 1963a 5000 4 h/d, 5 d/w, 104 w Rat NOAEL for tumors Maltoni et al. 1988 5000 4 h/d, 5 d/w, 78 w Mouse NOAEL for tumors Maltoni et al. 1988 10,000 Lifetime Alderly Park rat NOAEL for subcutaneous fibrosarcomas and increased hepatomas in males Tinston et al. 1981a 10,000 2 h Guinea pig (n = 12) NOAEL (occasional chewing motions; recovered immediately) Nuckolls 1940 14,000 6 h/d, 6 d/w, 10 mo Mouse Decreased swim time; decreased weight gain and decreased oxygen consumption beginning 4th to 6th mo Karpov 1963a 14,000 6 h/d, 6 d/w, 10 mo Rabbit, mouse, rat Hematological toxicity and histopathology of internal organs (blood vessels, lungs, CNS, heart, liver, kidneys, spleen) beginning 4th to 6th mo., slowed formation of conditioned reflexes and decreased ability to sum subthreshold stimuli Karpov 1963a

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Concentration, ppm Exposure Duration Species Effects Reference 24,000-27,000 2 h Guinea pig (n = 12) Slight lacrymation, eyes partially closed; occasional chewing motions; recovered quickly Nuckolls 1940 25,000 A few min Beagle dog NOAEL for sensitization to induction of cardiac arrhythmia by epinephrine Reinhardt et al. 1971 40,000 40 min Rabbit Increased reflex reaction time; decreased reflex strength Karpov 1963b 50,000 5 h/d, 8 w Sprague-Dawley rat NOAEL for hematotoxicity, histopathology, dominant lethality and reduced male fertility Lee and Suzuki 1981 50,000 A few min. Beagle dog Sensitization to induction of cardiac arrhythmia by epinephrine Reinhardt et al. 1971 50,000 Males: 131 w females: 118 w Alderly Park rat Increased incidence of sub-cutaneous fibrosarcomas and Zymbal gland carcinomas in males; decreased body-weight gain up to week 80 in males; and increased liver, kidney, adrenal, and pituitary weights in females Tinston et al. 1981a 50,000 Males: 83 w females: 94 w Alderly Park mouse Limited evidence of increased hepatomas in males Hyperactivity Tinston et al. 1981b 50,000 6 h/d, d 6-15 Pregnant CD rat Low incidence of micropthalmia and anopthalmia in offspring Palmer et al. 1978a 50,000 6 h/d, d 6-15 Pregnant New Zealand rabbit NOAEL for micropthalmia and anopthalmia in offspring Palmer et al. 1978b 51,000-54,000 5 min Guinea pig (n = 12) Slight lacrymation; deep breathing; occasional chewing motions; recovered quickly Nuckolls 1940 51,000-54,000 30 min Guinea pig (n = 12) Slight lacrymation; fast and deep breathing; occasional chewing motions; occasionally rubbed their noses and shook their heads; recovered quickly Nuckolls 1940 51,000-54,000 60 min Guinea pig (n = 12) Slight lacrymation; fast and shallow breathing; eyes partially closed; slight clear nasal discharge; recovered quickly Nuckolls 1940

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Concentration, ppm Exposure Duration Species Effects Reference 51,000-54,000 2 h Guinea pig (n = 12) Slight lacrymation; irregular breathing; eyes partially closed; occasionally rubbed their noses and shook their heads; recovered quickly Nuckolls 1940 60,000 5 h/d, 5 d/w, 8-12 w Rabbit LOAEL for cardiac arrhythmia in 1 of 14 exposed rabbits Van Stee and McConnell 1977a 60,000 5 h/d, 5 d/w, 4-12w Rabbit LOAEL for pale livers, modestly elevated serum enzymes Van Stee and McConnell 1977a 75,000 2 h Rat, guinea pig CNS effects (excitation and/or equilibrium disturbances) Weigland 1971 95,000-117,000 5 min Guinea pig (n = 12) Slight lacrymation; fast breathing; eyes partially closed; occasionally rubbed their noses, sniffed, shook their heads, and made chewing motions; recovered quickly Nuckolls 1940 95,000-117,000 30 min Guinea pig (n = 12) Slight lacrymation; labored breathing; eyes partially closed; occasional chewing motions and tremors; weakness in rear legs; recovered quickly Nuckolls 1940 95,000-117,000 60 min Guinea pig (n = 12) Occasional gross tremors and loss of equilibrium; difficulty standing; eyes partially closed; weakness in rear legs; stupor; recovered quickly Nuckolls 1940 95,000-117,000 2 h Guinea pig (n = 12) Stupor; eyes partially closed; difficulty standing; weakness in rear legs; recovered quickly Nuckolls 1940 180,000-226,000 5 min Guinea pig (n = 12) Stupor; eyes partially closed; unable to stand and walk; weakness in rear legs; slight nasal discharge and lacrymation; apparently recovered in 1 d. Nuckolls 1940 180,000-226,000 30 min Guinea pig (n = 12) Stupor; eyes partially closed; unable to stand and walk; convulsive leg movements and tremors; nasal discharge and lacrymation; labored breathing; apparently recovered in 1 d Nuckolls 1940

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Concentration, ppm Exposure Duration Species Effects Reference 180,000-226,000 60 min Guinea pig (n = 12) Animals lying on backs, unable to stand; convulsive leg movements; nasal discharge and lacrymation; eyes partially closed; audible breathing; apparently recovered in 1 d Nuckolls 1940 180,000-226,000 2 h Guinea pig (n = 12) Unable to stand; convulsive leg movements and tremors; nasal discharge and lacrymation; audible breathing; apparently recovered in 1 d Nuckolls 1940 200,000 2 h Rat, guinea pig Narcosis Weigland 1971 200,000 (epinephrine treated) 6 min Male Swiss mouse NOAEL for cardiac arrhythmia Aviado and Belej 1974 200,000 5 min Monkey Depressed cardiac contractility, decreased aortic blood pressure, NOAEL for cardiac arrhythmia Belej et al. 1974 250,000 60 min Mice Fine granular fat droplets in the cytoplasm of hepatocytes Morita et al. 1977 300,000 30-92 min Rabbit Reeling, weakness of forelegs, ataxia, flow of mucous fluid from mouth and nose, mydriasis, lacrymation, violent movement of body and extremities, cyanosis, death Sakata et al. 1981 316,000 2 h Mouse (n = 20) LC0 Karpov 1963b 367,000 2 h Mouse (n = 20) LClow Karpov 1963b 390,000 2 h Mouse (n = 20) LC50 with deaths both during exposure and on subsequent days Karpov 1963b 400,000 7-10 min Rabbit Reeling, weakness of forelegs, ataxia, flow of mucous fluid from mouth and nose, mydriasis, lacrymation, violent movement of body and extremities, cyanosis, death Sakata et al. 1981 400,000 6 min Swiss mouse (n = 108) Cardiac arrhythmia only with simultaneous epinephrine administration Aviado and Belej 1974

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 The available toxicity data have been used to establish safe concentrations for human exposures to HCFC-22 under various exposure scenarios. Table 9-2 presents the current limits been by various U.S. organizations. Table 9-3 presents spacecraft maximum allowable concentrations (SMACs) based on the data above. The rationale for the values in Table 9-3 immediately follow the table. TABLE 9-2 Exposure Limits Set By Other Organizations Organization Exposure Limit, ppm Reference ACGIH's TLV 1000 (TWA) ACGIH 1998 OSHA's PEL 1000 ACGIH 1991b OSHA's STEL Not set ACGIH 1991b NIOSH's REL 1000 (TWA) ACGIH 1991b NIOSH's STEL 1250 ACGIH 1991b TLV, Theshold Limit Value; TWA, time-weighted average; PEL, permissible exposure limit; STEL, short-term exposure limit; REL, recommended exposure limit. TABLE 9-3 Spacecraft Maximum Allowable Concentrationsa Duration Concentration, ppm Concentration, mg/m3 Target Toxicity 1 h 1000 3500 CNS depression 24 h 1000 3500 CNS depression 7 db 1000 3500 CNS depression 30 d 1000 3500 CNS depression 180 d 1000 3500 CNS depression a These SMACs are ceiling values. b Previous 7-d SMAC = 100 ppm (350 mg/m3). The rationale for this value, which was set sometime before 1990, was not documented. RATIONALE FOR ACCEPTABLE CONCENTRATIONS To set SMAC values for HCFC-22, acceptable concentrations (ACs) were calculated for the induction of cardiac sensitization to arrhythmias and CNS

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 depression using the guidelines established by the NRC (1992). For each exposure time (1 h, 24 h, 7 d, 30 d, and 180 d), the lowest AC was selected as the SMAC value (Table 9-4). ACs were not set using data from Karpov's studies (1963a,b) for the reasons set forth below. Although decreases in weight gains were reported, they have never been considered an adverse effect, so no ACs were calculated for that end point. ACs were not calculated for developmental toxicity because NASA flight rules do not permit pregnant astronauts to fly. Cardiac Sensitization to Arrhythmias Speizer et al.'s (1975) data on human exposures could not be used to set ACs for cardiac effects because of the large uncertainty in the peak concentrations to which the medical students were exposed. It is quite likely that the effects reported by Speizer et al. were due to high peak exposures and that without such peaks, the measured 300 ppm average would actually be a NOAEL. Thus, the ACs for sensitization to arrhythmias were based on data for dogs, the most sensitive species tested. The 25,000-ppm NOAEL for epinephrine-challenged dogs (Reinhardt et al. 1971) was adjusted for potential interspecies differences. An additional spaceflight factor of 5 was not applied to this NOAEL because the NRC SMAC Subcommittee concluded that it was unnecessarily conservative for cardiac sensitization data from epinephrine-challenged test animals (NRC 1996). For exposures to CFCs, cardiac sensitization to arrhythmias is generally dependent on blood concentrations but not on exposure duration after the blood concentration has reached a plateau (usually within 1 h). Therefore, no adjustment was made for duration of exposure. Thus, 1-h, 24-h, 7-d, 30-d, and 180-d AC = 25,000 ppm ÷ 10 (species)   = 2500 ppm. CNS Depression Three reports of CNS effects were found: Weigland (1971) showed excitation, equilibrium disturbances, and narcosis in rats and guinea pigs; Sakata et al. (1981) showed dose-dependent severity of equilibrium disturbances, muscle weakness and violent movements in rabbits; and Nuckolls (1940) showed dose-dependent tremors, weakness, convulsions, and ataxia in guinea pigs. Of those

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 studies, the highest NOAEL (10,000 ppm) was reported by Nuckolls. No effects were reported by Weigland or Sakata et al. at lower doses. Thus, ACs for CNS effects are based on Nuckoll's 10,000 ppm NOAEL for a 2-h exposure. The 10,000 ppm NOAEL is divided by 10 for potential interspecies differences to set a 1-h AC. Because CNS effects are generally dependent only on blood concentration and independent of exposure time beyond about 1 h, the value for the 1-h AC is used for all exposure durations ≥ 1 h. 1-h, 24-h, 7-d, 30-d, and 180-d AC = 10,000 ppm ÷ 10 (species)   = 1000 ppm. Pathology, Endurance, and Reflexes A number of considerations lead to the conclusion that the data reported by Karpov (1963a,b) should not be used to set ACs for HCFC-22 exposures. Karpov exposed rodents intermittently to HCFC-22 at 14,000 ppm for up to 10 mo and reported effects (tissue and organ pathology, decreased endurance, impaired reflexes, etc.) that were manifested only after several months of exposure. Karpov's descriptions of histopathology are often vague and non-quantitative, making it difficult to judge the true significance of the reported effects. Karpov uses nonspecific terms such as ''dystrophic changes" and language such as "the number of eosinophiles also changed, but with a tendency toward an increase," which can only be interpreted to mean that the observed effect was not statistically significant. No description is given of what statistical methods, if any, were used, and although Karpov uses the term "significant" to describe some reported differences, the context in which it is used suggests that it is not meant in a rigorous statistical sense. Despite the industrial importance of HCFC-22, it is unlikely that a long-term study such as Karpov's will be repeated, because the carcinogenicity studies by Tinston et al. (1981a,b), involving a lifetime intermittent exposure of rats and mice at concentrations up to 50,000 ppm, did not report any of the histopathology reported by Karpov in rats and mice. Other effects reported by Karpov, such as decreased endurance and impaired reflexes, were not measured by Tinston et al. (1981a,b). Although the above arguments individually might not be sufficient to preclude the use of Karpov's data, taken together, they make it difficult to support the use of these data for setting ACs.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Carcinogenicity HCFC-22 was reported by Tinston et al. (1981a) to cause an increase in the incidence of tumors in the salivary glands and Zymbal glands of male rats exposed for a lifetime to 50,000 ppm. Because a response was seen only in one sex of one out of two species tested and only at the highest dose and very late in the study, the investigators concluded that the observed response represents an increase in the spontaneous tumor incidence due to a nonspecific action or a weak promotional effect. That interpretation is supported by the lack of non-neoplastic histopathological changes in salivary glands and Zymbal glands in the Tinston et al.(1981a) study. Thus, HCFC-22 is judged not to present a significant risk of carcinogenicity, and no AC is set for this end point.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 TABLE 9-4 Acceptable Concentrations End Point, Exposure Data, Reference   Uncertainty Factors Acceptable Concentrations, ppm Species NOAEL Time Species Spaceflight 1 h 24 h 7 d 30 d 180 d Cardiac effects Dog 1 1 10 1 2500 2500 2500 2500 2500 NOAEL, 25,000 ppm for 5 min (epinephrine treated) (Reinhardt et al. 1971)   CNS depression Rat, guinea pig 1 1 10 1 1000 1000 1000 1000 1000 NOAEL, 10,000 ppm for 2 h (Nuckolls 1940)   SMACs           1000 1000 1000 1000 1000

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 REFERENCES ACGIH. 1991a. Chlorodifluoromethane. Pp 282-283 in Documentation of the Threshold Limit Values and Biological Exposure Indices. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. ACGIH. 1991b. Guide to Occupational Exposure Values—1991. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. ACGIH. 1998. 1998 TLVs and BEIs. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. Aviado, D.M. and M.A. Belej. 1974. Toxicity of aerosol propellants on the respiratory and circulatory systems. I. Cardiac arrhythmia in the mouse. Toxicology 2:31-42. Axelson, O., ed. 1985. Halogenated Alkanes and Alkenes and Cancer: Epidemiological Aspects. Environmental Carcinogens Selected Methods of Analysis. Lyon, France: International Agency for Research on Cancer. Belej, M.A., D.G. Smith, and D.M. Aviado. 1974. Toxicity of aerosol propellants in the respiratory and circulatory systems. IV. Cardiotoxicity in the monkey. Toxicology 2(4):381-395. Charles, J.B., M.W. Bungo, and G.W. Fortner. 1994. Cardiopulmonary Function. Pp. 301-302 in Space Physiology and Medicine, 3rd Ed., A.E. Nicogossian, C.L. Huntoon, and S.L. Pool, eds. Philadelphia: Lea & Febiger. James, J.T., T.F. Limero, H.J. Leaño, J.F. Boyd, and P.A. Covington. 1994. Volatile organic contaminants found in the habitable environment of the space shuttle: STS-26 to STS-55. Aviat. Space Environ. Med. 65:851-857. Karpov, B.C. 1963a. Material on toxicology of chronic effect of Freon-22. Leningrad Sanit. Gig. Med. Inst. 75:231-240. Karpov, B.C. 1963b. Lethal and threshold concentrations of Freons. Leningrad. Sanit. Gig. Med. Inst. 75:241-250. Lee, I.P., and K. Suzuki. 1981. Studies on the male reproductive toxicity for Freon 22. Fundam. Appl. Toxicol. 1:266-270. Litchfield, M.H., and E. Longstaff. 1984. The toxicological evaluation of chlorofluorocarbon 22 (CFC 22). Food Chem. Toxicol. 22(6):465-475. Longstaff, E., M. Robinson, C. Bradbrook, J.A. Styles, and I.F. Purchase. 1984. Genotoxicity and carcinogenicity of fluorocarbons: Assessment by short-term in vitro tests and chronic exposure in rats. Toxicol. Appl. Pharmacol. 72:15-31. Loprieno, N., and A. Abbondandolo. 1980. Comparative mutagenic evaluation of some industrial compounds. Pp. 333-356 in Short-term Test Systems for Detecting Carcinogens, K.H. Norpoth and R.C. Garner, eds. Berlin: Springer-Verlag. Maltoni, C., G. Lefemine, D. Tovoli, and G. Perino. 1988. Long term carcinogenicity bioassays on three chlorofluorocarbons (trichlorofluoromethane, FC11; dichlorodifluoromethane, FC12; chlorodifluoromethane, FC22) administered by inhalation to Sprague-Dawley rats and Swiss mice. Ann. NY Acad. Sci. 534:261-282. Morita, M., A. Miki, H. Kazama, and M. Sakata. 1977. Case report of deaths caused by Freon gas. Forensic Sci. 10:253-260. NRC. 1992. Guidelines for Developing Spacecraft Maximum Allowable Concentra-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 tions for Space Station Contaminants. Washington, DC: National Academy Press. NRC. 1996. P. 11 in Minutes of the meeting of the Subcommittee on SMACs, Aug. 27-28, 1996, Woods Hole, MA. Nuckolls, A.H. 1940. Report on the Comparative Life, Fire, and Explosion Hazards of Difloromonochloromethane ("Freon 22"). Miscellaneous Hazard No. 3134, Underwriters Laboratories, Inc., Chicago. Palmer, A.K., D.D. Cozens, R. Clark, and G.C. Clark. 1978a. Effect of Arcton 22 on Pregnant Rats: Relationship to Anopthalmia and Micropthalmia. Report Number ICI 174/78208. Huntingdon Research Centre, Huntingdon, UK. Palmer, A.K., D.D. Cozens, R. Clark, and G.C. Clark. 1978b. Effect of Arcton 22 on Pregnancy of the New Zealand White Rabbit. Report No. ICI 177/78505. Huntingdon Research Centre, Huntingdon, UK. Peter, H., J.G. Filser, L.V. Szentpaly, and H.J. Wiegand. 1986. Different pharmacokinetics of dichlorofluoromethane (CFC21) and chlorodifluoromethane (CFC-22). Arch. Toxicol. 58(4):282-283. Reinhardt, C.F., A. Azar, M.E. Maxfield, P.E.J. Smith, and L.S. Mullin. 1971. Cardiac arrhythmias and aerosol "sniffing." Arch. Environ. Health 22:265-279. Sakata, M., H. Kazama, A. Miki, A. Yoshida, M. Haga, and M. Morita. 1981. Acute toxicity of fluorocarbon-22: Toxic symptoms, lethal concentration, and its fate in rabbit and mouse. Toxicol. Appl. Pharmacol. 59:64-70. Speizer, F.E., D.H. Wegman, and A. Ramirez. 1975. Palpitation rates associated with fluorocarbon exposure in a hospital setting. N. Engl. J. Med. 292(12):624-626. Tinston, D.J., J.S. Chart, M.J. Godley, C.W. Gore, M.H. Litchfield, and M. Robinson. 1981a. Chlorodifluoromethane (CFC 22): Long-term Inhalation Study in the Rat. Report No. CTL/P/548. Imperial Chemical Industries Ltd., Central Toxicology Laboratory, Alderly Park, Cheshire, UK. Tinston, D.J., J.S. Chart, M.J. Godley, C.W. Gore, M.H. Litchfield, and M. Robinson. 1981b. Chlorodifluoromethane (CFC 22): Long-term Inhalation Study in the Mouse. Report No. CTL/P/547. Imperial Chemical Industries Ltd., Central Toxicology Laboratory, Alderly Park, Cheshire, UK. Van Stee, E.W., and E.E. McConnell. 1977a. Studies of the effects of chronic inhalation exposure of rabbits to chlorodifluoromethane. Environ. Health Perspect. 20:246-247. Van Stee, E.W., E.E. McConnell, J.A. Patel, and R.L. Hamlin. 1977b. The Inhalation Toxicity of the Refrigerant Chlorodifluoromethane (F-22). International Congress on Toxicology, Toronto, Ontario, Canada. Varene, N., M.-L. Choukroun, R. Marthan, and P. Varene. 1989. Solubility of Freon 22 in human blood and lung tissue. J. Appl. Physiol. 66(5):2468-2471. Weigland, W. 1971. Examinations of the inhalation toxicology of the fluoroderivatives of methane, ethane, and cyclobutane. [in German]. Zentr. Arbeitsmed. Arbeitsschutz 2:149. Woolen, B.H., J.R. Marsh, J.D. Mahler, T.R. Auton, D. Makepeace, J. Crocker, and P.G. Blain. 1992. Human inhalation pharmacokinetics of chlorodifluoromethane (HCFC22). Int. Arch. Occup. Environ. Health 64:383-387.