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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 5 Freon 12 This chapter summarizes the relevant epidemiologic and toxicologic studies on Freon 12, or dichlorodifluoromethane. 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 12. The committee’s recommendations for Freon 12 exposure levels are provided at the end 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 12 is a nonflammable, colorless gas at room temperature. Like Freon 114, it has a faint ether-like odor at high concentrations (Budavari et al. 1996). Selected chemical and physical properties are listed in Table 5-1. OCCURRENCE AND USE In industrial settings, Freon 12 has been used as an aerosol propellant, a foam-blowing agent, and a refrigerant (Garcia 2000; WHO 1990). The primary source of Freon 12 in the submarine environment is through the air-conditioning and refrigerant plants (Garcia 2000; Crawl 2003). Several measurements of Freon 12 on submarines have been reported. Data collected on nine nuclear-powered ballistic missile submarines indicate an average Freon 12 concentration of 11 ppm (range, 0-61 ppm) and data collected on 10 nuclear-powered attack submarines indicate an average Freon 12 concentration of 13 ppm (range, 0-1,033 ppm) (Hagar 2003). Holdren et al. (1995) reported the results of air sam-
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 TABLE 5-1 Physical and Chemical Properties of Freon 12 Synonyms and trade names FC 12, CFC-12, difluorodichloromethane, fluorocarbon-12, R 12 CAS registry number 75-71-8 Molecular formula CCl2F2 Molecular weight 120.92 Boiling point −29.8°C at 760 mm Hg Melting point −158°C Flash point NA Explosive limits NA Specific gravity 1.1834 g/mL (57°C) Vapor pressure 5.7 atm (20°C) Solubility Insoluble in water (0.028 g/100 g at 25°C); soluble in alcohol, ether Conversion factors 1 ppm = 4.95 mg/m3; 1 mg/m3 = 0.202 ppm Abbreviations: NA, not available or not applicable. Sources: Flash point and explosive limits from HSDB 2005; all other data from ACGIH 2001. pling at three locations conducted over 6 h during the missions of two submarines. Sampling indicated concentrations of 2.072-5.476 ppm and of 2.740-3.035 ppm, depending on the collection method, on one submarine, and concentrations of 0.452-3.015 ppm and of 2.092-2.938 ppm, depending on the collection method, on the other submarine. Raymer et al. (1994) reported the results of a similar sampling exercise (two submarines, three locations, and sampling duration of 6 h). Freon 12 concentrations were reported at 4.0 and 1.4 ppm in the fan rooms, 2.0 ppm in the galleys, and 1.8 and 4.0 ppm in the engine rooms. SUMMARY OF TOXICITY The toxicity of Freon 12 has been studied in a number of species exposed acutely and repeatedly. Most of those studies, however, were conducted in the 1970s and earlier and lack complete documentation. Some studies, although frequently cited in review articles, are unpublished or were published in foreign journals and were available only in published reviews. The information evaluated indicates that Freon 12 has relatively low acute toxicity by inhalation (for example, LC50s over 500,000 ppm in animals) with weak narcotic and moderate cardiac-sensitizing effects. The EC50s (the concentrations at which a specified effect is observed in 50% of a test population) for cardiac sensitization, the most serious toxic effect, have been reported to be at least 50,000 ppm in dogs and other animals given intravenous epinephrine and over 100,000 ppm in animals
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 with endogenous epinephrine. Respiratory and circulatory system effects, such as bronchoconstriction and changes in heart rate, have also been observed in animals acutely exposed at those concentrations. In general, the few data in humans are consistent with data in animals in the types of effects and effect levels. Because administered doses of epinephrine that caused cardiac arrhythmia with Freon 12 exposure were considerably higher than would occur endogenously, under normal conditions, neurologic or other effects—such as pulmonary effects—are more likely than cardiac effects at lower Freon 12 concentrations. Freon 12 concentrations associated with no or minimal effects in animals and a small number of healthy human subjects are about 1,000 ppm. Chlorofluorocarbon mixtures appear to have greater toxicity than individual compounds alone at the same concentration as the mixture, although reports are based on higher concentrations (for example, over 10,000 ppm), and no information is available on lower concentrations. Effects of repeated or longer-term exposures are generally similar to those of acute exposures. Thus, Haber’s law (concentration [C] × exposure time [t] = response [k]) for extrapolating toxicity between short-term and long-term exposures does not appear to apply for Freon 12. That observation is consistent with the pharmacokinetics of Freon 12, which is rapidly absorbed and eliminated almost entirely by inhalation with little metabolism. Equilibrium blood concentrations and appearance in cerebral spinal fluid occur within minutes of exposure, and elimination is complete within 20-50 min after exposure ceases. Freon 12 has not been reported to be genotoxic, and long-term studies in animals exposed orally or via inhalation and available epidemiologic data do not show evidence of carcinogenicity. No evidence of male reproductive toxicity was found. No studies were available to evaluate immunotoxicity via inhalation. Effects in Humans Accidental Exposures No published reports of deaths or other effects of humans resulting from accidental exposures to airborne Freon 12 were located. Freon 12 and other chlorofluorocarbons have been involved in cases of intentional inhalation that resulted in death that was most likely related to effects on the heart (for example, cardiac arrhythmia, possibly aggravated by increased catecholamine from stress or moderate hypercapnia) (NRC 1984; WHO 1990). Chlorofluorocarbons, including Freon 12, have been evaluated in connection with deaths of people who had asthma and who used inhalers containing chlorofluorocarbons. Chlorofluorocarbon toxicity in those cases has been discounted because of the small amount of chlorofluorocarbon exposure compared with known toxic levels from experimental studies and cases of deliberate abuse (WHO 1990), although Aviado (1994) believes that chlorofluorocarbons may have contributed to the deaths of those who had asthma.
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 Experimental Studies A few studies have been conducted in small numbers of healthy human volunteers. Most of them involved short-term exposure, such as 2.5 h or less (see Table 5-2). Exposures generally at tens of thousands of parts per million and above are associated with electroencephalographic (EEG) changes and decrements in neurobehavioral performance (Kehoe 1943, as cited by NRC 1984; Azar et al. 1972). Reduced ventilatory capacity and decreased heart rate were reported at a concentration as low as 10,000 ppm (Valić et al. 1982), but not by Azar et al. (1972), and cardiac arrhythmia and amnesia were noted in a subject at 100,000 ppm (Kehoe 1943, as cited in NRC 1984). No irritation or effects on the heart, central nervous system (CNS), or a variety of clinical measures were reported at 1,000 ppm (Azar et al. 1972; Emmen et al. 2000; Stewart et al. 1978). The longest exposure period examined in those studies was 8 h/day, 5 days/week for 2-4 weeks. The details of this study are discussed below. Some of the highest exposures in human studies were reported in an unpublished study involving two subjects (Kehoe 1943, as cited in NRC 1984, WHO 1990, Garcia 2000). One subject tolerated Freon 12 at up to 60,000 ppm for 80 min but showed cardiac arrhythmia followed by amnesia within 10 min when exposed at 110,000 ppm. The other, exposed at 40,000 ppm for 14 min and at 20,000 ppm for 66 min, reported a tingling sensation and humming in the ears and showed EEG changes, slurred speech, and decreased psychologic test scores but no cardiac effects. Valić et al. (1977) exposed 10 subjects to Freon 12 and several other chlorofluorocarbons, including mixtures of the compounds. Ventilatory capacity was measured after 15-sec and 45-sec exposures. Electrocardiographic (EKG) changes were measured at various intervals after the start of a 15-sec exposure period and continuously during a 60-sec exposure period. Significant reduction (although “not clinically alarming”) in ventilatory lung capacity (maximum expiratory flow at 50% [MEF50] or 75% [MEF75] of vital capacity), bradycardia, and increased variability in heart rate were reported for the individual compounds, and mixtures had stronger respiratory and cardiac effects. Exposure to Freon 12 at 27,000 ppm for 45 sec was reported to cause reductions in MEF50 and MEF75 of 3.4% and 5.6%, respectively. Smaller reductions were reported after a 15-sec exposure. In one subject, exposure to a 90%:10% mixture of Freon 12:Freon 11 (8,3000:1,800 mg/m3 for 15 sec and 8,900:1,600 mg/m3 for 60 sec) but not to the individual chlorofluorocarbons or other mixtures was associated with tachycardia and inversion of the T wave. Valić et al. (1982) exposed 11 subjects for 35 or 130 min to Freon 12 and reported acute reduction in ventilatory lung capacity at 10,000 ppm (significant decrease in MEF50 and MEF25 for a 35-min but not 130-min exposure) and 17,500 ppm (significant decrease in MEF50, MEF25, forced expiratory volume at 1 sec [FEV1], and forced vital capacity [FVC] for both exposure periods) but not at 90 ppm. Significant concentration-dependent decreases in heart rate at 10,000 ppm and 17,700 ppm were also reported.
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 TABLE 5-2 Summary of Human Toxicity of Freon 12 Exposure Period No. Subjects End Point NOAEL (ppm) Adverse-Effect Level (ppm) Reference 15 sec, 45 sec (pulmonary tests) 15 sec, 60 sec (EKG tests) 10 None of the subjects had a history of cardiovascular or pulmonary disease; pulmonary effects—3.4% decrease in MEF50, 5.6% decrease in MEF75; cardiac effects—reduced heart rate and respiratory sinus arrhythmia for all compounds tested; tachycardia and negative T wave in one subject exposed to 10%:90% mixture of Freon 11:Freon 12 — 27,000 Valić et al. 1977 10 min 1 Amnesia and cardiac arrhythmia — 110,000 Kehoe 1943, as cited in Garcia 2000 and NRC 1984 14 min, then 66 min 2 EEG changes, slurred speech, and decreased psychologic test scores in one subject; other subject tolerated 60,000 ppm for 80 min without such effects 40,000 then 20,000 — Kehoe 1943, as cited in NRC 1984 35 min, 130 min 11 Reduction in MEF50 and MEF25 (at 10,000 ppm, 35-min exposure but not 130-min exposure); reduction in FEV1 and FVC at 17,500 ppm only; decrease in heart rate at both concentrations 90 10,000; 17,500 Valić et al. 1982, as cited in WHO 1990 1 h; two exposures, one per week 4 males, 4 females, 20-24 years old No clinically significant changes in laboratory measures (of blood and urine), blood pressure, pulse, EKG or lung function 1,000 or 4,000 — Emmen et al. 2000 2.5 h; once a week, for 2 weeks 2 Healthy men 28 and 34 years old; no effects on clinical observations, laboratory tests, subjective impressions, EKG, equilibrium; 7% reduction in psychomotor scores 1,000 10,000 Azar et al. 1972 8 h/day, 5 days/week for 2-4 weeks 8 No effect on cognitive or motor function tests, clinical measures of blood and urine, spirometry, EKG, EEG, or irritation symptoms 1,000 — Stewart et al. 1978 Abbreviations: EKG, electrocardiography; EEG, electroencephalography; FVC, forced vital capacity; MEF25, maximum expiratory flow at 25% of vital capacity; MEF50, maximum expiratory flow at 50% of vital capacity; NOAEL, no-observed-adverse-effect level.
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 Azar et al. (1972) reported a small reduction (7%) in performance on psychomotor tests (clerical tasks, sorting, manual dexterity, and mental arithmetic) in two healthy men after 150 min at 10,000 ppm but no effects at 1,000 ppm. Subjects were tested in the chamber for 2.5 h/day, 5 days/week for 2 weeks separated by a week of no chamber exposures but 2 days of practice tests. During the weeks with testing in the chamber, control-air exposure was used on Mondays, Wednesdays, and Fridays. Exposure at 1,000 ppm and 10,000 ppm occurred on Tuesday and Thursday, respectively, in the first week, and the opposite order was used on these days in the second week of chamber testing. Scores at each concentration for each week were compared with the average of scores from the 3 days of control-air exposure. Other observations included clinical observations, blood tests, subjective impressions, and continuous EKG monitoring. The authors concluded that single exposures of 2.5 h or less at 10,000 ppm could be tolerated without permanently affecting health. In a more recent experimental study, Emmen et al. (2000) exposed four healthy men and four healthy women (20-24 years old) to Freon 12 at 1,000 ppm and 4,000 ppm for 1 h. Subjects were exposed twice in different weeks. No clinically significant changes from reactions in clean air were measured in blood and urine (hematology and clinical chemistry) 24 h after exposure; in blood pressure, pulse, and EKG before, during, or after exposure; or in lung function (peak expiratory flow) 45 min before and 75 min after exposure. Stewart et al. (1978) exposed healthy volunteers for the longest period. Up to four healthy men and four healthy women were exposed to Freon 12 at 250, 500, and 1,000 ppm for 1 min to 8 h to assess absorption, excretion, and physiologic effects. When those exposures caused no health effects in any subjects, the subjects were exposed at 1,000 ppm 8 h/day, 5 days/week for 2-4 weeks. Physical examinations, subjective symptom surveys, blood and urinary analysis for clinical measures, spirometry, EKG, EEG, adrenal gland function, motor or cognitive tests, or health monitoring over a year after exposure showed no treatment-related effects. In contrast, eight men exposed repeatedly to Freon 11 (considered to be more toxic than Freon 12) at 1,000 ppm showed minor decrements in some cognitive tests (Stewart et al. 1978). Occupational and Epidemiologic Studies Exposure to Freon 12 has been widespread because of its use as a refrigerant and as an aerosol propellant in consumer products and medicinal inhalers (Marier et al. 1973; Ritchie et al. 2001). Only a few occupational or epidemiologic studies that involved Freon 12 were located. Those studies also involve exposure to other chlorofluorocarbons. Edling and colleagues (Edling and Olson 1988 in Swedish, as cited in WHO 1990; Edling et al. 1990) examined 89 refrigeration workers exposed mainly to Freon 12 (56% of cases), although several other chlorofluorocarbons were involved. Chlorofluorocarbon concentrations measured by personal monitors exceeded 750 ppm at least once (as 1-min mean
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 values) for 60 of the 89 workers. The highest concentration recorded was 14,000 ppm, and the highest time-weighted average concentration for 8 h was 280 ppm. No significant differences in EKG measurements between nonexposed and exposed periods were found, nor was a concentration-related trend found when subjects were grouped by exposure, although effects in subjects in the medium-exposure group were borderline significant (Wilcoxon’s test, p = 0.05, one-tailed). No differences were found in simple reaction-time measurements before and after exposure. Mortality in 539 refrigeration construction and repair workers (employed more than 6 months) was not increased (18 deaths vs 26 expected) (Szmidt et al. 1981 in Swedish, as cited in WHO 1990 and Rusch 2000). Freon 12 was among several chlorofluorocarbons used by the workers. No significant increases in total tumor deaths, lung cancer deaths, or cardiovascular deaths were reported. Restricting the analysis to those employed more than 3 or 10 years did not change the findings. Exposure of six refrigeration workers to Freon 12 and hydrochlorofluorocarbon (HCFC) 22 at concentrations that occasionally reached 1,300 to 10,000 ppm was not associated with cardiac problems compared with plumbers who had no such exposure (Antti-Poika et al. 1990, as cited in Rusch 2000). Effects in Animals Toxicity of Freon 12 has been examined in several animal species, including rats, mice, guinea pigs, dogs, cats, and monkeys. Dogs in particular have been studied for the cardiac-sensitizing effects of Freon 12 and other chlorofluorocarbons. Studies in dogs have generally been conducted in conscious animals, whereas those in other species have used anesthetized animals. General anesthesia makes the heart less responsive to epinephrine, and this confounding factor needs to be taken into account in interpreting the animal data. Results of studies of Freon 12 in animals are generally consistent with those of experimental studies in humans (see Table 5-3). In general, at equivalent air concentrations of Freon 12, effects noted after brief exposure (for example, 5 min) appear to be similar to those reported after longer exposure (for example, an hour) or repeated exposure. Acute Toxicity Cardiac sensitivity in exercising dogs appears to occur at Freon 12 concentrations of about 100,000 ppm (Mullin et al. 1972). At those concentrations, CNS-depressant effects also occur (see Table 5-3). Dogs exposed to Freon 12 and intravenous epinephrine show signs of cardiac arrhythmia beginning around 50,000 ppm (Reinhardt et al. 1971), and the concentration of Freon 12 associated with arrhythmia increases with decreasing epinephrine dose (Rusch 2000).
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 TABLE 5-3 Summary of Animal Toxicity of Freon 12 Species (no.) Exposure Period End Point NOAEL (ppm) Adverse-Effect Level (ppm) Reference Dog (12) 30 sec No cardiac arrhythmia with fright 80,000 — Reinhardt et al. 1971 Rat (5) 2 min Anesthetized; reduced pulmonary compliance and tidal volume — 50,000 Watanabe and Aviado 1975 Rat (5, 5, 4) 5 min Unanesthetized; no arrhythmias; acceleration of heart rate (10% at 400,000), although not statistically significant — 100,000, 200,000, 400,000 and 20% O2 Watanabe and Aviado 1975 Mouse (3) 4 min Anesthetized; 8% increase in pulmonary resistance, 6% decrease in pulmonary compliance (tests of significance not reported) — 20,000 Brody et al. 1974 Mouse (4) 4 min Anesthetized before exposure; no cardiac arrhythmia with or without epinephrine; increase in height of QRS complex (13.9%) and decrease in heart rate (9.3%); slowing of heart rate reduced when epinephrine was also administered — 400,000 Brody et al. 1974 Dog (4) 5 min EC50 for cardiac arrhythmia with epinephrine. 20,000, 40,000 80,000 Clark and Tinston 1972 Dog (12) 5 min Cardiac arrhythmia in 5 dogs with epinephrine — 50,000 Reinhardt et al. 1971 Monkey (3) 5 min Anesthetized before exposure; 9% decrease in aortic blood pressure; changes in other measures not significant — 50,000 Aviado and Smith 1975
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 Monkey (4) 15% increase in pulmonary resistance and 10% increase in aortic heart rate; changes in pulmonary compliance (−11%), respiration minute volume (−1%), and aortic blood pressure (−15%) not significant. — 100,000 Aviado and Smith 1975 Monkey (3) 5 min Anesthetized before exposure; no change in heart rate 50,000, 100,000 — Belej et al. 1974 Nonsignificant decrease (10%) in myocardial force 50,000 — Significant decrease (20%) in myocardial force — 100,000 Dog (3) 5 min Anesthetized before exposure; increased pulmonary resistance and heart rate at both concentrations; reduced minute volume at 200,000 ppm; no significant effect on aortic blood pressure — 100,000, 200,000 Belej and Aviado 1975 Mouse (8 at 200,000 ppm, 6 at 400,000 ppm) 6 min No arrhythmia with or without epinephrine in anesthetized mice; supplemental oxygen administered 200,000, 400,000 — Aviado and Belej 1974 Rabbit, dog 10 min No cardiac arrhythmia; administered to anesthetized animals with tracheal cannula 200,000, 500,000 and 20% O2 — Paulet et al. 1975a Rat (4) 15 min once a week, exposed 4 times at each concentration Decrease in operant performance at 140, 000 ppm; however, operant behavior measured pre-exposure and postexposure over the course of the study did not significantly differ (no lasting effect) 40,000, 60,000, 80,000, 100,000 140,000 Richie et al. 2001
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 Species (no.) Exposure Period End Point NOAEL (ppm) Adverse-Effect Level (ppm) Reference Dog (8) 16 min Cardiac arrhythmia with exercise; anesthetic effects in 6 animals — ≥100,000 Mullin et al. 1972 Rat (20) <17 min Deficits in motor function; effect levels for Freon 12 with and without supplemental oxygen were similar — 170,000-460,000 Ritchie et al. 2001 Rabbit, dog 20 min Anesthetized; no significant effect on blood measures (electrolytes, pH, glucose, urea, protein, cholesterol) 200,000 and 20% O2 — Paulet et al. 1975b Dog (6) 1 h No cardiac arrhythmia with epinephrine 25,000 — Reinhardt et al. 1971 Rat (10), rabbit (5) Two 1-h exposures per day for 15 days No significant effect on basal metabolism, thirst or diuresis, plasma electrolytes 50,000 and 20% O2 — Paulet et al. 1975b Rat, guinea pig 2 h Deaths in rats but not in guinea pigs — 600,000a Schloz 1962, as cited in ACGIH 2001 Rat, guinea pig, cat Several hours No deaths 300,000-800,000a — Studies reviewed by ACGIH 2001 Mouse 24 h Histologic evidence of increased leukocyte infiltration of alveolar wall relative to controls; exudate in bronchioles — 10,000 Quevauviller et al. 1963
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 Cat (2), rat (5), guinea pig (3), dog (2) 3.5 h/day, 5 days/week for 4 weeks No adverse effects 100,000 — Scholtz 1962, as cited in WHO 1990 Rat (90 of each sex), mouse (60 of each sex) 4 h/day, 5 days/week; rat: 104 weeks; mouse: 78 weeks No evidence of carcinogenicity or effects on body weight 1,000, 5,000 — Maltoni et al. 1988 Dog (6) 6 h/day, 7 days/week for 90 days No adverse effects on behavior and appearance, food or water consumption, body weight, clinical measures, heart rate, EKG, blood pressure, sight, hearing, dentition, organ weights, or histologic examinations 5,000 — Leuschner et al. 1983 Rat (40) 6 h/day, 7 days/week for 90 days No adverse effects on behavior and appearance, food or water consumption, body weight, clinical measures, sight, hearing, dentition, organ weights, or histologic examinations 10,000 — Leuschner et al. 1983 Dog, monkey, guinea pig 7-8 h/day for 3.5-56 days Some deaths, CNS reactions. — 200,000 Summarized by Clayton 1967
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 observed for up to 4 weeks. No adverse effects on standard reproductive indexes were reported (EPA 1983, as cited in WHO 1990). Immunotoxicity Information was insufficient to assess the immunotoxicity of Freon 12. Genotoxicity The mutagenic potential of chlorofluorocarbons, including Freon 12, has been examined in a number of in vitro tests and in vivo in rats (dominant lethal mutation study of Freon 12 administered orally at 15 and 150 mg/kg per day). All studies reviewed by WHO (1990) and ACGIH (2001) were negative. Carcinogenicity As noted above, Smith and Case (1973, as cited in WHO 1990) reported no evidence of lung tumors in mice and dogs after 23 months of inhalation exposure at 970 mg/kg per day and 12 months at 2,240 mg/kg per day, respectively, to a mixture of chlorofluorocarbons containing about 50% Freon 12 (25% Freon 11, 25% Freon 114, and 0.5-1% Freon 113). Maltoni et al. (1988) examined the carcinogenicity of Freon 12 and Freon 11 in 180 rats and 120 mice of both sexes exposed at 1,000 or 5,000 ppm 4 h/day, 5 days/week for 104 weeks. No evidence of carcinogenicity related to Freon 12 or Freon 11 was reported. Chronic oral-carcinogenicity studies of Freon 12 in rats and dogs have also been negative (Sherman, 1974; reviewed by WHO 1990 and EPA 1995 IRIS RECORD—1995 is the last revised date). Szmidt et al. (1981 in Swedish, as cited in WHO 1990) found no significant increases in total tumor deaths or lung-cancer deaths in refrigerator construction and repair workers. Restricting the analysis to those employed more than 3 or 10 years did not change the findings. Freon 12 is not listed in the National Toxicology Program 11th Report on Carcinogens. TOXICOKINETIC AND MECHANISTIC CONSIDERATIONS The most serious and potentially life-threatening toxic effect of inhalation of chlorofluorocarbons, such as Freon 12, is cardiac toxicity, which has been demonstrated in multiple animal species. According to Aviado (1994), three situations increase the sensitivity of the heart to the effects of chlorofluorocarbons: the injection of epinephrine, coronary ischemia or cardiac necrosis, and experimental bronchitis or pulmonary thrombosis. A common feature of those situations is a direct or indirect increase in cardiac irritability caused by epineph-
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 rine. General anesthesia, however, reduces cardiac sensitivity to the effects of chlorofluorocarbons (Aviado 1994), so studies in which animals were anesthetized are not representative of exposures associated with cardiac effects in unanesthetized animals. Anesthesia in mice and rats has also been shown to block the accelerating effects of chlorofluorocarbons on heart rate and instead to result in bradycardia. According to Aviado (1994), the mechanism of chlorofluorocarbon toxicity originates in irritation of the respiratory tract, which by a simple reflex response influences the heart rate before absorption of the compound. That is followed by depression of cardiac function after chlorofluorocarbon absorption and by sensitization of the heart to sympathomimetic amines (Aviado 1994). Jiao et al. (2006) investigated potential mechanisms of cardiac-sensitization arrhythmia induced by simultaneous exposure to halocarbons and epinephrine. They used rat cardiomyocytes and found that the combination of the halocarbon CF3Br and epinephrine had a unique effect on the electrophysiology of cardiomyocytes, specifically, reduction in conduction velocity associated with phosphorylation of gap-junction channel proteins. Jiao et al. (2006) note that effects on other ion channels may contribute to the risk of arrhythmia during cardiac sensitization and that their cardiomyocyte recording system cannot directly demonstrate actual arrhythmic effects. Among the species studied, the guinea pig is the most resistant to cardiovascular effects (Aviado 1994). The rat and mouse are intermediate in susceptibility, and the dog and monkey are more sensitive species. Experimental data indicate that the dog may be more sensitive than the monkey to cardiac effects. Aviado cautions against assuming that responses in the monkey would be more similar to those in humans, because of the lack of studies that would allow such a definitive comparison and because some studies had indicated that monkeys have no response or a response opposite that in dogs and other species. In addition to the reflex-induced bronchospasm, chlorofluorocarbons are postulated to reduce pulmonary compliance by reducing pulmonary surfactants (Aviado 1994). On the basis of the effect of atropine pretreatment in blocking pulmonary resistance caused by chlorofluorocarbons in the anesthetized mouse, bronchoconstriction in the mouse appears to result from vagal innervation of the lungs. Depression of respiratory movements at high exposure is related to the anesthetic properties of these compounds. In general, the dog appears to be less sensitive to respiratory toxicity than the mouse or rat. The rapid onset and reversibility of symptoms (such as cardiac and CNS effects within seconds to minutes) and the little adherence to Haber’s Law are consistent with the rapid appearance of inhaled Freon 12 in the blood and its rapid elimination (Blake and Mergner 1974; Paulet et al. 1975a). Inhaled Freon 12 (500,000 ppm for 10 min) in dogs and rabbits diffused rapidly into the bloodstream, cerebral spinal fluid (evaluated in dogs only), urine, and bile and reached equilibrium in blood within 2 min in rabbits and 5 min in dogs (Paulet et al. 1975a). Emmen et al. (2000) reported nearly maximal blood concentrations in eight human subjects (exposure at 1,000 ppm and 4,000 ppm) in 15 min. Af-
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 ter 10-min exposure at 200,000 or 500,000 ppm, elimination of Freon 12 from the blood was complete within 85 sec in the rabbit and within 20-30 min in dogs (Paulet et al. 1975a). Although inhalation of high concentrations of Freon 12 results in its rapid appearance in the blood because of its low blood:air partition coefficient, little is absorbed from the lungs. Single breath studies in human volunteers indicated that much of what is inhaled is exhaled unabsorbed (Morgan et al. 1972). The amount that reached the bloodstream from such a brief exposure was rapidly cleared: only a small fraction remained 5 min after exposure (Morgan et al. 1972). Adir et al. (1975) reported that inhalation of an administered dose of 3,225-4,506 mg over 12-20 min to three dogs or a dose of 777 mg over 16.75 min to a human volunteer resulted in near maximal blood concentration within the first 5 min. Consistent with their finding of a blood:air partition coefficient for Freon 11 that is 5-6 times higher than that for Freon 12, Adir et al. (1975) reported 77% of the administered dose of Freon 11 over the exposure period was absorbed in dogs compared with 55% of Freon 12. Freon 12 was also eliminated more rapidly from the blood within about 50 min for the dogs and the human subject compared with longer than 100 min for Freon 11. A review by WHO (1990) reported that studies in rats and monkeys indicated that Freon 12 is slightly more readily absorbed than Freon 114. Emmen et al. (2000) reported biphasic elimination from blood in most of the eight human subjects that was independent of concentration (1-h exposure at 1,000 ppm or 4,000 ppm)—a mean half-life of 7 min for the first phase of elimination and a mean half-life of 36 min for the second phase. Elimination occurs largely by the lungs with little metabolism (less than 1%), as shown in dogs (6-20 min of ventilation at 8,000-12,000 ppm [Blake and Mergner 1974] and humans (less than 0.2%; 7-17 min of inhalation at 1,000 ppm [Mergner et al. 1975]). In the study of anesthetized dogs (Blake and Mergner 1974), essentially all the radiolabeled Freon 12 was exhaled within an hour, and only traces of radioactivity appeared in the urine or with exhaled carbon dioxide. That longer exposures (50-90 min) or pretreatment with phenobarbital did not change the results indicates little biotransformation. Adir et al. (1975) developed a pharmacokinetic model for predicting blood and tissue concentrations of Freon 12 in dogs and humans and 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 a dog’s heart to intravenously injected epinephrine (Azar et al. 1973). INHALATION EXPOSURE LEVELS FROM THE NATIONAL RESEARCH COUNCIL AND OTHER ORGANIZATIONS A number of organizations have established inhalation exposure levels or guidelines for Freon 12. Selected values are summarized in Table 5-4.
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 TABLE 5-4 Selected Inhalation Exposure Levels for Freon 12 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 2004 OSHA PEL-TWA 1,000 29 CFR 1910.1000 Spacecraft NASA SMAC Garcia 2000 1-h 540 24-h 95 30-day 95 180-day 95 Submarine NRC EEGL NRC 1984 1-h 10,000 24-h 1,000 aThe comparability of EEGLs and CEGLs with occupational-exposure and public-health standards or guidance levels is discussed in Chapter 1 (“Comparison to Other Regulatory Standards or Guidance Levels”). Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; NASA, National Aeronautics and Space Administration; NIOSH, National Institute for Occupational Safety and Health; NRC, National Research Council; OSHA, Occupational Safety and Health Administration; PEL, permissible exposure limit; REL, recommended exposure limit; SMAC, spacecraft maximum allowable concentration; STEL, short-term exposure limit; TLV, Threshold Limit Value; TWA, time-weighted average. COMMITTEE RECOMMENDATIONS The committee’s recommendations for EEGL and CEGL values for Freon 12 are summarized in Table 5-5. The current and proposed U.S. Navy values are provided for comparison. TABLE 5-5 Emergency and Continuous Exposure Guidance Levels for Freon 12 Exposure Level U.S. Navy Values (ppm) Committee Recommended Values (ppm) Current Proposed EEGL 1-h 2,000 2,000 4,000 24-h 1,000 1,000 1,000 CEGL 90-day 100 100 300 Abbreviations: CEGL, continuous exposure guidance level; EEGL, emergency exposure guidance level.
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 1-Hour EEGL Exposure limits for Freon 12 should be set to prevent narcosis and other CNS effects, cardiac arrhythmia, tachycardia or bradycardia, and bronchoconstriction. Liver effects (fatty liver and necrosis) were noted in guinea pigs after continuous 90-day or repeated subchronic exposure, but no other species have shown these effects even in chronic studies. Data from human experimental studies can be used to set EEGLs with support from animal studies. NRC (1984) recommended a 1-h EEGL of 10,000 ppm on the basis of a small decrease in psychomotor performance in two humans and no effects after exposure at 1,000 ppm for 2.5 h (Azar et al. 1972). NRC (1984) does not mention effects on ventilatory capacity and reductions in heart rate reported in a study of 11 subjects exposed to Freon 12 at 10,000 ppm and 17,200 ppm for 35 or 130 min (Valić et al. 1982). Effects at 10,000 ppm appeared to be mild with no significant change in FEV1 or FVC and a significant reduction in MEF50 and MEF25 after the 35-min exposure (5.8% and 12% decrease, respectively) but not the 130-min exposure. Such effects would not be considered clinically significant (Pellegrino et al. 2005) or detrimental to submariners’ performance in an emergency situation. Few studies by other research groups are available to evaluate pulmonary and heart-rate effects in humans at concentrations of about 10,000 ppm. Azar et al. (1972) reported no pulmonary or EKG effects but a 7% reduction in psychomotor scores in two subjects exposed for 2.5 h at 10,000 ppm but not at 1,000 ppm. Some studies have not found such effects at higher concentrations in animals (Table 5-3). Studies in humans and animals at around 1,000 ppm have generally reported few effects even after repeated exposure Emmen et al. (2000) exposed eight people and reported no pulmonary or EKG effects at air concentrations as high as 4,000 ppm for 1 h. This study is considered the most relevant for deriving a 1-h EEGL, with supporting information from the other short-term human studies involving a total of 21 people. No interspecies factor is necessary, because human data are used. No intraspecies factor was used, because of the consistency in responses from human subjects around 4,000 ppm. Specifically, effects in humans are reported to begin at about 10,000 ppm, and no effects were noted at concentrations as high as 4,000 ppm. Thirteen people exposed at 10,000 ppm for a little over 2 h (Valic et al. 1982; Azar et al. 1972) showed relatively mild effects that indicate that any possible effects at lower concentrations in more sensitive people would be acceptable for a 1-h exposure in an emergency situation. Eight people showed no significant effects related to chlorofluorocarbon toxicity at 4,000 ppm or 1,000 ppm for 1 h, and 10 additional subjects tested at 1,000 ppm for longer periods than 1 h (Azar et al. 1972; Stewart et al. 1978) showed a similar lack of effects in measures related to chlorofluorocarbon toxicity. Thus, the committee recommends a 1-h EEGL of 4,000 ppm.
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 24-Hour EEGL No 24-h exposure studies in humans are available to evaluate an EEGL for this period. Mice exposed at 10,000 ppm for 24 h showed no clinical effects but had microscopic lung changes, such as increased leukocyte infiltration of alveolar walls relative to controls, which showed similar effects to a smaller degree (Quevauviller et al. 1963). However, sufficient detail was not provided to ascertain whether the effects were treatment-related, and pulmonary inflammation differs from the respiratory effects (bronchospasm) of chlorofluorocarbons in other studies. Animals exposed continuously at around 800 ppm for 90 days showed few treatment-related effects (Prendergast et al. 1967; see Table 5-3); given the nature of the effects (liver effects in guinea pigs), development of them would be of less concern after a 24-h exposure. NRC (1984) recommended a 24-h EEGL of 1,000 ppm on the basis of the lack of effects on psychomotor performance in two human subjects after 2.5 h of exposure at 1,000 ppm (Azar et al. 1972) and rapid elimination of Freon 12 in expired air. A key study for setting an EEGL is that by Stewart et al. (1978). This relatively well-conducted study examined a number of end points and reported that exposure of eight healthy human subjects at 1,000 ppm 8 h/day, 5 days/week for 2-4 weeks resulted in no effects on cognitive or motor function, changes in clinical measures, spirometry, EKG, EEG, or irritation symptoms (Stewart et al. 1978). Although the literature does not indicate much difference in effect level between 1-h and multihour exposures, potential mild effects on respiration, the CNS, or heart rate might not be as tolerable for a 24-h period, so use of a more protective EEGL for a 24-h than for a 1-h exposure period is justified. Thus, on the basis of the weight of evidence, a 24-h EEGL of 1,000 ppm appears to be appropriate inasmuch as there was little or no effect in human and animal studies. Given the concurrence of a number of studies in animals and humans on that concentration and the acceptability of mild effects in an emergency situation, no additional uncertainty factors are warranted. 90-Day CEGL Longer-term and repeated studies of Freon 12 are generally without effect at about 1,000 ppm and in some cases higher (rats exposed at 10,000 ppm and dogs at 5,000 ppm 6 h/day for 90 days; Leuschner et al. 1983). Rats, guinea pigs, rabbits, monkeys, and dogs exposed at 807 ppm continuously for 90 days or at 836 ppm 8 h/day, 5 days/week for 6 weeks showed liver effects only in guinea pigs, which may be more sensitive to this effect than other species (Prendergast et al. 1967). Exposure to other chlorofluorocarbons has also been noted to be associated with fatty liver in guinea pigs (Aviado 1994). Studies in other species at higher concentrations and for longer exposure have not reported liver effects attributable to Freon 12 exposure.
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 Observations of lung congestion and nonspecific inflammatory changes in lung tissue were not noted to be treatment-related, as were the liver changes in guinea pigs reported by Prendergast et al. (1967). Although effects on the lungs have been associated with Freon 12 exposure at higher air concentrations, the lung effects also were noted in control animals and do not appear to be related to bronchoconstriction associated with Freon 12. Stewart et al. (1978) reported no effect on cognitive or motor function, clinical measures of blood and urine, spirometry, EKG, EEG, or irritation symptoms in eight healthy volunteers exposed at 1,000 ppm 8 h/day, 5 days/week for 2-4 weeks. A Freon 12 concentration of 1,000 ppm from Stewart et al. (1978) was thus used as the initial basis of a NOAEL, with support from the animal data of Prendergast et al. (1967). Application of an uncertainty factor of 3 to account for database uncertainties associated with the lack of longer-term continuous studies in humans resulted in a CEGL of 300 ppm. An uncertainty factor of 3 is supported by Freon 12 toxicokinetics, which indicate that cumulative effects would not occur with time, particularly at the concentrations tested, because Freon 12 is rapidly eliminated with little metabolism. The little metabolism also obviates the need to consider metabolic differences among humans. Thus, the mechanistic data, other studies in humans, and the longer-term animal studies are supportive of the use of an uncertainty factor of 3 applied to the NOAEL of Stewart et al. (1978). DATA ADEQUACY AND RESEARCH NEEDS Although several studies of various species are available, including controlled studies in a small number of human subjects, most of them are not recent (that is, within the last 20 years), and in many cases the full nature of effects and study methods could not be evaluated, because of limitations in reporting or because the studies were unpublished or otherwise not readily available for review. Information on the effects of chronic inhalation exposure, carcinogenicity, or male reproductive or immune system effects is generally less adequate. The available evidence, however, indicates that Freon 12 is rapidly absorbed and eliminated with little metabolism and that neither cancer nor most other toxic effects would be expected at the proposed EEGLs and CEGL. Additional studies to define the nature of effects at 1,000-10,000 ppm and the effects of chronic exposure would increase confidence in that prediction. Evidence from the literature also indicates that mixtures of chlorofluorocarbons may result in a lower effect level than predicted from the effect levels of individual chlorofluorocarbons alone. Thus, if mixtures of chlorofluorocarbons could be present in submarines, effect levels for the mixtures should be evaluated. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2001. Dichlorodifluoromethane in Documentation of the Threshold Limit Values and Biological
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 Exposure Indices, 7th Ed. American Conference of Governmental Industrial Hygienists, 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. Antti-Poika, M., J. Heikilla, and L. Saarinen. 1990. Cardiac arrhythmias during occupational exposure to fluorinated hydrocarbons. Br. J. Ind. Med. 47(2):138-140. Aviado, D.M. 1994. Fluorine-containing organic compounds. Pp. 1188-1220 in Patty's Industrial Hygiene and Toxicology, Fourth 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 systems. I. Cardiac arrhythmia in the mouse. Toxicology 2(1):31-42. Aviado, D.M., and D.G. Smith. 1975. Toxicity of aerosol propellants in the respiratory and circulatory systems. VIII. Respiration and circulation in primates. Toxicology 3(2):241-252. 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. Azar, A., H.J. Trochimowicz, J.B. Terrill, and L.S. Mullin. 1973. Blood levels of fluorocarbon related to cardiac sensitization. Am. Ind. Hyg. Assoc. J. 34(3):102-109. Belej, M.A., and D.M. Aviado. 1975. Cardiopulmonary toxicity of propellants for aerosols. J. Clin. Pharmacol. 15(1 Pt 2):105-115. Belej, M.A., D.G. Smith, and D.M. Aviado. 1974. Toxicity of aerosol propellants in the respiratory and circulatory systems. IV. Cardiotoxicity in the monkey. Toxicology 2(4):381-395. Blake, D.A., and G.W. Mergner. 1974. Inhalation studies on the biotrans-formation and elimination of 14C-trichlorofluoromethane and 14C-dichlorodi-fluoromethane in beagles. Toxicol. Appl. Pharmacol. 30(3):396-407. Brody, R.S., T. Watanabe, and D.M. Aviado. 1974. Toxicity of aerosol propellants on the respiratory and circulatory systems. III. Influence of bronchopulmonary lesion on cardiopulmonary toxicity in the mouse. Toxicology 2(2):173-184. 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 Toxicological 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. Clayton, J. W., Jr. 1967. Fluorocarbon toxicity and biological action. Fluor. Chem. Rev. 1(2):197-242. Crawl, J.R. 2003. Review/Updating of Limits for Submarine Air Contaminants. Presentation at the First Meeting on Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants, January 23, 2003, Washington, DC. Edling, C., and C.G. Olson. 1988. Health Risks with Exposure to Freons [in Swedish]. Department of Occupational Medicine, University Hospital, Uppsala, Sweden (as cited in WHO 1990). Edling, C., C.G. Ohlson, G. Ljungkvist, A. Oliv, and B. Soederholm. 1990. Cardiac arrhythmia in refrigerator repairmen exposed to fluorocarbons. Br. J Ind. Med 47(3):207-212.
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 Emmen, H.H., E.M. Hoogendijk, W.A. Klopping-Ketelaars, H. Muijser, E. Duistermaat, J.C. Ravensberg, D.J. Alexander, D. Borkhataria, G.M. Rusch, and B. Schmit. 2000. Human safety and pharmacokinetics of the CFC alternative propellants HFC 134a (1,1,1,2-tetrafluoroethane) and HFC 227 (1,1,1,2,3,3,3-hexafluoropropane) following whole-body exposure. Regul. Toxicol. Pharmacol. 32(1):22-35. EPA (U.S. Environmental Protection Agency). 1983. Health Assessment Document for 1,1,2-trichloro-1,2,2-trifluoroethane (Chlorofluorocarbon CFC-113). EPA-600/8-82-002F. NTIS PB 84-118843. Office of Air Quality Planning and Standards, U.S. Environmental Protection Agency, Research Triangle Park, NC. EPA (U.S. Environmental Protection Agency). 1995. Difluorodichloromethane (CAS NR 75-71-8). Integrated Risk Information System, U.S. Environmental Protection Agency [online]. Available: http://www.epa.gov/iris/subst/0040.htm [accessed June 15, 2007]. Garcia, H.D. 2000. Dichlorodifluoromethane (Freon 12). Pp. 227-239 in Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Vol. 4. Washington, DC: National Academies Press. Hagar, R. 2003. Submarine Atmosphere Control and Monitoring Brief for the COT Committee. Presentation at the First Meeting on Emergency and Continuous Exposure 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 Battelle, Columbus, OH. June 1995. HSDB (Hazardous Substances Data Bank). 2005. Difluorodichloromethane (CAS NR 75-71-8). TOXNET, Specialized Information Services, U.S. National Library of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~2uEZl7:1 [accessed April 30, 2007]. Jiao, Z., V.R. De Jesús, S. Iravanian, D.P. Campbell, J. Xu, J.A. Vitali, K. Banach, J. Fahrenbach, and S.C. Dudley. 2006. A possible mechanism of halocarbon-induced cardiac sensitization arrhythmias. J. Mol. Cell Cardiol. 41(4):698-705. Kehoe, R.A. 1943. Report on Human Exposure to Dichlorodifluoromethane in Air. Kettering Laboratory, University of Cincinnati. Cincinnati, OH. Leuschner, F., B.W. Neumann, and F. Hübscher. 1983. Report on subacute toxicological studies with several fluorocarbons in rats and dogs by inhalation. Arzneimittelforschung. 33(10):1475-1476. 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. N.Y. Acad. Sci. 534:261-282. Marier, G., G.H. MacFarland, and P. Dussault. 1973. A study of blood fluorocarbon levels following exposure to a variety of household aerosols. Household Pers. Prod.Ind. 10(12):68, 70, 92, 99 (as cited in WHO 1990). Mergner, G.W., D.A. Blake, and M. Helrich. 1975. Biotransformation and elimination of 14C-trichlorofluoromethane (FC-11) and 14C-dichlorodifluoro-methane (FC-12) in man. Anaesthesiology 42(3): 345-351. 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 (as cited in WHO 1990).
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 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. NIOSH (National Institute of Occupational Safety and Health). 2004. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) No. 2004-103. National Institute of Occupational Safety and Health, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, Cincinnati, OH. NRC (National Research Council). 1984. Fluorocarbon 12. Pp. 34-40 in Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Vol. 2. Washington, DC: National Academies Press. Paulet, G., J. Lanoë, A. Thos, P. Toulouse, and J. Dassonville. 1975a. Fate of fluorocarbons in the dog and rabbit after inhalation. Toxicol. Appl. Pharmacol. 34(2):204-213. Paulet, G., G. Roncin, E. Vidal, P. Toulouse, and J. Dassonville. 1975b. Fluorocarbons and general metabolism in the rat, rabbit, and dog. Toxicol. Appl. Pharmacol. 34(2):197-203. Pellegrino, R., G. Viegi, V. Brusasco, R.O. Crapo, F. Burgos, R. Casaburi, A. Coates, C. P. van der Grinten, P. Gustafsson, J. Hankinson, R. Jensen, D.C. Johnson, N. MacIntyre, R. McKay, M.R. Miller, D. Navajas, O.F. Pedersen and J. Wanger. 2005. Interpretative strategies for lung function tests. Eur. Respir. J. 26(5):948-968. Prendergast, J.A., R.A. Jones, L.J. Jenkins, and J. Siegel. 1967. Effects on experimental animals of long-term inhalation of trichloroethylene, carbon tetrachloride, 1,1,1-trichloroethane, dichlorodifluoromethane, and 1,1-dichloroethylene. Toxicol. Appl. Pharmacol. 10(2):270-289. 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. Raymer, J.H., E.D. Pellizzari, R.D. Voyksner, G.R. Velez, and N. Castillo. 1994. Qualitative Analysis of Air Samples from Submarines. Project RTI/5937/00-01F. Prepared for Geo-Centers, Inc., Newton Upper Falls, MA, by Research Triangle Institute, Research Park, NC. December 22, 1994. Reinhardt, C.F., A. Azar, M.F. Maxfield, P.E. Smith, and L.S. Mullin. 1971. Cardiac arrhythmias and aerosol “sniffing.” Arch. Environ. Health 22(2):265-279. Ritchie, G.D., E.C. Kimmel, L.E. Bowen, J.E. Reboulet, and J. Rossi. 2001. Acute neurobehavioral effects in rats from exposure to HFC 134a or CFC 12. Neurotoxicology 22(2):233-248. Rusch, G.M. 2000. Organic chlorofluoro hydrocarbons. Pp. 505-619 in Patty’s Toxicology, Vol. 5. Organic Halogenated Hydrocarbons/ Aliphatic Carboxylic Acids/ Ethers/Aldehydes, 5th Ed., E. Bingham, B. Cohrssen, and C.H. Powell, eds. New York: John Wiley and Sons. Scholz, J. 1962. New toxicological investigations on certain types of Freon used as propellants [in German]. Fortschr. Biol. Aerosol-Forsch.4:420-429 (as cited in WHO 1990). Sherman, H. 1974. Long-Term Feeding Studies in Rats and Dogs with Dichlorodifluoromethane (Freon 12 Food Freezant). Medical Research Project No. 1388; Report No. 24-74. Haskell Laboratory, Newark, DE (as cited in WHO 1990). 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.
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Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2 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. Szmidt, M., O. Axelson, and C. Edling. 1981. Cohort study of Freon-exposed workers [in Swedish]. Acta Soc. Med. Svec. Hygiea 90:77-79 (as cited in WHO 1990). Valić, F., Z. Skurić, Z. Bantić, M. Rudar, and M. Hećej. 1977. Effects of fluorocarbon propellants on respiratory flow and ECG. Br. J. Ind. Med. 34(2):130-136. Valić, F., Z. Skurić, and E. Zuskin. 1982. Experimental exposure to Freon 12, 22, and 502 [in Croatian with English summary]. Rad Jazu. 402(18):229-243 (as cited in WHO 1990). 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. WHO (World Health Organization). 1990. Fully Halogenated Chlorofluorocarbons. Environmental Health Criteria 113. Geneva: World Health Organization [online]. Available: http://www.inchem.org/documents/ehc/ehc/ehc113.htm [accessed September 30, 2004].