6
Freon 114

This chapter summarizes the relevant epidemiologic and toxicologic studies on Freon 114, or 1,1,2,2-tetrafluoro-1,2,-dichloroethane. Selected chemical and physical properties, toxicokinetic and mechanistic data, and inhalation exposure levels from the National Research Council (NRC) and other agencies are also presented. The committee considered all that information in its evaluation of the Navy’s current and proposed 1-h, 24-h, and 90-day exposure guidance levels for Freon 114. The committee’s recommendations for Freon 114 exposure levels are provided at the conclusion of this chapter with a discussion of the adequacy of the data for defining those levels and research needed to fill the remaining data gaps.

PHYSICAL AND CHEMICAL PROPERTIES

Freon 114 is a noncorrosive, nonflammable, colorless gas. At high concentrations, it has been found to have an ether-like odor (Budavari et al. 1996). Selected chemical and physical properties are listed in Table 6-1.

OCCURRENCE AND USE

Freon 114 has been used historically as a refrigerant and aerosol propellant in industrial settings, consumer products, and medical devices (NRC 1984; WHO 1990). The primary source of Freon 114 in the submarine environment is the air-conditioning system and refrigerant plants (NRC 1984; Crawl 2003). Several measurements of Freon 114 on submarines have been reported. Data collected on nine nuclear-powered ballistic missile submarines indicate an average Freon 114 concentration of 8 ppm (range, 0-146 ppm) and data collected on 10 nuclear-powered attack submarines indicate an average concentration of



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6 Freon 114 This chapter summarizes the relevant epidemiologic and toxicologic stud- ies on Freon 114, or 1,1,2,2-tetrafluoro-1,2,-dichloroethane. Selected chemical and physical properties, toxicokinetic and mechanistic data, and inhalation ex- posure levels from the National Research Council (NRC) and other agencies are also presented. The committee considered all that information in its evaluation of the Navy’s current and proposed 1-h, 24-h, and 90-day exposure guidance levels for Freon 114. The committee’s recommendations for Freon 114 exposure levels are provided at the conclusion of this chapter with a discussion of the adequacy of the data for defining those levels and research needed to fill the remaining data gaps. PHYSICAL AND CHEMICAL PROPERTIES Freon 114 is a noncorrosive, nonflammable, colorless gas. At high con- centrations, it has been found to have an ether-like odor (Budavari et al. 1996). Selected chemical and physical properties are listed in Table 6-1. OCCURRENCE AND USE Freon 114 has been used historically as a refrigerant and aerosol propel- lant in industrial settings, consumer products, and medical devices (NRC 1984; WHO 1990). The primary source of Freon 114 in the submarine environment is the air-conditioning system and refrigerant plants (NRC 1984; Crawl 2003). Several measurements of Freon 114 on submarines have been reported. Data collected on nine nuclear-powered ballistic missile submarines indicate an aver- age Freon 114 concentration of 8 ppm (range, 0-146 ppm) and data collected on 10 nuclear-powered attack submarines indicate an average concentration of 129

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130 Exposure Guidance Levels for Selected Submarine Contaminants TABLE 6-1 Physical and Chemical Properties of Freon 114 Synonyms and trade names FC-114, cryofluorane, fluorocarbon 114, dichlorotetra- fluoroethane, 1,2-dichlorotetrafluoroethane, halocarbon 114, tetrafluorodichloroethane, 1,1,2,2-tetrafluoro-1,2- dichloroethane, 1,2-dichloro-1,1,2,2-tetrafluoroethane CAS registry number 76-14-2 Molecular formula C2Cl2F4 Molecular weight 170.93 Boiling point 3.8°C Melting point –94°C Flash point Nonflammable Explosive limits NA Specific gravity of liquid 1.5312 at 0°C Vapor pressure 1,444 mm Hg at 20°C Solubility Soluble in ether, alcohol, water (0.01%) 1 ppm = 7 mg/m3; 1 mg/m3 = 0.14 ppm Conversion factors Abbreviations: NA, not available or not applicable. Sources: Flash point from OSHA 1999; all other data from Budavari et al. 1989, 1996; NRC 1984. 8 ppm (range, 0-99 ppm) (Hagar 2003). Holdren et al. (1995) reported the re- sults of air sampling at three locations conducted over 6 h during the missions of two submarines. Sampling indicated concentrations of 1.225-1.540 ppm and 0.822-0.914 ppm, depending on the collection method, on one submarine and 1.608-2.072 ppm and 1.256-1.490 ppm, depending on the collection method, on the other submarine. Raymer et al. (1994) report the results of a similar sam- pling exercise (two submarines, three locations, and sampling duration of 6 h). Freon 114 concentrations were reported as 4.2 and 7.0 ppm in the fan rooms, 2.8 and 7.0 ppm in the galleys, and 5.6 ppm in the engine rooms. SUMMARY OF TOXICITY The toxicity of Freon 114 has been studied in a number of mammalian species for acute effects, particularly those involving cardiopulmonary function. Few repeat-exposure studies have been conducted with Freon 114. Most of the studies with Freon 114 were conducted before 1975, and only a few toxicity end points were included. Freon 114, like other chlorofluorocarbons (CFCs), has a relatively low degree of acute toxicity by inhalation (for example, the 2-h inha- lation LC50 in rats is over 600,000 ppm); central nervous system (CNS) and pulmonary-depressant and cardiac-sensitizing effects occur at relatively high exposure concentrations. Estimated EC50 values in dogs for cardiac sensitization

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131 Freon 114 are less than 50,000 ppm when the intravenous (iv) epinephrine dose is 8 µg/kg, 100,000 ppm when it is 5 µg/kg, and over 100,000 ppm in dogs exercised to induce endogenous epinephrine release. Respiratory and circulatory effects, such as bronchospasm and changes in heart rate, have also been observed in animals with acute, high-concentration exposure to Freon 114. The few human data are consistent with the animal data in terms of mild respiratory and cardiac effects at 21,000 ppm. Because the cardiac arrhythmias seen after Freon 114 exposure of animals require high exposure to Freon 114 and epinephrine nearly simultane- ously, CNS-depressant effects are more likely than cardiac effects to occur at lower concentrations. Effects of repeated exposure to Freon 114 are generally similar to those of acute exposure. Freon 114 is rapidly absorbed and eliminated almost entirely by exhalation with little metabolism. It produced no mutations in an abbreviated Ames/Salmonella test. Data for assessing reproductive, im- mune system, and carcinogenic effects of exposure to Freon 114 were not avail- able for review. Effects in Humans Accidental Exposures Reinhardt et al. (1971) reported that from 1967 to 1971 65 deaths were as- sociated with the practice of “sniffing,” or intentionally inhaling, aerosol prod- ucts, including those with fluorocarbon propellants. Freon 114 was widely used in consumer aerosol products at the time, but no deaths were specifically attrib- uted to it. The CFCs commonly used as aerosol propellants, including Freon 114, have been evaluated as potential causal agents in the deaths of young asth- matics using bronchodilator inhalers. However, none of the reports identifies Freon 114 as a cause of death. Experimental Studies Valić et al. (1977) demonstrated in humans that CFCs, including Freon 114, are able to induce bronchospasm, a biphasic change in ventilatory capacity (maximum expiratory flow at 50% [MEF50] and 75% [MEF75] of vital capac- ity), bradycardia, and inversion of the T wave with a single acute inhalation. Valić and co-workers exposed 10 men (20-24 years old) to Freon 114 at 21,000 ppm for 15 or 60 sec or to a 30:70 mixture of Freon 12 and 114 (about 7,000:14,000 ppm for 15 sec or about 8,300:15,680 ppm for 60 sec). After expo- sure for 45 sec, significant biphasic reduction in ventilatory lung capacity (MEF50), bradycardia, and increased variability in heart rate were reported for Freon 114, and the mixture had a more pronounced effect. Exposure to Freon 114 and to the Freon 12 and 114 mixture for 15 sec caused similar reductions in MEF50. Cardiac effects included inversion of the T wave in a few cases and atrioventricular block in one case with a 15-sec exposure to Freon 114 but no

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132 Exposure Guidance Levels for Selected Submarine Contaminants life-threatening cardiac arrhythmia. No data were reported on effects on MEF75 after exposure to Freon 114. No threshold for cardiopulmonary effects was demonstrated in this study. However, Aviado (1994) concluded from the work of Stewart et al. (1978) with Freon 11 that human exposure at 1,000 ppm 8 h/day, 5 days/week for 18 exposures was without evidence of electrocardio- graphic changes, pulmonary-function changes, or subjective effects. Because Freon 11 is considered more cardiotoxic than Freon 114 (Aviado 1994), the no- observed-adverse-effect level (NOAEL) of Freon 114 would be expected to be higher than 1,000 ppm. Occupational and Epidemiologic Studies No occupational or epidemiologic studies of Freon 114 were identified. Deaths related to CFC exposure have been reported in the occupational envi- ronment associated with solvent use, foam-blowing, and refrigeration leaks; however, none of the reports is linked to Freon 114 exposure (see Aviado [1994] for a review of this topic). Effects in Animals The toxicity of Freon 114 has been studied in several animal species, in- cluding rats, mice, guinea pigs, dogs, cats, and monkeys. The primary effects of exposure to Freon 114 via inhalation are cardiopulmonary effects that can be induced in mice, rats, dogs, and rhesus monkeys. The majority of cardiopulmon- ary testing has been conducted in dogs with protocols that involve either iv in- jection of epinephrine or increases in endogenous epinephrine through exercise or induction of fright. Studies in dogs have generally been conducted in con- scious animals; those in other species have used anesthetized animals. Because general anesthesia makes the heart less responsive to epinephrine, it is a con- founding factor that needs to be considered in interpreting the animal data. In guinea pigs, fatty infiltration of the liver has been reported after exposure to Freon 114; however, this effect has not been reported in other species. In gen- eral, the effects observed in acute-exposure animal studies are consistent with the few human data available on Freon 114, and the effects observed in repeat- dose animal studies are consistent with those observed in acute-exposure animal studies. Acute Toxicity Acute-toxicity data on Freon 114 are summarized in Table 6-2. Reviews of Freon 114 have been conducted by Aviado (1994), ACGIH (1986, 2001), WHO (1990), and NRC (1984).

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TABLE 6-2 Summary of Toxicity of Freon 114 in Animals Adverse-Effect Species (no.) Exposure Period End Point NOAEL (ppm) Level (ppm) Reference Dog (12) 30 sec Mild effect on heart rhythm in 1 dog, marked effect — 800,000 Reinhardt et al. 1971 on heart rhythm in 1 dog, convulsions in 5 dogs Dog (7) 1.5-16 min 1 dog had marked cardiac effects while running at — 40,630 Mullin et al. 1972 300 fpm to induce epinephrine release; response was replicated in follow-up exposure; exposure cut short because dogs could not tolerate it Dog (7) 1.5-16 min 1 dog had marked cardiac response after 1.5 min of — 60,600 Mullin et al. 1972 exposure; exposure cut short because dogs could not tolerate it Dog (12) 5 min Cardiac arrhythmia in 1 dog with epinephrine — 25,000 Reinhardt et al. 1971 Dog (12) 5 min — 50,000 Reinhardt et al. 1971 Marked cardiac response in 7 dogs; EC50, <50,000 ppm Dog (4) 5 min Cardiac sensitization in dogs given epinephrine at 25,000, 50,000 100,000 Clark and Tinston 1972 5 μg/kg; EC50, 100,000 ppm Dog (3) 5 min Pulmonary resistance, pulmonary compliance, 25,000 50,000, Belej and Aviado 1975 respiratory minute volume, heart rate, and aortic 100,000, blood pressure measured in anesthetized dogs, 200,000 supplemental oxygen administered Rhesus 5 min Cardiac arrhythmia and other cardiopulmonary — 50,000, Belej et al. 1974; Aviado monkey (3) effects in anesthetized open-chest preparations 100,000, and Smith 1975 200,000 (Continued) 133

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TABLE 6-2 Continued 134 Adverse-Effect Species (n) Exposure Period End Point NOAEL (ppm) Level (ppm) Reference Mouse (3 or 4 6 min No cardiac changes in anesthetized animals, 400,000 — Aviado and Belej 1974 males) supplemental oxygen administered Mouse (3 or 4 6 min Cardiac changes in anesthetized animals given 100,000 200,000, Aviado and Belej 1974 males) epinephrine, second-degree block observed 400,000 Dog (6) 16 min No cardiac arrhythmia while running for 25 min at 25,300 — Mullin et al. 1972 300 fpm to induce epinephrine release Rat (8) <30 min Cardiac and pulmonary function at constantly rising 50,000 100,000 Friedman et al. 1973 concentration of Freon 114 in anesthetized animals Mouse 30 min Five of 10 died at 700,000 ppm, eight of 10 at 500,000 700,000, Paulet and Desbrousses (10/group) 800,000 ppm 800,000 1969 Mouse 30 min No deaths ~700,000 — Paulet 1969, as cited in WHO 1990 Rat 30 min No deaths ~750,000 — Paulet 1969, as cited in WHO 1990 Rabbit 30 min No deaths ~750,000 — Paulet 1969, as cited in WHO 1990 Guinea pig 2h Irregular breathing but “no toxic action” — 8,000-47,000 Nuckolls 1933, as cited in ACGIH 1986 Rat 2h Incoordination — ~300,000 Schloz 1961, as cited in WHO 1990 Rat 2h Deep narcosis — ~600,000 Schloz 1961, as cited in WHO 1990

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Rat, guinea pig 2 h Disturbed equilibrium in rats and guinea pigs — 300,000- Schloz 1962, as cited in 400,000 WHO 1990 Dog (1) 8h No death 200,000 — Yant et al. 1932, as cited in WHO 1990 Dog (1) 16 h Death — 200,000 Yant et al. 1932, as cited in WHO 1990 Guinea pig 24 h Incoordination — ~400,000 Schloz 1961, as cited in WHO 1990 Mouse (3) 24 h No clinical effects but microscopic evidence of — 10,000 Quevauviller et al. 1963 hemorrhage in lungs Dog (5) 8 h/day, 3-4 All five died — 200,000 Yant et al. 1932, as cited days in WHO 1990 Guinea pig (6) 8 h/day, 4 days Fatty degeneration of liver — 200,000 Yant et al. 1932, as cited in WHO 1990 Dog (3) 8 h/day, 21 days Incoordination, tremors, convulsions during initial 3-5 — 141,000 Yant et al. 1932, as cited days of exposure; tolerance developed in WHO 1990 Rat (10) 2.5 h/day, 5 Decreased body-weight gain and blood — 200,000 Paulet and Desbrousses days/week, 2 polymorphonuclear leukocytes, increased blood 1969 weeks lymphocytes, vascular congestion, and exudates in lungs Mouse (10) 2.5 h/day, 5 Decrease of 9% in body weight — 200,000 Paulet and Desbrousses days/week, 2 1969 weeks (Continued) 135

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TABLE 6-2 Continued 136 Adverse-Effect Species (n) Exposure Period End Point NOAEL (ppm) Level (ppm) Reference Rat (20 adult, 2.5 h/day, 5 No significant effect on mortality, body-weight gain, 10,000 — Paulet and Desbrousses 10 immature), days/week, 2 blood-cell counts, pulmonary pathology, or 1969 mouse (20 months electrolytes adult) Cat, rat, guinea 3.5 h/day, 5 No adverse effects 100,000 — Schloz 1962, as cited in pig, dog days/week, WHO 1990 20 exposures over 4 weeks Guinea pig (8) 8 h/day, Fatty degeneration of liver — 141,000 Yant et al. 1932, as cited 21 days in WHO 1990 Dog (3/sex per 6 h/day, 7 No significant effect on mortality, body weight, 5,000 — Leuschner et al. 1983 group) days/week, clinical examinations, EKG, blood pressure, 90 days hematology, clinical chemistry, urinalysis, necropsy, organ weights, or histopathology Rat (20/sex per 6 h/day, 7 No significant effect on mortality, body weight, 10,000 — Leuschner et al. 1983 group) days/week, clinical examinations, hematology, clinical chemistry, 90 days urinalysis, necropsy, organ weights, or histopathology Rat, rabbit 2 h/day, 5 No significant changes in hematology, histopathology, 10,000 — Desoille et al. 1973 days/week, or EEG 8 months (rats), 9 months (rabbit)

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Mouse (30), Mice, rats, No significant effect on body weight, hematology, 164-2,240 mg/kg — Smith and Case 1973 rat (8/sex per puppies: 5 min clinical chemistry, or histopathology per day; mixture group), dog twice a day; containing 25- (1-3/sex per dogs: twice a 50% Freon 114 group) day to discharge of propellant Abbreviations: CNS, central nervous system; EKG, electrocardiography; EEG, electroencephalography; fpm, feet per minute; MEF50, MEF75- maximum expiratory flow at 50%, 75% of vital capacity. 137

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138 Exposure Guidance Levels for Selected Submarine Contaminants Paulet and Desbrousses (1969) reported that mortality in mice exposed to Freon 114 for 30 min was none of 10 at 500,000 ppm, five of 10 at 700,000 ppm, and eight of 10 at 800,000 ppm. Exposure of a dog to Freon 114 for 16 h at about 200,000 ppm was lethal, but exposure for 8 h was not lethal (Yant et al. 1932, as cited in WHO 1990). No deaths were reported in mice, rats, or rabbits exposed to Freon 114 for 30 min at about 700,000, about 720,000, or about 750,000 ppm, respectively (Paulet 1969, as cited in WHO 1990). Nuckolls (1933, as cited in ACGIH 1986) reported irregular breathing but no toxic action in guinea pigs exposed at 8,000- 47,000 ppm for 2 h. Scholz (1961, as cited in WHO 1990) reported incoordina- tion in guinea pigs exposed at about 400,000 ppm for 24 h. Scholz (1961, as cited in WHO 1990) reported incoordination (at about 300,000 ppm) and deep narcosis (at about 600,000 ppm) in rats exposed to Freon 114 for 2 h. Quevau- viller et al. (1963) exposed three mice to Freon 114 at 10,000 ppm for 24 h without observing clinical effects, but hemorrhage was observed in the lungs on microscopic examination. Cardiac sensitization (an increase in the reactivity of the heart to epineph- rine) was demonstrated in one of 12 beagles exposed to Freon 114 at 25,000 ppm for 5 min (Reinhardt et al. 1971). Seven of the 12 dogs experienced a marked cardiac response at 50,000 ppm for 5 min. The marked response in- cluded ventricular fibrillation and cardiac arrest in two dogs. The authors re- ported that at high concentrations of Freon 12, an exposure time of only 30 sec was sufficient to induce cardiac sensitization and that hypoxia made the heart more sensitive to induction of sensitization. In an experiment designed to induce the release of endogenous epinephrine, they exposed 12 beagles to an atmos- phere of Freon 114 at 800,000 ppm and oxygen at 200,000 ppm while surprising the dogs with loud noises. That exposure paradigm resulted in mild effects in one dog, a marked effect in one dog (bigeminal rhythm with areas suggestive of multiple ventricular beats), and convulsions in five dogs (mild seizures charac- terized by spasticity of the extremities). Similar effects in dogs were demon- strated by Mullin et al. (1972) at a Freon 114 concentration of 40,630 ppm but not 25,000 ppm in dogs exercising on a treadmill to induce release of endoge- nous epinephrine. Clark and Tinston (1972) reported an EC50 for cardiac sensiti- zation of 100,000 ppm in beagles that were pretreated with epinephrine at 5 µg/kg and exposed to Freon 114 for 5 min. Exposure at 25,000 and 50,000 ppm did not cause cardiac abnormalities in epinephrine-pretreated dogs. Anesthetized mice exposed to Freon 114 at 100,000-400,000 ppm did not develop cardiac arrhythmias, but pretreatment with epinephrine induced second-degree block in one or two mice exposed at 200,000 or 400,000 ppm, respectively (Aviado and Belej 1974). The effects of Freon 114 on cardiac and pulmonary function were meas- ured in anesthetized dogs that were given Freon 114 vapor at 25,000, 50,000, 100,000, or 200,000 ppm via the endotracheal route for 5 min with 15-min washout periods between exposures (Belej and Aviado 1975). At 25,000 ppm, no effects on measures of pulmonary resistance, pulmonary compliance, respira-

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139 Freon 114 tory minute volume, heart rate, and aortic blood pressure were observed. At 50,000 ppm, there was a significant reduction in pulmonary compliance but not the other measures. At 100,000 and 200,000 ppm, pulmonary resistance in- creased, pulmonary compliance was reduced, and heart rate increased signifi- cantly; a reduction in aortic blood pressure occurred only at 200,000 ppm. Car- diac and pulmonary effects have also been studied after administration of Freon 114 as an aerosol directly into the upper airway or into the trachea of dogs. Dose measurement was by cylinder actuations (five, 10, or 20 actuations); each actua- tion resulted in the release of 120 mL of Freon 114 under pressure. Aerosol ap- plication into the upper airway resulted in an irritation reflex that induced brady- cardia and bronchoconstriction. Administration of 15-20 actuations into the trachea induced tachycardia. Bronchodilation was induced by one to 15 actua- tions, and 20 actuations induced bronchoconstriction and exaggerated epineph- rine-induced tachycardia. Cardiac and pulmonary function was studied in anesthetized rats exposed to Freon 114 at a constantly rising concentration (Friedman et al. 1973). No ef- fect on function was observed at 50,000 ppm, but at 100,000 ppm, heart rate and tidal volume decreased, and pulmonary resistance increased. At 150,000 ppm, respiratory rate decreased, and pulmonary resistance no longer increased. Cardiac and pulmonary function was also studied in anesthetized rhesus monkeys with an open-chest model (Belej et al. 1974; Aviado and Smith 1975). Groups of three monkeys were exposed to Freon 114 at 50,000-200,000 for 5 min. Concentrations of 100,000-200,000 ppm induced tachycardia, hypotension, respiratory depression, and an increase in respiratory stimulation. The majority of the findings were statistically significant only at 200,000 ppm. The authors reported cardiac arrhythmia at 50,000-100,000 ppm, but no data were presented on this end point. After a series of studies in different species, Aviado (1975a,b) classified Freon 114 as a low-pressure propellant of intermediate toxicity on the basis of respiratory and cardiac effects in multiple species (monkeys, dogs, rats, and mice) at exposures of 50,000-200,000 ppm. Repeated Exposure and Subchronic Toxicity No adverse effects were reported in cats, rats, dogs or guinea pigs exposed to Freon 114 at 100,000 ppm 3.5 h/day for 20 exposures (Scholz 1961, as cited in WHO 1990). Groups of 30 rats (20 adult and 10 immature) and 20 mice (adult) were exposed to Freon 114 at 10,000 ppm 2.5 h/day, 5 days/week for 2 months with no deaths or other adverse effects on body-weight gain, blood-cell counts, and pulmonary pathology (Paulet and Desbrousses 1969). Exposure of rats at 200,000 ppm 2.5 h/day, 5 days/week for 2 weeks produced a decrease in body- weight gain, a decrease in blood polymorphonuclear leukocytes, and an increase in blood lymphocytes (Paulet and Desbrousses 1969). Vascular congestion and

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140 Exposure Guidance Levels for Selected Submarine Contaminants exudates were observed microscopically in the pulmonary alveoli and bronchi- oles. Mice exposed with the same experimental protocol lost about 9% of their body weight. Exposure of dogs to Freon 114 at 200,000 ppm 8 h/day was lethal to all five dogs in 3-4 days (Yant et al. 1932, as cited in WHO 1990). At 141,000 ppm, dogs developed incoordination, tremor, and convulsions during the first exposures, but tolerance developed after 3-5 days of the 21-day study (Yant et al. 1932, as cited in WHO 1990). In the guinea pig, slight liver effects (fatty degeneration) were observed at 200,000 ppm (8 h/day for 4 days) and 141,000 (8 h/day for 21 days) (Yant et al. 1932, as cited in WHO 1990). Leuschner et al. (1983) found no adverse effects in dogs (three per sex per group) exposed to Freon 114 at 5,000 ppm 6 h/day, 7 days/week for 90 days. Similarly, groups of 20 rats per sex exposed at 10,000 ppm 6 h/day, 7 days/week for 90 days showed no adverse effects (Leuschner et al. 1983). Exposure to Freon 114 had no toxic effects on mortality, body weight, clinical examinations, hematology, clinical chemistry, urinalysis, necropsy, organ weights, and histo- pathology in both rats and dogs. The dogs were also examined for electrocardio- graphic effects and effects on blood pressure (before and after norepinephrine administration), and no adverse effects were found. Repeated brief inhalation exposure of mice, rats, and dogs (5 min or the time it took to discharge an aerosol container) resulted in doses of a propellant containing 25-50% Freon 114 of 164-2,240 mg/kg per day for 2 weeks to 23 months. Other than ataxia and slight sedation in dogs that lasted only a few min- utes, no effect on body weight and no hematologic, clinical-chemistry, or histo- pathologic effects were observed (Smith and Case 1973). Repeated application of a 40% solution of Freon 114 in sesame oil had no effect on rabbit skin (Schloz 1962, as cited in WHO 1990). Repeated application of a Freon 114 spray resulted in local irritation of rat skin and the mucous mem- branes of rabbit eyes (Quevauviller 1965 and Quevauviller et al. 1964, as cited in ACGIH 2001). No injury to the eye was observed microscopically. Chronic Toxicity Desoille et al. (1973) exposed male rats and rabbits to Freon 114 at 10,000 ppm 2 h/day, 5 days/week for 8 months (rats) or 9 months (rabbits). No signifi- cant changes in clinical end points, hematology, histopathology, or electroe- ncephalography were identified. Reproductive Toxicity in Males No relevant information on male reproductive toxicity after exposure to Freon 114 was located. Although some hydrogenated CFCs have been reported

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141 Freon 114 to disrupt spermatogenesis, no CFCs have been reported to cause similar effects (Aviado 1994). Immunotoxicity No relevant information on immunotoxicity after exposure to Freon 114 was located. No other CFC has been reported to cause immunotoxicity (Aviado 1994). Genotoxicity Freon 114 was negative for reverse mutation in Salmonella typhimurium strains TA 100 and TA1535 in the presence of a rat liver, Aroclor 1254-induced S9 mixture (Longstaff et al. 1984). Carcinogenicity A group of 30 female mice was exposed via inhalation to a propellant mixture that contained 25% Freon 114 for 23 months without evidence of lung tumors (Smith and Case 1973). The dose of Freon 114 that was inhaled was cal- culated to be 970 mg/kg per day based on the respiratory volume of mice (Smith and Case 1973). No other animal cancer bioassay data were identified on Freon 114. Freon 11, a prototypical CFC, did not show carcinogenicity in a National Cancer Institute (NCI) rodent bioassay (Aviado 1994). That result is important because it differentiates CFCs from carbon tetrachloride, which did produce evidence of carcinogenicity in a similar NCI bioassay (Aviado 1994). TOXICOKINETIC AND MECHANISTIC CONSIDERATIONS The most serious effect of Freon 114 after inhalation is cardiac toxicity, which has been demonstrated in four animal species. According to Aviado (1994), three situations increase the sensitivity of the heart to effects of CFCs— injection of epinephrine, coronary ischemia or cardiac necrosis, and bronchitis or pulmonary thrombosis. A common feature of those situations is a direct or indirect increase in cardiac irritability caused by epinephrine. In contrast, gen- eral anesthesia reduces cardiac sensitivity to the effects of CFCs (Aviado 1994). The mechanism of CFC toxicity originates in irritation of the respiratory tract, which by a simple reflex response influences the heart rate before absorption of the CFC (Aviado 1994). That is followed by depression of cardiac function after absorption of the CFC and sensitization of the heart to sympathomimetic amines (Aviado 1994). Of the species studied after exposure to CFCs, the guinea pig is the most resistant to cardiovascular effects. The rat and the mouse are interme- diate in susceptibility, and the dog and the monkey are more sensitive. Data de-

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142 Exposure Guidance Levels for Selected Submarine Contaminants veloped with Freon 114 indicate that the dog may be more sensitive than the monkey to cardiac effects. According to Aviado, there is no reason to consider the monkey the more appropriate species for extrapolation of CFC effects to humans. In addition to the reflex-induced bronchospasm caused by CFCs, CFCs are postulated to reduce pulmonary compliance by reducing pulmonary surfac- tants (Aviado 1994). Freon 114 can be absorbed through the skin and gastrointestinal tract, but inhalation is the most common route of exposure, and exhalation the most im- portant route of elimination. Peak blood concentrations of Freon 114 are reached immediately at the end of a short-term aerosol or vapor exposure (Dollery et al. 1970; Morgan et al. 1972). Using 38Cl-labeled Freon 114, Morgan et al. (1972) found that although Freon 114 appears rapidly in the blood after inhalation, it is poorly absorbed and relatively rapidly exhaled because of its poor lipid solubil- ity. Pulmonary elimination of 38Cl-labeled Freon 114 is rapid after cessation of exposure: more than 50% is eliminated within the first minute after exposure. It is assumed that Freon 114, like Freon 12, diffuses rapidly into the cerebral spi- nal fluid and is excreted in the urine and bile (Paulet et al. 1975). Retention of 38 Cl-labeled Freon 114 in the human body was 12.3% " 4.1% (SD) 30 min after inhalation of a single breath (Morgan et al. 1972). After 30 min, the amount of exhaled Freon 114 is low, and further excretion is slow. Similar results were obtained in dogs exposed to an aerosol of Freon 114 by Shargel and Koss (1972). When dogs were exposed to Freon 114 vapor at 50,000 ppm via a face mask, blood concentrations of Freon 114 peaked at about 15 min; after exposure at 100,000 ppm, a plateau was reached at about 10 min (Clark and Tinston 1972). The threshold for cardiac sensitization induced by a dose of epinephrine at 5 µg/kg was 50,000 ppm (a concentration at which none of four dogs was sensitized) to 100,000 ppm (a concentration at which two of four dogs were sen- sitized) (Clark and Tinston 1972). Cardiac sensitization associated with Freon 114 is a temporary effect that requires maintenance of critical concentrations of Freon 114 and epinephrine to persist in the dog (Clark and Tinston 1972). Re- duction of blood Freon 114 concentrations below a critical concentration elimi- nates sensitization of the heart. Adir et al. (1975) developed a pharmacokinetic model for predicting blood and tissue concentrations of Freon 12 in dogs and humans. On the basis of the model, they concluded that continuous 8-h exposure at 1,000 ppm would result in a venous blood concentration that was well below concentrations reported to sensitize the dog heart to intravenously injected epinephrine (Azar et al. 1973). Because the EC50s for cardiac sensitization of Freon 12 and Freon 114 are simi- lar (80,000 ppm and 100,000 ppm, respectively), their blood concentrations at the EC50s are similar (35 µg/mL and 34 µ/mL, respectively), and their uptake and elimination curves are similar (Clark and Tinston 1972), the safety level predicted for Freon 12 by Adir et al. (1975) may also apply to Freon 114.

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143 Freon 114 INHALATION EXPOSURE LEVELS FROM THE NATIONAL RESEARCH COUNCIL AND OTHER ORGANIZATIONS A number of organizations have established or proposed inhalation expo- sure levels or guidelines for Freon 114. Selected values are summarized in Table 6-3. COMMITTEE RECOMMENDATIONS The committee’s recommendations for EEGL and CEGL values for Freon 114 are summarized in Table 6-4. The current and proposed U.S. Navy values are provided for comparison. EEGL and CEGL values for Freon 114 should prevent significant CNS depression; changes in cardiac rhythm, including cardiac arrhythmia; and pul- monary changes, including bronchospasm and reduction in pulmonary compli- ance. The scientific literature has not identified other potential human health effects of exposure to Freon 114 or other prototypical CFCs. The accumulation of fat in the liver has been reported in guinea pigs exposed to Freon 114; how- ever, this effect has not been observed in other animal species. In a series of experiments with mice, rats, monkeys, and dogs exposed to Freon 114 at high concentrations for brief periods (5 min), Aviado (1973) identified the dog as the most sensitive species for induction of cardiac and pulmonary effects and 50,000 ppm as the lowest effective concentration of Freon 114. In other studies with dogs, 50,000 ppm is a NOAEL for cardiac effects in dogs given epinephrine at 5 µg/kg, 25,000 ppm is a NOAEL for induction of cardiac effects in exercising dogs, and 25,000 ppm is a concentration at which one of 12 dogs receiving epi- nephrine at 8 µg/kg had cardiac effects (Mullin et al. 1972; Reinhardt et al. 1971; Clark and Tinston 1972). Valić et al. (1977) demonstrated bronchospasm and mild cardiac effects in young men exposed to Freon 114 at 21,000 ppm for 15, 45, or 60 sec. Studies demonstrating CNS-depressant effects have been con- ducted only at high exposures in laboratory animal species. On the basis of a review of the cardiac and pulmonary toxicity of a series of CFCs, including Freon 114 and Freon 12, Aviado (1975a,b, 1994) was able to classify the CFCs as of high, intermediate, and low toxicity. Cardiac and pulmo- nary test results from studies on multiple species resulted in classification of Freon 114 and Freon 12 as having intermediate toxicity and significantly less toxic than Freon 11. Freon 114 and Freon 12 are similar in cardiac and pulmo- nary toxicity; hypotension occurs in dogs exposed to Freon 114 but not in dogs exposed to Freon 12. There are some differences in respiratory response be- tween Freon 114 and Freon 12, but they tend to be related to the species tested and do not indicate a clear difference between Freon 114 and Freon 12. Al- though Freon 12 and Freon 114 appear to behave similarly, the 1-h EEGL and

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144 Exposure Guidance Levels for Selected Submarine Contaminants TABLE 6-3 Selected Inhalation Exposure Levels for Freon 114 from the NRC and Other Agenciesa Organization Type of Level Exposure Level (ppm) Reference Occupational ACGIH TLV-TWA 1,000 ACGIH 2001 NIOSH REL-TWA 1,000 NIOSH 2005 OSHA PEL-TWA 1,000 29 CFR 1910.1000 Submarine NRC EEGL NRC 1984 1-h 10,000 24-h 1,000 CEGL 90-day 100 a The comparability of EEGLs and CEGLs with occupational-exposure and public-health standards or guidance levels is discussed in Chapter 1 (“Comparison with Other Regula- tory Standards or Guidance Levels”). Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; CEGL, continuous exposure guidance level; EEGL, emergency exposure guidance level; NIOSH, National Institute for Occupational Safety and Health; NRC, National Research Council; OSHA, Occupational Safety and Health Administration; PEL, permissible expo- sure limit; REL, recommended exposure limit; TLV, Threshold Limit Value; TWA, time- weighted average. TABLE 6-4 Emergency and Continuous Exposure Guidance Levels for Freon 114 U.S. Navy Values (ppm) Exposure Level Committee Recommended Values (ppm) Current Proposed EEGL 1-h 2,000 2,000 2,000 24-h 1,000 1,000 1,000 CEGL 90-day 100 100 125 Abbreviations: CEGL, continuous exposure guidance levels; EEGL, emergency exposure guidance level. 90-day CEGL differ for the two compounds (see sections that follow), because the database on Freon 114 is not as robust as that on Freon 12, and a more con- servative approach was required for Freon 114. Intraspecies uncertainty factors were not applied to the derivation of the EEGL and CEGL values, because there is little evidence of metabolic or pharmacokinetic differences underlying the toxicity of Freon 114. Furthermore, data on epinephrine-sensitized animals were included in the assessment of Freon

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145 Freon 114 114, and this provides an additional level of safety for potentially sensitive individuals. 1-Hour EEGL As indicated above (see Table 6-2), 25,000 ppm is the lowest observed- adverse-effect level (LOAEL) for cardiac effects in the epinephrine-sensitized dog and the NOAEL for cardiac effects in exercising dogs exposed for 16 min to Freon 114. Valić et al. (1977) was able to demonstrate mild cardiac and pulmo- nary effects in young men exposed to Freon 114 at 21,000 ppm for less than 60 sec. Using 21,000 ppm as the LOAEL for exposure of humans to Freon 114, the application of an uncertainty factor of 10 to convert a LOAEL to a NOAEL re- sults in a proposed EEGL of about 2,000 ppm based on cardiac and pulmonary effects. No time adjustment has been made in this proposal, because exposure at 21,000 ppm appears to result in a blood Freon 114 concentration that is ap- proaching, but below, the critical level for induction of significant cardiac ef- fects in humans, whereas exposure at 2,000 ppm should result in a blood con- centration that is well below the critical level for cardiac effects. Exercising dogs, which are considered a sensitive test model, exposed at a similar concen- tration (25,000 ppm) did not show cardiac effects after a 16-min exposure to Freon 114. Exposure at 2,000 ppm would not be expected to result in a blood Freon 114 concentration that would approach the critical level for cardiac ef- fects. A proposed EEGL can also be based on CNS depression; however, the da- tabase on CNS depression is not as robust as that on cardiac and pulmonary end points. In rats, mice and rabbits, exposure at 700,000-750,000 ppm for 30 min produced no deaths (Paulet 1969). Paulet and Desbrousses (1969) reported no effect in mice exposed at 500,000 ppm, but 700,000 ppm was an LC50. Incoordi- nation, an indication of CNS depression, was observed in rats during or shortly after exposure to Freon 114 at about 300,000 for 2 h (Scholz 1961, as cited in WHO 1990). If 300,000 ppm is used as the LOAEL for CNS depression, an un- certainty factor of 3 can be applied to account for interspecies differences in sensitivity to Freon 114, an uncertainty factor of 10 can be applied to estimate a NOAEL from a LOAEL, and a database uncertainty factor of 3 can be applied to account for the quality of the data. Application of those three uncertainty factors results in a proposed 1-h EEGL of about 3,000 ppm. Additional evidence that exposure at 2,000-3,000 ppm is unlikely to result in adverse effects is provided by the absence of effects in dogs examined after repeated exposure at 5,000 ppm 6 h/day, 7 days/week for 90 days, in rats after exposure at 10,000 ppm 2-6 h/day for as long as 8 months, and in rabbits after exposure at 10,000 ppm 2 h/day for 9 months (Paulet and Desbrousses 1969; Desoille et al. 1973; Leuschner et al. 1983).

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146 Exposure Guidance Levels for Selected Submarine Contaminants On the basis of the overall weight-of-evidence approach, an EEGL value of 2,000 ppm is proposed to protect against CNS, cardiac, and pulmonary effects associated with exposure to Freon 114. 24-Hour EEGL Two studies with 24-h exposure durations have been published. Guinea pigs exposed to Freon 114 at about 400,000 ppm for 24 h of were reported to show incoordination (Scholz 1961, as cited in WHO 1990). Mice exposed to Freon 114 at 10,000 ppm for 24 h showed no clinical signs of toxicity, but hem- orrhage was visible in the lungs on histopathologic examination (Quevauviller et al. 1963, as cited in ACGIH 1986). Studies by Paulet and Desbrousses (1969), Desoille et al. (1973), and Leuschner et al. (1983) did not find similar evidence of pulmonary hemorrhage in multiple species of experimental animals even after multiple exposures to Freon 114. Pulmonary hemorrhage has not been identified as an effect associated with exposure to any of the CFCs (Aviado 1994). Pulmo- nary hemorrhage was not considered a significant effect of exposure of humans to Freon 114, because of the lack of reproducible data demonstrating pulmonary hemorrhage after exposure and because it commonly occurs during euthanasia of experimental animals. Using 10,000 ppm as a NOAEL, the committee applied an uncertainty factor of 3 to account for interspecies differences in sensitivity and an uncertainty factor of 3 to account for inadequacies in the database. No time adjustment was used to derive the EEGL, because the length of the expo- sure period in the animal studies was 24 h. Application of the two uncertainty factors results in a proposed 24-h EEGL of 1,000 ppm. 90-Day CEGL A number of repeat-exposure studies of Freon 114 have been conducted at high concentrations for short periods, typically 2-3 h, each day. A small number of longer-duration studies have been conducted with Freon 114. In studies of dogs and guinea pigs exposed to Freon 114 at 141,000 ppm 8 h/day for 21 days, acute CNS signs were initially seen in dogs, but tolerance developed, and fatty livers were observed in guinea pigs (Yant et al. 1932, as cited in WHO 1990). Leuschner et al. (1983) reported that dogs exposed at 5,000 ppm and rats ex- posed at 10,000 ppm showed no adverse effects after exposures that lasted 6 h/day, 7 days/week for 90 days. Because dogs are generally considered more sensitive to the effects of Freon 114 than rodents, the 5,000-ppm dog exposure reported by Leuschner et al. (1983) was used as a NOAEL for Freon 114. In contrast with the database on Freon 12, there are no 90-day continuous-exposure studies or human repeated-exposure studies on which to base the CEGL value. Therefore, unlike the situation with Freon 12, a time-adjustment factor of 4 is applied to the NOAEL from the dog study, yielding a value of 1,250 ppm. In the absence of more robust data from animal and human exposure studies, that ap-

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147 Freon 114 proach will result in a more conservative CEGL value. Application of two un- certainty factors of 3 to account for interspecies variability and the quality of the database results in a proposed CEGL value of 125 ppm. DATA ADEQUACY AND RESEARCH NEEDS Most of the studies in the database on Freon 114 were conducted before 1975 and the publication of standardized protocols and good-laboratory-practice guidelines for the assessment of potentially toxic substances. Therefore, they evaluated few toxicity end points, and effects on many organ systems and func- tions were not assessed. The database on Freon 114 includes few repeat-dose animal studies and no comprehensive long-term or continuous-exposure animal studies. In contrast with the database on some other CFCs, few data are avail- able on human exposure to Freon 114. It is recommended that inhalation studies designed to specifically address a broad array of organ systems under the con- tinuous-exposure conditions typical in the submarine environment be conducted. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1986. Dichloro- tetrafluoroethane. Pp. 191-193 in Documentation of the Threshold Limit Values and Biological Exposure Indices, 5th Ed. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. ACGIH (American Conference of Governmental Industrial Hygienists). 2001. Dichloro- tetrafluoroethane in Documentation of the Threshold Limit Values and Biological Exposure Indices, 7th Ed. American Conference of Governmental Industrial Hy- gienists, Cincinnati, OH. Adir, J., D.A. Blake, and G.M. Mergner. 1975. Pharmacokinetics of fluorocarbon 11 and 12 in dogs and humans. J. Clin. Pharmacol. 15(11-12):760-770. Aviado, D.M. 1973. Toxicity of propellants. Pp. 291-345 in Proceedings of the 4th An- nual Conference on Environmental Toxicology, 16-18 October 1973. AMRL-TR- 73-125. Aerospace Medical Research Laboratory, Air Force Systems Command, Wright-Patterson Air Force Base, OH. Aviado, D.M. 1974. Toxicity of propellants. Prog. Drug Res. 18:365-397. Aviado, D.M. 1975a. Toxicity of aerosol propellants in the respiratory and circulatory systems. X. Proposed classification. Toxicology 3(3):321-332. Aviado D.M. 1975b. Toxicity of aerosols. J. Clin. Pharmacol. 15(1 Pt. 2):86-104. Aviado, D.M. 1994. Fluorine-containing organic compounds. Pp. 1188-1220 in Patty’s Industrial Hygiene and Toxicology, 4th Ed., Vol. II, Part B, G.D. Clayton and F.E. Clayton, eds. New York: John Wiley & Sons. Aviado, D.M., and M.A. Belej. 1974. Toxicity of aerosol propellants on the respiratory and circulatory system. I. Cardiac arrhythmia in the mouse. Toxicology 2(1):31- 42. Aviado, D.M., and J. Drimal. 1975. Five fluorocarbons for administration of aerosol bronchodilators. J. Clin. Pharmacol. 15(1 Pt. 2):116-128.

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148 Exposure Guidance Levels for Selected Submarine Contaminants Aviado, D.M., and D.G. Smith. 1975. Toxicity of aerosol propellants on the respiratory and circulatory systems. VIII. Respiration and circulation in primates. Toxicology 3(2):241-252. Azar, A., H.J. Trochimowicz, J.B. Terrill, and L.S. Mullin. 1973. Blood levels of fluoro- carbon related to cardiac sensitization. Am. Med. Hyg. Assoc. J. 34(3):102-109. Belej, M.A., and D.M. Aviado. 1975. Cardiopulmonary toxicity for propellants for aero- sols. J. Clin. Pharmacol. 15(1 Pt.2):105-115. Belej, M.A., D.G. Smith, and D.M. Aviado. 1974. Toxicology of aerosol propellants in the respiratory and circulatory systems. IV. Cardiotoxicity in the monkey. Toxi- cology 2(4):381-395. Budavari, S., M.J. O’Neil, A. Smith, and P.E. Heckelman, eds. 1989. Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 11th Ed. Rahway, NJ: Merck. Budavari, S., M.J. O’Neil, A. Smith, and P.E. Heckelman, eds. 1996. Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 12th Ed. Rahway, NJ: Merck. Clark, D.G., and D.J. Tinston. 1972. The influence of fluorocarbon propellants on the arrhythmogenic activities of adrenaline and isoprenaline. Pp. 212-217 in Toxico- logical Problems of Drug Combinations: Proceedings of the 13th Meeting of the European Society for the Study of Drug Toxicity, June 1971, Berlin, S.B. Baker, and G.A. Neuhaus, eds. Amsterdam: Excerpta Medica. Crawl, J.R. 2003. Review/Updating of Limits for Submarine Air Contaminants. Presenta- tion at the First Meeting on Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants, January 23, 2003, Washington, DC. Desoille, H., L. Truffert, C. Gierard-Wallon, J. Ripault, and M. Philbert. 1973. Experi- mental research on the long-term chronic toxicity of dichlorotetrafluoroethane. Arch. Mal. Prof. Med. Trav. Secur. Soc. 34:117-125 (as cited in ACGIH 1986). Dollery, C.T., D.S. Davies, G.H. Draffan, F.M. Williams, and M.E. Conolly. 1970. Blood concentration in man of fluorinated hydrocarbons after inhalation of pressured aerosols. Lancet 2(7684):1164-1166. Friedman, S.A., M. Cammarato, and D.M. Aviado. 1973. Toxicology of aerosol propel- lants on the respiratory and circulatory system. II. Respiratory and bronchopul- monary effects in the rat. Toxicology 1(4):345-355. Hagar, R. 2003. Submarine Atmosphere Control and Monitoring Brief for the COT Committee. Presentation at the First Meeting on Emergency and Continuous Ex- posure Guidance Levels for Selected Submarine Contaminants, January 23, 2003, Washington, DC. Holdren, M.W., J.C. Chuang, S.M. Gordon, P.J. Callahan, D.L. Smith, G.W. Keigley, and R.N. Smith. 1995. Final Report on Qualitative Analysis of Air Samples from Submarines. Prepared for Geo-Centers, Inc., Newton Upper Falls, MA, by Bat- telle, Columbus, OH. June 1995. Leuschner, F., B.W. Neumann, and F. Huebscher. 1983. Report on subacute toxicological studies with several fluorocarbons in rats and dogs by inhalation. Arzneimittelfor- schung 33(10):1475-1476. Longstaff, E., M. Robinson, C. Bradbrook, J.A. Styles, and I.F. Purchase. 1984. Genotox- icity and carcinogenicity of fluorocarbons: Assessment by short-term in vitro tests and chronic exposure in rats. Toxicol. Appl. Pharmacol. 72(1):15-31. Morgan, A., A. Black, M. Walsh, and D.R. Belcher. 1972. The absorption and retention of inhaled fluorinated hydrocarbon vapors. Int. J. Appl. Radiat. Isot. 23:285-291. Mullin, L.S., A. Azar, C.F. Reinhardt, P.E. Smith, and E.F. Fabryka. 1972. Halogenated hydrocarbon-induced cardiac arrhythmias associated with release of endogenous epinephrine. Am. Ind. Hyg. Assoc. J. 33(6):389-396.

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149 Freon 114 NIOSH (National Institute for Occupational Safety and Health). 2005. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 2005-149. National Institute for Occupational Safety and Health, Centers for Disease Control and Pre- vention, U.S. Department of Health and Human Services, Cincinnati, OH [online]. Available: http://www.cdc.gov/niosh/npg/ [accessed June 8, 2007]. NRC (National Research Council). 1984. Fluorocarbon 114. Pp. 51-55 in Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Vol. 2. Wash- ington, DC: National Academy Press. Nuckolls, A.H. 1933. The Comparative Life, Fire and Explosion Hazards of Common Refrigerants. Miscellaneous Hazard No. 2375. Underwriter’s Laboratories, Chi- cago., IL (as cited in ACGIH 1986). OSHA (Occupational Safety and Health Administration). 1999. Occupational Safety and Health Guideline for Dichlorotetrafluoroethane (Refrigerant 114). U.S. Depart- ment of Labor, Occupational Safety and Health Administration [online.] Avail- able: http://www.osha.gov/SLTC/healthguidelines/dichlorotetrafluoroethane/ recognition.html [accessed July 2, 2007]. Paulet, G. 1969. De l’action des hydrocarbures chlorofluorés sur l’organisme. Labo- Pharma. Probl. Tech. 180:74-78 (as cited in WHO 1990). Paulet, G., and S. Desbrousses. 1969. Dichlorotetrafluoroethane. Average term acute and chronic toxicity [in French]. Arch. Mal. Prof. 30(9):477-492. Paulet, G., J. Lanoe, A. Thos, P. Toulouse, and J. Dassonville. 1975. Fate of fluorocar- bons in the dog and rabbit after inhalation. Toxicol. Appl. Pharmacol. 34(2):204- 213. Quevauviller, A. 1965. Hygiene and safety of propellants for medicamentous aerosols [in French]. Prod. Probl. Pharm. 20:14-29. Quevauviller, A., M. Chaigneau, and M. Schrenzel. 1963. Experimental study in mice of the tolerance of the lung to chlorofluorinated hydrocarbons [in French]. Ann. Pharm. Fr. 21(11):727-734. Quevauviller, A., M. Schrenzel, and V.N. Huyen. 1964. Local tolerance (skin, mucous membranes, wounds, and burns) in animals to chlorofluorohydrocarbons [in French]. Therapie 19:247-263. Raymer, J.H., E.D. Pellizzari, R.D. Voyksner, G.R. Velez, and N. Castillo. 1994. Qualita- tive Analysis of Air Samples from Submarines. Project RTI/5937/00-01F. Pre- pared for Geo-Centers, Inc., Newton Upper Falls, MA, by Research Triangle Insti- tute, Research Park, NC. December 22, 1994. Reinhardt, C.F., A. Azar, M.F. Maxfield, P.E. Smith, and L.S. Mullin. 1971. Cardiac arrythmias and aerosol “sniffing”. Arch. Environ. Health 22(2):265-279. Scholz, J. 1961. Progress in Biological Aerosol Research [in German]. Stuttgart: F.K. Schattaver Verlag (as cited in WHO 1990). Scholz, J. 1962. New toxicological investigation on certain types of Freon used as propel- lants [in German]. Fortschr. Biol. Aerosol-Forsch. 4:420-429 (as cited in WHO 1990). Shargel, L., and R. Koss. 1972. Determination of fluorinated hydrocarbon propellants in the blood of dogs after aerosol administration. J. Pharm. Sci. 61(9):1445-1449. Smith, J.K. and M.T. Case. 1973. Subacute and chronic toxicity studies of fluorocarbon propellants in mice, rats, and dogs. Toxicol. Appl. Pharmacol. 26(3):438-443. Stewart, R.D., P.E. Newton, E.D. Baretta, A.A. Herrmann, H.V. Forster, and R.J. Soto. 1978. Physiological response to aerosol propellants. Environ. Health Perspect. 26:275-285.

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150 Exposure Guidance Levels for Selected Submarine Contaminants Valić, F., Z. Skurić, Z., Bantić, M. Rudar, and Hećej. 1977. Effects of fluorocarbon pro- pellants on respiratory flow and ECG. Br. J. Ind. Med. 34(2):130-136. WHO (World Health Organization). 1990. Fully Halogenated Chlorofluorocarbons. Envi- ronmental Health Criteria 113. Geneva: World Health Organization [online]. Available: http://www.inchem.org/documents/ehc/ehc/ehc113.htm [accessed June 18, 2007]. Yant, W.P., H.H. Schrenk, and F.A. Patty. 1932. The Toxicity of Dichlorotetrafluoro- ethane. U.S. Bureau of Mines Report No. 3185. U.S. Bureau of Mines, Washing- ton, DC (as cited in WHO 1990).