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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 B11 Dichlorodifluoromethane (Freon 12) Hector D. Garcia, Ph.D. Johnson Space Center Toxicology Group Medical Operations Branch Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Dichlorodifluoromethane is a colorless, nonflammable gas with almost no odor (ACGIH 1991a). Formula: Cl2F2C CAS no.: 75-71-8 Chemical name: Dichlorodifluoromethane Synonyms: FC-12, fluorocarbon 12, CFC-12, Freon 12, Genetron 12, Halon Molecular weight: 120.92 Boiling point: –29.8°C Melting point: –158°C Specific gravity: 1.1834 g/mL (57°C) Vapor pressure: 4332 torr at 20°C Solubility: Insoluble in water (0.028 g/100 g at 25°C) Soluble in alcohol and ether Reactivity: Most halocarbons react violently with highly reactive materials, such as alkali and alkaline earth metals, sodium, potassium, and barium, in their free metallic form. Finely ground magnesium and aluminum might react at higher temperatures. Conversion factors at 25°C, 1 atm: 1 ppm = 4.94 mg/m3 1 mg/m3 = 0.202 ppm
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 OCCURRENCE AND USE Dichlorodifluoromethane (CFC - 12) does not occur naturally. It is an ozonedepleting chlorofluorocarbon and has been used principally as a plastic foam blowing agent, an aerosol propellant, and a refrigerant. Low concentrations (≤ 0.175 ppm) of CFC - 12 have been seen in the spacecraft atmosphere in 5 of 28 shuttle missions and 5 Spacelabs (James et al. 1994). UPTAKE, METABOLISM, AND TOXICOKINETICS During a 10-min inhalation exposure of dogs and rabbits at concentrations of 200,000 or 500,000 ppm, CFC - 12 rapidly diffused into the blood, cerebrospinal fluid (CSF), urine, and bile and reached steady-state concentrations in the blood within 2 min for the rabbit and 5 min for the dog (Paulet et al. 1975). After cessation of exposure, CFC -12 is eliminated, primarily (98%) through the breath, within 20-50 min. Small quantities of CFC -12 are eliminated in the urine and bile, with the bile containing higher concentrations than the urine. After intravenous injection of CFC-12 into dogs, about 1.5 h was required to achieve pseudo-distribution equilibrium in the tissue compartments (Niazi and Chiou 1977). Niazi and Chiou proposed a three-compartment open model for the disposition of CFC -12 in dogs with average half-lives of 1.47, 7.95, and 58.5 min for the three disposition phases. Disposition followed dose-independent kinetics after multiple dosing (Niazi and Chiou 1977). Thus, for multiple or continuous exposures, concentrations of CFC -12 in some tissues might accumulate to higher concentrations than would be apparent in blood. Radiolabeled CFC -11 inhaled for 7-17 min at 1000 ppm by a man and a woman was recovered quantitatively in the exhaled breath with only trace amounts of radioactivity found in exhaled carbon dioxide (0.08% in both subjects) and recovered as nonvolatile materials in the urine (0.02% and 0.03%) (Mergner et al. 1975). It is likely that the trace amounts of metabolites were products of radiolabeled impurities. In tests on rats, rabbits, and dogs exposed at either 200,000 ppm for 20 min or 50,000 ppm for 2 h/d for 15 d, CFC -12 does not appear to disturb the basal metabolic rate or metabolic pathways (Paulet et al. 1975). TOXICITY SUMMARY A considerable amount of research has been done on CFC -12, mostly on cardiopulmonary effects induced by short-term exposures. Demonstrated toxic
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 effects of exposure to CFC-12 include sensitization to and induction of cardiac arrhythmias, reduced respiratory capacity, and central-nervous-system (CNS) effects at high concentrations. Acute and Short-Term Exposures Cardiac Arrhythmia In two human volunteers, no adverse effects in continuous EKG monitoring were seen during a 2.5-h exposure to CFC-12 at 10,000 ppm (Azar et al. 1972). At 110,000 ppm, however, a "significant degree of cardiac arrhythmia" was reported in a single volunteer within the first 10 min of exposure (Kehoe 1943). A second volunteer in that same series of experiments was exposed at 40,000 ppm for 14 min, after which the concentration was reduced to 20,000 ppm for the remainder of an 80-min exposure. No cardiac effects were reported for that individual (Kehoe 1943). Ten healthy young volunteers breathing CFC-12 at 134,000 to 135,000 mg/m3 (27,000 to 27,300 ppm) for 15, 45, or 60 s experienced variations in heart rate exceeding those noted before exposure. In a few cases, inversion of the T wave and, in one case, atrioventricular block were observed; no life-threatening cardiac arrhythmias were observed (Valic et al. 1977). Stewart et al. (1978) examined the effects of CFC-12 inhalation on a group of 43 male and 32 female volunteers. Subgroups of 2-11 volunteers were exposed at 0, 250, 500, or 1000 ppm for durations of 1, 2, 6, 8, or 10 h or repetitively for 8 h/d, 5 d/w for 3.5 w. A no-observed-adverse-effect level (NOAEL) of 1000 ppm (the highest concentration tested) was based on EKG results and a large number of other toxicity tests in 38 volunteers exposed for ≤ 1 h. Repetitive exposures (8 h/d, 5 d/w for 3.5 w) of eight males at 1000 ppm were similarly without adverse effects (Stewart et al. 1978). Cardiac sensitization to epinephrine, resulting in multiple ventricular beats or cardiac arrest, has been seen in dogs inhaling CFC-12 at 5000 ppm for 5 min but not at 2500 ppm for 6 h/d for 5 d (Reinhardt et al. 1971; Trochimowicz and Reinhardt 1975). The average blood concentration associated with cardiac sensitization in these experiments was 25 µg/mL (arterial) or 20 µg/mL (venous). Arrhythmias were induced in dogs inhaling CFC-12 at 800,000 ppm plus 20% oxygen when the dogs were frightened by a loud noise to induce release of endogenous epinephrine. Exercising on a treadmill, likewise known to cause release of endogenous epinephrine, induced arrhythmias in dogs at CFC-12 concentrations two or three times higher than needed when using injections of epinephrine (Trochimowicz and Reinhardt 1975).
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 CFC-12 was also shown to be dysrhythmogenic in rats and monkeys but not in mice (Doherty and Aviado 1975). In unanesthetized rats, there was an acceleration of the heart rate but no abnormalities in the EKG pattern during inhalation of CFC-12 at 100,000, 200,000, and 400,000 ppm (Watanabe and Aviado 1975). In anesthetized rats, there was no alteration in heart rate and rare minor alterations in the EKG pattern. In rats with experimentally induced pulmonary emphysema, inhalation of CFC-12 at 400,000 ppm resulted in EKGs displaying ventricular extrasystoles (Watanabe and Aviado 1975). Lessard and Paulet (1985) examined the mechanism of action of CFC-12 on cardiac fibers isolated from sheep hearts. They concluded that the most likely mechanism consistent with their results and those reported by others is a simple mechanical constraint on intramembrane structures by simple dissolution of CFC-12 in the internal lipid layer of biological membranes. Respiratory Effects Ten healthy young volunteers breathing CFC-12 at 134,000 to 135,000 mg/m3 (27,000 to 27,300 ppm) for 45 s experienced a 3.4% reduction in maximum expiratory flow at 50% of the control vital capacity (MEF 50%) and a 5.6% reduction at MEF 75% (chest three-quarters empty) (Valic et al. 1977). Similar reductions (2.4% and 6.7%) were obtained for 15-s exposures to similar concentrations of CFC-12 (Valic et al. 1977). Stewart et al. (1978) reported that exposure of 38 volunteers to CFC-12 at 1000 ppm (the highest concentration tested) for ≤ 1 h resulted in a NOAEL for effects on pulmonary function measured by computerized spirometry, which included the maximum mid-expiratory flow rate. Seventeen repetitive exposures (8 h/d, 5 d/w for 3.5 w) of eight males at 1000 ppm were similarly without adverse effects (Stewart et al. 1978). At much higher concentrations, CFC-12 exposures produced respiratory effects in animals. In dogs, inhalation of 100,000 ppm for 5 min caused a significant increase in pulmonary resistance and 200,000 ppm also reduced the respiratory minute volume (Belej et al. 1974). Decreased pulmonary compliance and tidal volume and a variable effect on pulmonary resistance were found in rats exposed to CFC-12 at 50,000 ppm (Watanabe and Aviado 1975). CNS Effects Stewart et al. (1978) reported that exposure of 38 volunteers to CFC-12 at 1000 ppm (the highest concentration tested) for ≥ 1 h resulted in a NOAEL for
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 CNS effects (Stewart et al. 1978). Seventeen repetitive exposures (8 h/d, 5 d/w for 3.5 w) of eight males at 1000 ppm were similarly without adverse effects. In guinea pigs exposed to CFC-12 at concentrations ranging from 21,000 to 304,000 ppm for durations of 5, 30, 60, or 120 min, 51,000 ppm was found to be a NOAEL for up to 2 h; and 193,000 ppm was a lowest-observed-adverse-effect level (LOAEL), inducing slight retching movements during a 30-min exposure (Nuckolls 1933). Longer exposure times at 193,000 ppm and increased concentrations up to 304,000 ppm led to increasingly severe signs of CNS effects, including deeper breathing, tremors, weakness, lethargy, and inability to stand. All effects appeared to be reversible within 1 d of exposure (Nuckolls 1933). Subchronic and Chronic Exposures Carcinogenicity Maltoni et al. (1988) found no exposure-related cancers in male and female Sprague-Dawley rats exposed to CFC-12 at 0 (150 rats), 1000 (90 rats), and 5000 (90 rats) ppm and in male and female Swiss mice exposed at 0 (90 mice), 1000 (60 mice), and 5000 (60 mice) ppm for 4 h/d, 5 d/w for 104 and 78 w. The highest tested concentration (5000 ppm) might not have been sufficient, however, to firmly establish CFC-12 as noncarcinogenic. No other carcinogenicity studies of CFC-12 were found. Genotoxicity CFC-12 was found to be negative for genotoxicity in the Ames Salmonella bacterial mutation assay, the BHK21 cell-transformation assay (Longstaff et al. 1984; Longstaff 1988), and the CHO/HGPRT mammalian cell-mutation assay (Krahn et al. 1980). Reproductive and Developmental Toxicity No studies on CFC-12's potential effects on reproduction or development were found.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Spaceflight Effects Spaceflight, on rare occasions, has been accompanied by non-life-threatening cardiac dysrhythmias at a higher frequency than observed in tests of the affected individuals on earth. Such a putative spaceflight-induced predisposition to cardiac dysrhythmias might enhance the arrhythmogenic effects of CFC-12 in a manner similar to the sensitization seen in animals upon injection of epinephrine. Synergistic Effects Ten healthy young volunteers breathing a 30:70 mixture of CFC-12 and CFC-114 (1,1,2,2-tetrafluoro-1,2-dichloroethane) at a CFC-12 concentration of 7070-8280 ppm for 15, 45, or 60 s experienced a reduction of ventilatory capacity, which was much more pronounced (more than additive) than after exposure to the individual compounds (Valic et al. 1977). The sensitizing effect of epinephrine in lowering the concentration of CFC-12 required to induce cardiac dysrhythmias has been described in the preceding sections. There appears to be a threshold concentration of CFC-12 (near 2500 ppm) below which dysrhythmias are not produced in rats, even with injection of epinephrine. Table 11-1 presents a summary of the toxicity data on CFC-12.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 TABLE 11-1 Toxicity Summary Concentration, ppm Exposure Duration Species Effects Reference 1000 1-10h Human (n = 38) NOAEL for cardiac, pulmonary, CNS, hematology and clinical chemistry effects Stewart et al. 1978 1000 8-10 h Human (n = 23) NOAEL for cardiac, pulmonary, CNS, hematology and clinical chemistry effects Stewart et al. 1978 1000 8 h/d, 5 d/w, 3.5 w Human (n = 8) NOAEL for cardiac, pulmonary, CNS, hematology and clinical chemistry effects Stewart et al. 1978 10,000 2.5 h Human (n = 2) NOAEL for cardiac dysrhythmia Azar et al. 1972 27,000-27,300 15, 45, 60 s Human (n = 10) NOAEL for cardiac dysrhythmia; LOAEL for reduced ventilatory capacity and tachycardia Valic et al. 1977 40,000 (14 min) + 20,000 (66 min) 14 min + 66 min Human (n = 1) NOAEL for cardiac dysrhythmia Kehoe 1943 70,000 35 min Human (n = 1) NOAEL for cardiac dysrhythmia Kehoe 1943 110,000 10 min Human (n = 1) LOAEL for cardiac dysrhythmia Kehoe 1943 2500 6 h/d, 5 d Dog NOAEL for cardiac sensitization to dysrhythmia Trochimowicz and Reinhardt 1975; Reinhardt et al. 1971 5000 5 min Dog LOAEL for cardiac sensitization to dysrhythmia Trochimowicz and Reinhardt 1975; Reinhardt et al. 1971 5000 4 h/d, 5 d/w, 104 w Rat, mouse NOAEL for carcinogenicity Maltoni et al. 1988
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Concentration, ppm Exposure Duration Species Effects Reference 100,000 5 min Dog Increased pulmonary resistance Belej et al. 1974 200,000 5 min Dog Increased pulmonary resistance; reduced minute volume Belej et al. 1974 51,000 120 min Guinea pig NOAEL for CNS effects Nuckolls 1933 193,000 30 min Guinea pig LOAEL for slight retching movements Nuckolls 1933 193,000 60, 120 min Guinea pig Slight retching movements; slight tremors Nuckolls 1933 285,000-304,000 30 min Guinea pig Weakness, lethargy, inability to walk Nuckolls 1933 285,000-304,000 45, 120 min Guinea pig Inability to stand; occasional trembling Nuckolls 1933 800,000 30 s Dog Cardiac dysrhythmia when frightened by a loud noise Trochimowicz and Reinhardt 1975
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 RATIONALE FOR ACCEPTABLE CONCENTRATIONS Table 11-2 presents exposure limits for CFC-12 set by other organizations and Table 11-3 presents the SMACs established by NASA. To set SMAC values for CFC-12, acceptable concentrations (ACs) were calculated for the induction of each adverse effect (cardiac arrhythmia and CNS effects) 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 11-4). TABLE 11-2 Exposure Limits Set by Other Organizations Organization Exposure Limit, ppm Reference ACGIH's TLV 1000 (TWA) ACGIH 1998 OSHA's PEL 1000 (ceiling) ACGIH 1991b OSHA's STEL Not set ACGIH 1991b NIOSH's REL 1000 (ceiling) ACGIH 1991b NIOSH's STEL Not set ACGIH 1991b TLV, Theshold Limit Value; TWA, time-weighted average; PEL, permissible exposure limit; STEL, short-term exposure limit; REL, recommended exposure limit. TABLE 11-3 Spacecraft Maximum Allowable Concentrations Duration Concentration, ppm Concentration, mg/m3 Target Toxicity 1 h 540 2600 Tachycardia 24 h 95 470 Cardiac sensitization to arrhythmia 7 da 95 470 Cardiac sensitization to arrhythmia 30 d 95 470 Cardiac sensitization to arrhythmia 180 d 95 470 Cardiac sensitization to arrhythmia a Previous 7-d SMAC = 100 ppm (490 mg/m3).
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Cardiac Sensitization to Arrhythmias ACs for cardiac effects are based on the reports of Azar et al. (1972), Valic* et al. (1977), and Stewart et al. (1978). The results of Valic* et al. show a LOAEL for heart-rate effects of 27,000 ppm for a 15-s exposure; symptoms did not increase in severity within 60 s of exposure. The results of Azar et al. suggest a NOAEL near 10,000 ppm. Using the data of Valic et al. as a starting point and dividing the LOAEL by 10 to estimate a NOAEL yields 2700 ppm. To set a 1-h AC, that value is then divided by 5 for potential spaceflight effects on cardiac arrhythmias. 1-h AC = 27,000 ppm ÷ 10 ÷ 5 = 540 ppm. ACs for exposures that are > 1 h are based on the NOAEL for cardiac effects in 23 humans after exposure to CFC-12 for 8-10 h at 1000 ppm (Stewart et al. 1978). An adjustment of 10/√23 = 2.08 was applied for the low number of human subjects, and a spaceflight factor of 5 was applied. ≥ 24-h AC = 1000 ppm ÷ 2.08 ÷ 5 = 95.9 ppm rounded to 95 ppm. Respiratory Effects ACs for respiratory effects are based on the NOAEL for reductions in ventilatory capacity in 23 humans after exposure to CFC-12 for 8-10 h at 1000 ppm (Stewart et al. 1978). An adjustment of 10/√23 = 2.08 was applied for the low number of human subjects. ≥ 24-h AC = 1000 ppm ÷ 2.08 = 480 ppm. The independence of respiratory symptoms from exposure duration is supported by the fact that the NOEAL of Stewart et al. (1978) occurred at a concentration times exposure duration (C × t) of 136,000 ppm•h (1000 ppm × 136 h), whereas the reduced ventilatory capacity reported by Valic et al. (1977) occurred at a C × t of 112.5 ppm•h (27,000 ppm × 0.0042 h).
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 TABLE 11-4 Acceptable Concentrations End Point, Exposure Data, Reference Species Uncertainty Factors Acceptable Concentrations, ppm NOAEL Small nb Species Spaceflight 1 h 24 h 7 d 30 d 180 d Tachycardia Human 10 1 1 5 540 NSa NS NS NS LOAEL, 27,000 ppm for 15 s (Valic* et al. 1977) Cardiac sensitization to arrhythmia Human 1 2.08 1 5 NS 95 95 95 95 NOAEL, 10,000 ppm ≥ 8 h (Stewart et al. 1978) Respiratory effects Human 1 2.08 1 1 NS 480 480 480 480 NOAEL, 1000 ppm ≥ 8 h (Stewart et al. 1978) SMACs 540 95 95 95 95 a NS, not set. b To correct for the small number of human test subjects, the factor is 10/√n.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 REFERENCES ACGIH. 1991a. Dichlorodifluoromethane. Pp 420-422 in Documentation of the Threshold Limit Values and Biological Exposure Indices, Vol. 1, 6th Ed. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. ACGIH. 1991b. Guide to Occupational Exposure Values—1991. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. Azar, A., C.F. Reinhardt, M.E. Maxfield, P.E. Smith, and L.S. Mullin. 1972. Experimental human exposures to fluorocarbon 12 (dichlorodifluoromethane). Am. Ind. Hyg. Assoc. J. 33(4):207-216. 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 2:381-395. Doherty, R.E., and D.M. Aviado. 1975. Toxicity of aerosol propellants in the respiratory and circulatory systems. VI. Influence of cardiac and pulmonary vascular lesions in the rat. Toxicology 3(2):213-224. 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. Kehoe, R.A. 1943. Report on Human Exposure to Dichlorodifluoromethane in Air. Kettering Laboratory, University of Cincinnati. Cincinnati, OH. Krahn, D.F., F.C. Barsky, and K.T. McCooey. 1980. CHO/HGPRT Mutation Assay: Evaluation of Gases and Volatile Liquids. Pp. 91-103 in Genotoxic Effects of Airborne Agents, R.R. Tice, D.L. Costa, and K.M. Schaich, eds. New York: Plenum Press. Lessard, Y., and G.Paulet. 1985. Mechanism of liposoluble drugs and general anaesthetic's membrane action: Action of difluorodichloromethane (FC12) on different types of cardiac fibres isolated from sheep hearts. Cardiovasc. Res.19:465-473. Longstaff, E. 1988. The carcinogenic and mutagenic potential of several fluorocarbons. Ann. NY Acad. Sci. 534:283-297. 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. 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. Mergner, G.W., D.A. Blake, and M. Helrich. 1975. Biotransformation and elimination of 14C-trichlorofluoromethane (FC-11) and 14C-dichlorodifluoromethane (FC-12) in man. Anesthesiology 42:345-351. Niazi, S., and W.L. Chiou. 1977. Fluorocarbon aerosol propellants. XI. Pharmaco-Kinetics of dichlorodifluoromethane in dogs following single and multiple dosing. J.Pharm. Sci. 66:49-53.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 NRC. 1992. Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants. Washington, DC: National Academy Press. Nuckolls, A.H. 1933. Underwriter's Laboratories' Report on the Comparative Life, Fire, and Explosion Hazards of Common Refrigerants. Miscellaneous Hazard No. 2375. Underwriter's Laboratories. Chicago, IL. Paulet, G., J. Lanoe, A. Thos, P. Toulouse, and J.Dassonville. 1975. Fate of fluorocarbons in the dog and rabbit after inhalation. Toxicol. Appl. Pharmacol. 34:204-213. Paulet, G., G. Roncin, E. Vidal, P. Toulouse, and J. Dassonville. 1975. Fluorocarbon and general metabolism in the rat, rabbit, and dog. Toxicol. Appl. Pharmacol. 34:197-203. Reinhardt, C.F., A. Azar, M.E. Maxfield, P.E. Smith, Jr., and L.S. Mullin. 1971. Cardiac arrhythmia and aerosol ''sniffing." Arch. Environ. Health 22:265-279. Stewart, R.D., P.E. Newton, E.D. Baretta, A.A. Herrmann, and R.J. Soto. 1978. Physiological response to aerosol propellants. Environ. Health Perspect. 26:275-285. Trochimowicz, H.J., and C.F. Reinhardt. 1975. Studies clarify potential toxicity of aerosol propellants. DuPont Innovation 6(3):12-16. Valic*, F., Z. Skuric*, Z. Bantic*, M. Rudar, and M.Hecej.* 1977. Effects of fluorocarbon propellants on respiratory flow and ECG. Br. J. Ind. Med. 34(2):130-136. Watanabe, T., and D.M. Aviado. 1975. Toxicity of aerosol propellants in the respiratory and circulatory systems. VII. Influence of pulmonary emphysema and anesthesia in the rat. Toxicology 3(2):225-240.
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