B5 Freon 113

Hector D. Garcia, Ph.D., and John T. James, Ph.D.

Johnson Space Center Toxicology Group

Biomedical Operations and Research Branch

Houston, Texas

PHYSICAL AND CHEMICAL PROPERTIES

Freon® 113 is a colorless, odorless, nonflammable liquid at room temperature (Sax, 1984; Imbus and Adkins, 1972).

Formula:

CCl2FCClF2

CAS number:

76-13-1

Chemical name:

1,1,2-trichloro-1,2,2-trifluoroethane

Synonyms:

FC113; fluorocarbon 113; Frigen 113; CFC-113; TCTF; Freon TF; Genesolv D; Freon PCA; Isotron 113; Cleaning compound S; Cleaning compound solvent trichlorotrifluoroethane (MIL-C-81302).

Molecular weight:

197.5

Boiling point:

47.6°C

Melting point:

−35°C

Specific gravity:

1.5635 g/L (25°C)

Vapor pressure:

284 mm Hg at 20°C

Solubility:

Insoluble in water; soluble in alcohol, ether, and benzene

Conversion factors at 25°C, 1 atm:

1ppm = 8.0 mg/m3

1mg/m3 = 0.12 ppm



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BS Freon 113 Hector D. Garcia, Ph.D., and John T. James, Ph.D. Johnson Space Center Toxicology Group Biomedical Operations and Research Branch Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Freon® 113 is a colorless, odorless, nonflammable liquid at room tem- perature (Sax, 1984; Imbus and Adkins, 1972). Formula: CCl2 FCCIF2 CAS number: 76-13-1 Chemical name: 1, l ,2-trichloro-1,2,2-trifluoroethane Synonyms: FC113; fluorocarbon 113; Frigen 113; CFC-113; TCTF; Freon TF; Genesolv D; Freon PCA; lsotron 113; Cleaning compound S; Clean- ing compound solvent trichlorotri- fluoroethane (MIL-C-81302). Molecular weight: 197.5 Boiling point: 47.6°C Melting point: -35°C Specific gravity: 1.5635 g/L (25°C) Vapor pressure: 284 mm Hg at 20°C Solubility: Insoluble in water; soluble in alcohol, ether, and benzene Conversion factors at 25°C, 1 atm: 1 ppm = 8.0 mg/m 3 1 mg/m3 = 0.12 ppm 121

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122 SMACS FOR SELECTED AIRBORNE CONTAMINANTS OCCURRENCE AND USE FC 113 does not occur naturally. It is manufactured for use principally as a dry-cleaning solvent, refrigerant, and blowing agent. It is also used as a cleaning solvent for metals and sensitive electronic parts and in the maintenance of hydraulic piping systems in submarines. FC 113 has been piped into each of three clean rooms at Kennedy Space Center for use in cleaning, hydrocarbon sampling, particle sampling and general degreasing. FC113 is not used in the spacecraft during flight, but has been used to clean and degrease spacecraft components between missions. It has been detected in the atmosphere in the spacecraft in almost every mission, usually at low levels, the highest to date being 8. 7 ppm (Liebich et al., 1975). PHARMA CO KINETICS Inhaled FC 113 distributes in a dose-dependent manner into the perirenal fat and brain of rats; the concentrations were 126, 506, and 1133 nmol/g of fat after exposure to 200, 1000, and 2000 ppm, respectively, for 6 h/d, 5 d/w, for 2 w (Savolainen and Pffiitli, 1980). Blood concentrations of FC113 in dogs inhaling FC113 at 1000, 5000, or 10,000 ppm increased rapidly during the first 5 min, then more slowly or not at all for the remainder of a 10-min exposure (Trochimowicz et al., 1974). The kinetics of blood-level variations suggest a tissue uptake of FC113 during exposure, followed by a release into the venous blood after the exposure is terminated. FC113 is rapidly eliminated from the blood- stream and expelled through the lungs after cessation of exposure, having a venous half-life of approximately 15 min. A study (Woolen et al., 1990) in seven male human volunteers of blood and breath levels during, and for several days after, exposure to FC 113 for 4 h at concentrations of 240, 490, or 920 ppm suggested a three compart- ment model (e.g. blood, tissues, fat) with half-lives for the elimination of FCl 13 in the breath of 0.22, 2.3, and 29 h, respectively. Blood concentra- tions of FC 113 approached a plateau after approximately 30 min exposure and peak concentrations were related to the exposure concentrations. Pulmonary retention of 14% was measured during exposure but only 2.6- 4.3% of the dose was recovered unchanged in breath after the exposure

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FREON 113 123 period, suggesting that FCl 13 could be metabolized following inhalation exposure. The data from this study do not permit a firm conclusion to be drawn as to whether FC 113 is metabolized by humans (Auton and Woolen, 1991). In another study (Reinhardt et al. , 1971), four human male volunteers were exposed to FC113 for 5 d at 500 ppm, 3 h each morning and 3 h each afternoon, followed 3 d later by exposure for 5 d at 1000 ppm, 3 h each morning and 3 h each afternoon. Measurements were taken of FC 113 levels in end tidal breaths taken 1 min after the end of each exposure. The highest measured level was 115 ppm on the afternoon following the first exposure at 1000 ppm in one subject. End tidal breath levels taken on the third day following the last exposure showed FCl 13 concentrations of 1.5 ppm in one subject and less than 1 ppm in the other three subjects. Al- though this result demonstrates that almost all FC 113 that might have been retained in the tissues under these exposure conditions was eliminated after two successive exposure-free days, it is not sufficient to establish that a gradual tissue build up of FC 113 would not occur under continuous expo- sure conditions. TOXICITY SUMMARY Acute Toxicity ( < 24 h Exposure) Lethality Human fatalities have been reported for exposures to FCl 13 in Japan and in the United States. One Japanese death involved a worker who was exposed for less than 30 min to an atmosphere containing 13.7-17.5% oxygen and FC113 at 118,000-140,000 ppm (11.8-14%, v/v) (Yonemitsu et al., 1983). One of two other Japanese workers died after being occupa- tionally exposed for about 1 h to an undetermined concentration of FC 113 (Hoshika et al., 1989). The dead worker had signs of central-nervous- system (CNS) toxicity: urination and defecation as well as probable lung injury (discharge from nose and ears). The survivor was exposed for about half an hour before going to the clinic complaining of heart palpitations and heavy-headedness. He was found to be anemic and had colitis. Within a 3-y period, four active-duty Navy and one civilian employee died in three

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124 SMACS FOR SELECTED AIRBORNE CONTAMINANTS separate incidents attributed to FCl 13 exposure of unstated duration in areas that could permit accumulation of vapors, including confined spaces and low-lying areas aboard ships (Arnitz, 1985). FCl 13 may be responsi- ble for some fatalities in cases of individuals intentionally inhaling aerosol propellants, although FC 113 was not one of the halocarbon propellants identified in the 110 "sudden sniffing deaths" reported by Bass (1970). The 4-h LC50 for rats is from 52,000 to 68,000 ppm (O.L. Dashiell, J.W. Sarver, and T.K. Bogdanowicz, DuPont, unpublished data, 1971), while lethal concentrations for a 2-h exposure of rats, guinea pigs, mice, and rabbits range from 50,000 to 120,000 ppm. The 15-min LC50 in rats is 130,000 ppm (Clark and Tinston, 1982). The oral LD 50 in rats is 43 g/kg (Michaelson and Huntsman, 1964). No-Observed-Adverse-Effect Level (NOAEL) Two human males exposed to 1,500 ppm for 2.5 h showed no adverse psychomotor effects (Stopps and McLaughlin, 1967). Because only two subjects were exposed at a single FC 113 concentration and only behavioral effects (manual dexterity, depth perception, card sorting) were examined, limited weight can be given these results. Dogs exposed for 10 min to 2500 ppm FC113 showed no cardiac sensitization to epinephrine-induced arrhythmias (Reinhardt et al., 1973). Cardiac Arrhythmia Clinical experience indicates that halohydrocarbons might be cardiac arrhythmogens (Back and Van Stee, 1977) at high concentrations. Hine et al. (1%8) monitored EKGs during exposure of humans to nominal concen- trations of bromotrifluoromethane at 50,000, 100,000, and 150,000 ppm. Auriculoventricular (AV) dissociation and premature ventricular contrac- tions (maximum 16.9%) were recorded during exposure to the highest concentrations. In a study of the cardiac effects of FC 113, four dogs were exposed to FC113 for 10 min via face mask to 1000, 5000, and 10,000 ppm (Reinhardt et al., 1973). At 10,000 ppm, three of four dog exposures resulted in life-threatening cardiac arrhythmias (multiple consecutive ventricular beats or ventricular fibrillation) after a challenge dose of

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FREON 113 125 epinephrine at 8 µg/kg. At 5,000 ppm, the incidence was 10 of 29 dog exposures, and at 2500 ppm, the incidence was 0 of 12 dog exposures. In another study from the same lab, FCl 13 did not produce cardiac sensitization in dogs at 1000 ppm, and arterial blood concentrations (2.6 µg/mL) were proportionally lower than arterial blood concentrations associated with cardiac sensitization (12.5 µg/mL) (Trochimowicz, 1973). An inspired concentration of 5000 ppm was required to sensitize the dog heart to the arrhythmic action (multiple consecutive ventricular beats or ventricular fibrillation) of exogenous epinephrine (Trochimowicz et al., 1974; Trochimowicz, 1973). The EC 50 for cardiac sensitization to epinephrine in dogs for a 5-min exposure to FC 113 was reported to be 7000 ppm (Clark and Tinston, 1982). In mice, inhalation of 5000-ppm FC 113 is required to sensitize the heart to epinephrine-induced arrhythmias, and a level of 10,000 ppm will induce arrhythmias without exogenous epinephrine (Aviado and Belej, 1974). Sensitization is only a temporary effect, however, since an epinephrine injection given 10 min after exposure (at which time much of the FC 113 had probably been eliminated from the blood) did not cause arrhythmia (Clark and Tinston, 1971). CNS Effects The EC 50 for CNS stimulation (tremors of the limbs) for a 10-min exposure ofrats to FC113 was found to be 28,000 ppm (Clark and Tinston, 1982). Eye and Skin A single application or instillation of FC 113 was found to be practically nonirritating to the ocular mucosa and skin of rabbits (Duprat et al., 1976). Sleepiness In a limited study involving six rats exposed to 12,000 ppm for up to 24 mo, a slight sleepiness was observed that disappeared immediately after daily exposure stopped (Desoille et al., 1968).

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126 SMACS FOR SELECTED AIRBORNE CONTAMINANTS Subchronic Toxicity (1-13 w Exposure) NOAEL Four male volunteers exposed at 500 or 1000 ppm for 6 h/d, 5 d/w for 2 w showed no adverse effects on performance of complex mental tasks or changes in clinical status or biochemical tests (Reinhardt et al., 1971). Although the exposure of humans makes this study potentially valuable, the small number of subjects limits its usefulness. Twenty-one rats exposed to FCl 13 at 2520 ppm for 7 h/d, 5 d/w for 6 w showed no signs of toxicity during the exposure period and no gross or microscopic pathology attributed to FCl 13 exposure (Limperos, 1954). Similarly, no changes in behavior or external appearance were seen in rats exposed to FC113 at 10,000 ppm or dogs exposed to FC113 at 5000 ppm; both species were exposed for 6 h/d, 7 times a week for 90 d (Leuschner et al., 1983). Biochemical Effects on the CNS Reported biochemical effects on the CNS of the rat include dose-depend- ent accumulation in brain tissue and perirenal fat, an increase of NADPH-diaphorase activity at 200 ppm and a decrease in cerebral gluta- thione at 2000 ppm in the first week of exposure for 2 w, 5 d/w, 6 h/d (Savolainen and Pffafli, 1980). During the second week, these effects disappeared while RNA tended to increase, and glutathione peroxidase activity tended to decrease at the highest dose. After a withdrawal period of 7 d, no FC113 was detected and the neurochemical effects had disap- peared, except that brain RNA at the highest exposure was below the control range. It is not clear whether these biochemical changes are detrimental or merely adaptive. Dose-response or time-response effects were not demonstrated. Hepatotoxicity Male rats exposed to FC113 at 1000 or 2000 ppm for 5 d/w, 6 h/d for 1or2 w showed subtle changes in liver cells (Vainio et al., 1980). Indica-

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FREON 113 127 tions of lipid accumulation were seen in the light microscope. In the electron microscope, a slight to moderate increase of the smooth endoplas- mic reticulum with vacuolization was seen in the 1000- and 2000-ppm groups after 1 and 2 w of exposure. These same groups also showed an increased number of autophagous vacuoles, reduced glycogen, and conden- sations in some mitochondria. All these observations were subjective in nature. Biochemical studies on these rats after 1 w of exposure showed dose-related decreases in the levels of NADPH cytochrome-c reductase and microsomal cytochrome P-450 and increases in UDP glucuronosyltrans- ferase activity in liver but not in kidney (Vainio et al., 1980). These reported effects were reduced or absent after 2 w of exposure; hence, the meaning of the effects reported at 1 w is uncertain. It is not clear whether the histological and biochemical changes reported at 1000 and 2000 ppm actually occurred, and if they did, whether they were detrimental or merely adaptive. Chronic Toxicity(> 13 w Exposure) NOAEL A group of 50 workers, exposed for an average of 2. 77 y in an envi- ronment that contained FC113 at 46-4700 ppm, were given clinical and laboratory examinations and compared to 50 workers who were not so exposed. No significant differences were seen between the two groups, other than one individual who complained of dryness of the skin due to FC113 exposure (Imbus and Adkins, 1972). Carcinogenicity and Genotoxicity A 2-y joint study by DuPont and Allied Corporation has concluded that FC113 has no carcinogenic or toxic effects in rats exposed to 0, 2000, 10,000, or 20,000 ppm (v/v) by inhalation for 6 h/d, 5 d/w for 104 w (Trochimowicz et al., 1988). No significant toxic effects were observed, including histopathology of 43 tissues, hematology, gross appearance, behavior, and mortality (Trochimowicz et al., 1988). A 5-10% decrease in body-weight gain was seen at the 10,000- and 20,000-ppm exposure levels.

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128 SMACS FOR SELECTED AIRBORNE CONTAMINANTS FC113 was found to have no dominant lethal effects in mice (Epstein et al., 1972) given i.p. doses of 200 mg/kg or 1000 mg/kg. FC113 was not mutagenic in Salmonella (Longstaff, 1988). A 1988 study has shown that preparation of microsomal enzymes from livers of mice exposed to FCl 13 at 20,000 ppm for a total of 8 h greatly enhanced the metabolic activation of procarcinogenic polyaromatic hydro- carbons (aminotluorene, acetylaminotluorene) (Mahurin and Bernstein, 1988) as compared with microsomal enzymes prepared from the livers of sham-exposed mice, although FCl 13 itself was not mutagenic as measured by a microbial assay. Kidney Effects A study of Danish metal workers occupationally exposed to trichloro- ethylene or FC113 concluded that chlorinated organic solvents can induce subclinical nephropathy after long-term exposure. Concentrations were not estimated, however (Rasmussen et al., 1988). Memory and Psychomotor Effects A study of 99 workers engaged in degreasing with halogenated hydro- carbons found the following signs and symptoms of psychoorganic syn- drome in the three workers who had heavy exposure to only FCl 13 for 2.5-4.5 y: impaired psychomotor speed, impaired learning, and impaired long-term memory (Rasmussen et al., 1988). Mechanistic Studies Comparison of the relative potencies of a wide range of halogenated and unsubstituted hydrocarbons that can produce rapidly reversible effects on the CNS and the heart suggests that these effects are probably structurally nonspecific, i.e. these chemicals may be regarded as physical toxicants whose effects are predictable from their physicochemical properties (Clark and Tinston, 1982). These chemicals probably exert their toxic effects not by combining with some specific target or receptor but by simply being

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FREON 113 129 present in some part of the cell in a concentration sufficient to disorganize its function temporarily. Such a model would predict that there should be a threshold tissue concentration below which this class of chemicals would have no effect on a given tissue. Some effects, nevertheless, might be subtle and might require long-term continuous exposure before becoming significant. Spaceflight Effects There have been several reports of cardiac arrhythmias in U.S. astro- nauts (Bungo, 1980) and Soviet cosmonauts (Gazenko et al., 1990) during spaceflights. During the third month of a flight aboard the Soviet Mir Space Station, the flight engineer of the second prime crew showed cardiac rhythm irregularities in response to emotional and physical stress. During an extravehicular activity (EVA) (April 11, 1987), he registered a series of atrial extrasystoles with episodes of trigeminy. While performing graded physical exercise on a treadmill soon after the EV A, he displayed marked tachycardia incommensurate with the exercise level and a significant number of isolated supraventricular extrasystoles. Utilization of a number of medical measures, adjustment of the prophylactic program, and stringent organization of the work-rest schedule led to gradual normalization of cardiac rhythm during exercise. No further cardiac arrhythmias were seen on two subsequent EV As (June 12 and 16, 1987), but at the end of June, supraventricular extrasystoles were again noted during exercise, although the cosmonaut himself did not experience any associated sensations. Postflight cardiological examination of this cosmonaut revealed no organic changes in his myocardium, nor was any further disruption of cardiac rhythm noted. During the first four flights of the space shuttle, one crew member exhibited uniform PVCs (premature ventricular contractions) during nearly every minute of re-entry after the onset of gravitational loading. Although preflight examinations had revealed occasional PVCs in this crew member, the rate of ectopics per minute during re-entry was perhaps eight-fold higher than preflight. A second crew member, who had no significant prior history of ventricular ectopia, exhibited rare PVC during the entry phase. Serum electrolytes were not abnormal in either crew member (Bungo and Johnson, 1983).

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130 SMACS FOR SELECTED AIRBORNE CONTAMINANTS Unfortunately, there have been insufficient data collected on the base- line incidence of cardiac arrhythmias of individuals on earth to assess the health risk associated with these putative anomalies. Even in the shuttle program, EKG measurements are routinely taken only during EVAs. Synergism FC 113 has been widely used domestically and industrially as a propel- lant for pesticide mixtures containing piperonyl butoxide (PB) as a syner- gist to inhibit detoxifying enzymes. FC113 and PB, both relatively low-toxicity compounds, were found to be highly toxic and carcinogenic when a 10%-FC113, 5%-PB mixture dissolved in tricaprylin was injected subcutaneously into neonatal mice, although neither compound alone was toxic or carcinogenic under the same conditions (Epstein et al., 1967). There is no basis to expect PB to be present in spacecraft air.

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TABLES-I Toxicity Summary for FCI 13 Exposure Concentration Duration S12ecies Effects Reference 1000 ppm 6 hid, 5 d/w for 2 Human No observed adverse effects. Reinhardt et al., 1971 w 1500 ppm 2.75 h Human No psychomotor effects. Stopps and McLaughlin, 1967 2500 ppm 2.75 h Human Slight, reversible psychomotor effects. Stopps and McLaughlin, 1967 46-4700 ppm 6 h/d, 5 d/w Human No observed adverse effects. Imbus and Adkins, 1972 for2.77 y "Heavy" 2.5-4.5 y Human Impaired memory and learning; impaired psychomotor Rasmussen et al., 1988 speed. 200 ppm 6 hid, 5 d/w Rat No changes in liver cell histology. Vainio et al., 1980 for2 w 200 ppm 6 h/d, 5 d/w Rat Temporary increase in NADPH-diaphorase level (no dose Savolainen and Pffafli, for2 w response). 1980 1000 ppm 6 hid, 5 d/w Rat Altered liver cell histology. Vainio et al., 1980 for 1 w 2500 ppm 10 min Dog No cardiac sensitization. Reinhardt et al., 1973 2520 ppm 30 times for 7 h/d, Rat No observed adverse effects at autopsy 1 d post-exposure Limperos, 1954 5 d/w; 1 time for 4.3 h 5000 ppm 10 min Dog Cardiac sensitization. Trochimowicz et al., 1974 ..... ~ .....

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.... ~ TABLE 5-1 (Continued) N Exposure Concentration Duration S~ecies Effects Reference 5000 ppm 6 hid, 7 times/w Dog No observed adverse effects. Leuschner et al., 1983 for90 d 10,000 ppm 6 hid, 7 times/w Rat No observed adverse effects. Leuschner et al., 1983 for90 d 12,000 ppm 24mo Rat Slight sleepiness. Desoille et al., 1968 17,600 ppm 2h Rat Mild excitement; no loss of coordination. Moderate Limperos, 1954 congestion ofliver and kidneys. 33,300 ppm 6h Rat Moderate initial excitement. Marked excitement in 3-4 h. Limperos, 1954 Dyspnea in 3 h. Lungs slightly emphysematous and atelectatic at IO d post-exposure. 39,100 ppm 2h Rat Excitement, incoordination. Liver and kidney pale; some Limperos, 1954 fatty deposition. 50,000 ppm 4h Rat Death. Dashiell, Sarver, Bogdanowicz, DuPont, unpublished, 1971 50,900 ppm 10 min Rat Excitement, incoordination. Mild liver congestion; kidney Limperos, 1954 pale with focal necrosis. 50,900 ppm 4h Rat Excitement, incoordination; no loss of consciousness. Limperos, 1954 67,000 ppm 4h Rat Convulsions, tremors, incoordination. Limperos, 1954 71,300 ppm 6h Rat Marked excitement in 5 min. Incoordination in 20 min. No Limperos, 1954 abnormal findings at autopsy at 10 d post-exposure.

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78,700ppm 4h Rat Incoordination in 15 min. Convulsive in 30-40 min. Limperos, 1954 Prostrate but conscious in 2.5 h. Recovered 20 min after exposure. No abnormal findings at autopsy at 11 d post- exposure. 86,900 ppm 4h Rat Convulsive in 10 min; unconscious in 20 min; dyspnea and Limperos, 1954 cyanosis in 40 min to 4 h. Death with pulmonary edema in 1 of2 rats; no pathology in surviving rat at 11 d post- exposure. 141,150 ppm 60-100 min Rat Unconscious in 10 min. One rat died in 1 h, the other in Limperos, 1954 100 min. At autopsy, lungs were congested and edematous; thymus was congested. ~ ~ ~

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134 SMACS FOR SELECTED AIRBORNE CONTAMINANTS TABLE 5-2 Exposure Limits Set by Other Organizations Organization Concentration, ppm ACGIH's TLV (TWA) 1000 ACGIH's TLV (STEL) 1250 (ceiling) OSHA's PEL 1000 OSHA's STEL 1250 (ceiling) NIOSH's REL 1000 NIOSH's STEL 1250 (ceiling) NRC's 1-h EEGL 1500 (12.1 g/m3) NRC's 24-h EEGL 500 (4.0 g/m3) NRC's 90-d CEGL 100 (0.8 g/m3) TLV = threshold limit value. TWA = time-weighted average. PEL = permissible exposure limit. STEL = short-term exposure limit. REL = recommended exposure limit. EEGL = emergency exposure guidance level. CEGL = continuous exposure guidance level. TABLE 5-3 Spacecraft Maximum Allowable Concentrations Duration ppm mg/m3 Target Toxicity lh 50 400 Cardiac Sensitization 24h 50 400 Cardiac Sensitization 7 OCR for page 121
FREON 113 135 Of these end points, the only definitely adverse effect is cardiac sensi- tization. Mild, subclinical, "adaptive" effects on the liver, such as the equivocal changes in enzyme activities and smooth endoplasmic reticulum in liver cells reported after exposure of rats to 1000 ppm for 6 h/d, 5 d/w for 1 w, are not considered to be significant changes. Cardiac arrhythmias are unacceptable because, although they might not be incapacitating by themselves, some types might signal a substantially increased risk of incapacitating or fatal cardiac injury. The SMAC for a 1- h exposure to FC113 was set at 50 ppm on the basis of the findings that a 10-min exposure to 2500 ppm did not sensitize dog hearts to the arrhythmogenic action of epinephrine and then applying a species ex- trapolation factor of 10 and an additional factor of 5 for possible space- flight-enhanced sensitivity to arrhythmias. No time extrapolation should be applied to the 50-ppm 1-h SMAC because this effect is dependent on blood concentration, which reaches a plateau in about 30 min in humans ( 10 min in dogs). The SMACs for 24 h, 7 d, 30 d, and 180 d exposures to FCl 13 were also set at 50 ppm on the basis that arrhythmogenicity is dependent on blood concentration, which reaches a plateau in about 30 min, and is apparently independent of time (Trochimowicz et al., 1974). This 50-ppm value is well below the concentration of 1000 ppm which, based on only two test subjects, appears to have no effect on manual dexterity in humans exposed 6 h/d, 5 d/w for 1 w immediately after expo- sure to 500 ppm for 1 won the same schedule (Reinhardt et al., 1971). REFERENCES Arnitz, W.E. 1985. Discontinued use of trichlorotritluoroethane. Office of Chief of Naval Operations. Document No. Xl-F-85-05. Auton, T.R. and B.H. Woolen. 1991. A physiologically based mathe- matical model for the human inhalation pharmacokinetics of 1, l ,2-tri- chloro-1,2,2-trifluoroethane. Int. Arch. Occup. Environ. Health 63: 133-138. Aviado, D.M. and M.A. Belej. 1974. Toxicity of aerosol propellants in the respiratory and circulatory systems. I. Cardiac arrhythmia in the mouse. Toxicology 2:31-42. Back, K.C. and E.W. Van Stee. 1977. Toxicology of haloalkane propel-

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136 SMACS FOR SELECTED AIRBORNE CONTAMINANTS lants and fire extinguishants. Annu. Rev. Pharmacol. Toxicol. 17: 83-95. Bass, M. 1970. Sudden sniffing death. J. Am. Med. Assoc. 12:2075- 2079. Brogren, C.-H., J.M. Christensen, and K. Rasmussen. 1986. Occupa- tional exposure to chlorinated organic solvents and its effect on the renal excretion of N-acetyl-P-D-glucosaminidase. Arch. Toxicol. Suppl. 9:460-464. Bungo, M. 1989. The cardiopulmonary system. Pp. 197-199 in Space Physiology and Medicine. Nicogossian, A.E., C.L. Huntoon, and S.L. Pool, eds. Lea & Febiger, Philadelphia. Bungo, M.W. and P.C. Johnson. 1983. Cardiovascular examinations and observations of deconditioning during the space shuttle orbital flight test program. Aviat. Space Environ. Med. 1001-1004. Clark, D.G. and D.J. Tinston. 1971. The Influence of Fluorocarbon Propellants on the Arrhythmogenic Activities of Adrenaline and Iso- prenaline. Pp. 212-217 in Proceedings of the 12th Meeting of the European Society for the Study of Drug Toxicity. European Society of Toxicology, Basel, Switzerland. Clark, D.G. and D.J. Tinston. 1982. Acute inhalation toxicity of some halogenated and non-halogenated hydrocarbons. Hum. Toxicol. 1:239- 247. Desoille, H., L. Truffert, A. Bourguignon, P. Delavierre, M. Philbert, and C. Girard-Wallon. 1968. Etude experimentale de la toxicite du trichlorotrifluoroethane (Freon 113). Arch. Mal. Prof. Med. Trav. Secur. Soc. 29:381-388. Duprat, P., L. Delsaut, and D. Gradiski. 1976. Pouvoir irritant des principaux solvants chlores aliphatiques sur la peau et les muqueuses oculaires du lapin. Eur. J. Toxicol. 9: 171-177. Epstein, S.S., E. Arnold, J. Andrea, W. Bass, and Y. Bishop. 1972. Detection of chemical mutagens by the dominant lethal assay in the mouse. Toxicol. Appl. Pharmacol. 23:288-325. Epstein, S.S., S. Joshi, J. Andrea, P. Clapp, H. Falk, and N. Mantel. 1967. Synergistic toxicity and carcinogenicity of "Freons" and piper- onyl butoxide. Nature 214:526-528. Gazenko, O.G., A.I. Grigor'yev, S.A. Bugrov, V.V. Yegorov, V.V. Bogomolov, I.B. Kozlovskaya, and I.K. Tarasov. 1990. Review of the major results of medical research during the flight of the second prime

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