B6 1,2-Dichloroethane

King Lit Wong, Ph.D.

Johnson Space Center Toxicology Group

Biomedical Operations and Research Branch

National Aeronautics and Space Administration

Houston, Texas

PHYSICAL AND CHEMICAL PROPERTIES

The compound 1, 2-dichloroethane (EDC) is a colorless liquid with an odor characteristic of chlorinated hydrocarbons (ACGIH, 1991).

Synonym:

Ethylene dichloride

Formula:

CH2ClCH2Cl

CAS number:

107-06-2

Molecular weight:

99.0

Boiling point:

83.5°C

Melting point:

-35.5°C

Specific gravity:

0.94

Vapor pressure:

87 mmHg at 25°C

Saturated vapor concentration:

114,474 ppm at 25°C

Conversion factors at 25°C, 1 atm:

1 ppm = 4.05 mg/m3

1 mg/m3 = 0.25 ppm

OCCURRENCE AND USE

EDC has been used in vinyl chloride manufacture, as a solvent, degreaser, and fumigant (ACGIH, 1991). EDC has been detected at a trace concentration (just enough was collected on Tenax for gas chromatography-mass spectrometry qualitative identification, but not for



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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 B6 1,2-Dichloroethane King Lit Wong, Ph.D. Johnson Space Center Toxicology Group Biomedical Operations and Research Branch National Aeronautics and Space Administration Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES The compound 1, 2-dichloroethane (EDC) is a colorless liquid with an odor characteristic of chlorinated hydrocarbons (ACGIH, 1991). Synonym: Ethylene dichloride Formula: CH2ClCH2Cl CAS number: 107-06-2 Molecular weight: 99.0 Boiling point: 83.5°C Melting point: -35.5°C Specific gravity: 0.94 Vapor pressure: 87 mmHg at 25°C Saturated vapor concentration: 114,474 ppm at 25°C Conversion factors at 25°C, 1 atm: 1 ppm = 4.05 mg/m3 1 mg/m3 = 0.25 ppm OCCURRENCE AND USE EDC has been used in vinyl chloride manufacture, as a solvent, degreaser, and fumigant (ACGIH, 1991). EDC has been detected at a trace concentration (just enough was collected on Tenax for gas chromatography-mass spectrometry qualitative identification, but not for

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 quantitative analysis) in air samples taken in a shuttle mission (NASA, 1990). Off-gassing was most likely its source in that mission. TOXICOKINETICS AND METABOLISM Toxicokinetics Reitz et al. (1982) did a toxicokinetic study in rats using the maximally tolerated concentration of EDC (i.e., 150 ppm) from a 2-y bioassay of Maltoni et al. (1980). When the rats were exposed at 150 ppm for 6 h, the blood concentration reached a plateau in about 2 h; this observation indicated that EDC was absorbed readily. When the 6-h exposure ended, the compound was rapidly cleared from the blood with a bi-exponential decay, and the half-lives of the two phases were 6 and 35 min. During the 48 h after the 6-h exposure, only 1.8% of the amount of EDC absorbed by the body (the total body burden) was exhaled unchanged. Much of the total body burden was excreted in those 48 h as metabolites: 84.4% in urine, 7.0% as CO2, and 1.7% in feces, so that only 4.4% of the total body burden remained in the rat's body after 48 h. Metabolism Anders and Livesey (1980) showed that EDC is metabolized by two competing pathways. A proposed metabolic scheme is shown in Figure 6-1 (IPCS, 1987). In one pathway, EDC is oxidized by the cytochrome P-450 system to 2-chloroacetaldehyde, which could react with macromolecules in the cell. 2-Chloroacetaldehyde could be further oxidized by aldehyde dehydrogenase to 2-chloroacetic acid, which is oxidized to 2-chloroethanol or conjugated with glutathione, and be eliminated eventually. Another pathway involves direct conjugation with glutathione to form S-(2-chloroethyl)-glutathione, which could either form glutathione episulfonium ion or react with glutathione to form ethane and hydrogen chloride. Glutathione episulfonium ion could react with cellular macromolecules, or it could conjugate with glutathione to form S, S'-ethane bisglutathione, which is then eliminated after being transformed into other metabolites.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 FIGURE 6-1   Proposed metabolic pathways for 1, 2-dichloroethane. Source: Adapted from IPCS, 1987.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Because both metabolic pathways generate a metabolite (i.e., 2-chloroacetaldehyde and glutathione episulfonium ion) that could react with macromolecules, it is of interest to compare their genotoxic potency. Storer and Conolly (1985) compared the amount of hepatic DNA damage in EDC-exposed mice pretreated with dimethyl maleate, which depleted glutathione, or piperonyl butoxide, which inhibited the cytochrome P-450 system. They demonstrated that EDC resulted in more hepatic DNA damage during inhibition of the cytochrome P-450 than during depletion of glutathione. Therefore, the metabolites in the glutathione conjugation pathway are more genotoxic than those in the oxidative pathway (Storer and Conolly, 1985). It appears that glutathione episulfonium ion is probably the major genotoxic metabolite of EDC. The cytochrome P-450 oxidative pathway of EDC metabolism is saturable at lower EDC concentrations than the glutathione conjugation pathway (NRC, 1987). Based on a physiologically based pharmacokinetic model, the cytochrome P-450 oxidative pathway tends to be saturated at an oral EDC dose of about 1 mg/kg in mice (NRC, 1987). In rats, as the EDC dose increased to above 25 mg/kg, there was a transient depletion of glutathione in the liver (D'Souza et al., 1988). Therefore, at oral EDC doses below 1 mg/kg, the model predicts that the amount of glutathione-conjugate metabolite formed in the liver of mice increases linearly with the dose (NRC, 1987). At doses between 1 and 25 mg/kg, the amount of glutathione-conjugate metabolite in the liver does not increase linearly with the dose, but instead it curves upward, probably because of the saturation of the cytochrome P-450 pathway. Between a dose of 25 and 150 mg/kg, however, the amount of glutathione-conjugate metabolite begins to reach a plateau because of glutathione depletion. TOXICITY SUMMARY EDC is known to cause death, central-nervous-system (CNS) depression, miscellaneous symptoms, corneal opacity, gastrointestinal (GI) and hepatic toxicity, and impairment of host defense toward microbes. It has also been shown to cause tumors in rodents.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Acute and Short-Term Exposures The literature on the toxic effects of EDC after a single exposure or after exposures repeated for no more than 7 d is reviewed here. Lethality A number of fatal cases of accidental EDC poisoning have been reported in the literature. Most of them involve occupational exposures. These workers were generally found unconscious after an acute exposure to a presumably very high, but unknown, concentration of EDC. Their symptoms and signs could include CNS depression, weakness of the limbs, cyanosis, rales over the chest, tachycardia, jaundice, and anuria. Autopsies showed lung edema and congestion, fatty liver, hepatic necrosis, cavernous formations in liver, hyalinized or swollen glomeruli, swollen renal tubules with the lumen filled with dead cells or hyaline and granular casts, and granular degeneration of renal tubules (Brass, 1949; Hadengue and Martin, 1953; Troisi and Cavallazzi, 1961). In one case, pulmonary edema was the cause of death, and a victim of another case probably died of circulatory collapse (Brass, 1949; Hadengue and Martin, 1953). Quantitative information is lacking on the lethal concentration of EDC in humans. In contrast, several studies have been done to determine the lethal concentrations of EDC for laboratory animals (Heppel et al., 1946; Spencer et al., 1951; Bonnet et al., 1980). Analyses of these animal data revealed that species differences exist in EDC's acute lethal effect. The species sensitivities ranked in decreasing order are mice, guinea pigs, rabbits, rats, dogs, and cats. Bonnet et al. (1980) showed that the 6-h LC50 of EDC was only 262 ppm in mice and 1646 ppm in rats. Heppel et al. (1946) compared the sensitivities of rats, rabbits, guinea pigs, cats, and dogs to acute EDC exposures. They reported that in two daily exposures to EDC at 1000 ppm for 7 h/d, 58% of guinea pigs and 33% of rabbits died, but none of the rats, cats, and dogs died. When the exposures were extended to 7 h/d, 5 d/w for several weeks, 55 % of the rats died after 1 w of exposure, but none of the dogs and cats died after 3 w. Because three of six dogs became sick

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 after 3-4 w of exposure and only one of six cats was affected after 4 w of exposure, cats appeared to be the most tolerant species among the ones tested. Even though rhesus monkeys were also tested in their study, no valid species comparison can be made with monkeys because only two monkeys and no controls were used in the 1000-ppm group. In addition to species differences, there are sex differences in EDC's lethal effect in some of the species. In an experiment conducted in which rats and guinea pigs were exposed to EDC at 400 ppm, 7 h/d, 5 d/w, for up to 8 w, it took 10 exposures to kill 15 female rats, compared with 40 exposures to kill 15 male rats. It took only 10 exposures to kill eight male guinea pigs but 24 exposures to kill eight female guinea pigs (Spencer et al., 1951). Therefore, female rats are more sensitive than male rats, but the reverse is true in guinea pigs. Spencer et al. (1951) studied extensively the acute exposure concentrations of EDC that produced lethality in rats. They showed that the acute lethal effect of EDC increased with the product of exposure concentration and duration in rats (Table 6-1). TABLE 6-1 Lethality of EDC Concentration and Duration of Exposure Exposure Concentration, ppm Duration for 0.01% Mortality, h Duration for 50% Mortality, h 12,000 0.2 0.5 3000 1.0 3.0 1500 2.0 5.5 1000 3.5 7.0 Cause of Death and Internal Injuries As mentioned above, pulmonary edema and circulatory collapse have been postulated to be the cause of death in humans acutely poisoned by EDC (Brass, 1949; Hadengue and Martin, 1953). Among laboratory animals, rats are the best studied. The cause of death from acute EDC poisoning in rats depends on the exposure concentration. An exposure at 20,000 ppm killed the rats with extremely severe CNS depression in 0.3-0.4 h (Spencer et al., 1951). In contrast, at 12,000 ppm or lower,

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Spencer's group found that CNS depression was not the cause of death because no coma or death occurred during the exposure. In rats exposed to EDC at the LC50 of 12,000 ppm for 0.5 h, 3000 ppm for 3 h, or 1000 ppm for 7 h, the most pronounced histopathological effect was in the kidney with necrosis and degeneration of the tubular epithelium, interstitial edema, hemorrhage, and congestion. There were also varying degrees of parenchymatous degeneration and hemorrhagic necrosis in the liver, but no fatty degeneration. Based on the lesions described by Spencer et al. (1951), severe renal injuries appeared to cause the death of rats acutely exposed to EDC at 12,000 ppm or lower. In addition to determining the acute lethal concentrations of EDC, Spencer et al. (1951) also determined acute exposure concentrations that did not produce any internal injuries. They found that the exposure conditions shown in Table 6-2 were devoid of any adverse macroscopic or microscopic effects. Miscellaneous Symptoms In nonfatal cases of acute EDC exposure of workers, the symptoms included dizziness, headache or pressure in the head, nausea, vomiting, epigastric cramps, and weakness (Wirtschafter and Schwartz, 1939; Jordi, 1944). Except for dizziness, the symptoms could last for a few days. The victims could also develop hypoglycemia and leucocytosis. Based on the industrial experience in Russia, Rosenbaum (1947) stated that repeated exposures to EDC at 75-125 ppm could result in acute poisonings with the development of dizziness, headache, weakness, mucosal irritation, nausea, and vomiting. TABLE 6-2 EDC Exposure Conditions Without Adverse Effects Exposure Concentration, ppm Exposure Duration, h 12,000 0.1 3000 0.3 1000 1.5 300 3.0 200 7.0

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 CNS Depression As discussed previously, EDC could cause unconsciousness at 20,000 ppm during an exposure lasting 0.3-0.4 h in rats. However, Spencer et al. (1951) found that acute exposures of rats to lower concentrations of EDC, such as 12,000 ppm for 1 h or 3,000 ppm for a few hours, resulted in ''drunkenness'' instead of unconsciousness. Dizziness has been reported in nonfatal cases of acute EDC exposure of workers (Wirtschafter and Schwartz, 1939; Jordi, 1944). The only quantitative data on the depressive effects of EDC in humans were gathered by Borisova (1957, 1960). Borisova measured the light perception threshold in three human subjects during an exposure to EDC at 1 to 12.5 ppm. At 1.5 to 12.5 ppm, the light-perception threshold was reduced in a concentration-dependent fashion, but there was no reduction at 1 ppm. Because Borisova used only three men in this study, the data are not used in setting the SMACs. Corneal Opacity A study by Heppel et al. (1944) demonstrated that an exposure of dogs to EDC at 1000 or 1500 ppm for 7 h resulted in bilateral corneal opacity, which cleared up within a week. In repetitive exposures of dogs at 1000 ppm for 7 h/d, 5 d/w, for several weeks, they reported that the corneal opacity increased in intensity during the five exposure days in the first week. The opacity cleared up during 2 d (weekends) of no exposure. As the weekly exposures were repeated, the cornea developed tolerance toward the clouding effect of EDC, and the cornea became almost totally resistant after a few weeks. A similar phenomenon was observed by Heppel et al. (1944) in dogs exposed at 400 ppm for a similar duration. By the fifth week of exposure, 400 ppm was only mildly effective in producing corneal opacity. By the tenth week, the cornea failed to show any cloudiness at all. When Heppel's group exposed 11 species, including dogs, foxes, rabbits, cats, raccoons, guinea pigs, rats, and hogs to EDC at 3000 ppm, only the corneas of the dog and fox were affected. Because corneal opacity has never been documented in accidental and nonaccidental EDC exposures of humans, it is not used as a toxic end point in deriving EDC's SMACs.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Bacterial Respiratory Infection Female mice exposed to EDC at 10 ppm for 3 h resulted in decreased pulmonary bactericidal activity against inhaled Klebsiella pneumoniae and in increased mortality upon inhalation challenge of Streptococcus zooepidemicus (Sherwood et al., 1987). During the challenge, the mice inhaled about 20,000 to 40,000 Klebsiella or Streptococcus bacteria in 30 min. A 3-h exposure to EDC at 5 ppm, however, increased mortality from streptococcal challenge but did not change pulmonary bactericidal activity. A single exposure or five daily 3-h inhalation exposures to EDC at 2.5 ppm failed to produce any change in the mortality from streptococcal challenge and pulmonary bactericidal activity. Subchronic and Chronic Exposures Miscellaneous Symptoms The symptoms of subchronic EDC intoxication resemble those of nonfatal acute EDC poisoning, consisting mainly of CNS and GI symptoms. McNally and Fostvedt (1941) reported intoxication in two workers exposed to EDC on the job. These workers extracted cholesterol from spinal cords by grinding 2500 pounds of spinal cords in 750 to 900 gallons of EDC. They inhaled EDC vapors during centrifugation of homogenized spinal cords to separate the cholesterol and also when they emptied barrels containing the cholesterol. Both of them presented drowsiness, anorexia, nausea, vomiting, and epigastric discomfort. Nystagmus and fine tremor of the tongue developed in one of the workers, and nervousness was detected in the other worker. Symptom data from studies in which EDC exposure concentrations were measured are summarized as follows. Cetnarowicz (1959) studied Polish workers involved in purifying mineral oil with a solvent containing 80% EDC and 20% benzene. In a study of 10 workers exposed for 2-8 mo to a mixture of EDC at 62-200 ppm and benzene at 3-8 ppm, all workers complained of mucosal irritation, which disappeared as they adapted to it. Six of them developed dizziness, sleepiness, a sweetish aftertaste, dry mouth, nausea, vomiting, and constipation. Three of 10 workers complained of epigastric pain. Among six workers exposed

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 for 2-8 mo to EDC at 10-37 ppm and benzene at 3-8 ppm, only one complained of the CNS and GI symptoms. Although benzene is known to cause headache, drowsiness, nausea, and loss of appetite (Finkel et al., 1983), the difference in the severity of the symptoms between the two groups can be attributed to the difference in EDC exposure concentrations, because the benzene concentrations were the same in both groups. The data of Cetnarowicz (1959) can be interpreted to mean that the lowering of the EDC exposure concentration from 62-200 ppm to 10-37 ppm decreases the severity of the CNS and GI symptoms of EDC. Byers (1945) reported that U.S. workers exposed to EDC at concentrations not much higher than 100 ppm for 7.5 h/d developed nausea, vomiting, abdominal pain, lassitude, and malaise in a few hours after they left work. These delayed effects of EDC were reduced somewhat, but not totally eliminated, when the EDC concentration was decreased to 70 ppm. EDC poisoning was reported in two workers exposed on the job to a measured EDC concentration of 120 ppm for 10 min three to four times a day and also to an estimated concentration of greater than 120 ppm daily for 10-15 min (Guerdjikoff, 1955). After several weeks (3 w for one of the workers), they developed fatigue, irritability, nervousness, anorexia, and epigastric pains. As the exposure continued for 7 or 9 mo, the workers gradually experienced tingling sensations of the eyes, headaches, insomnia, dizziness, slight hand trembling, difficulty in walking, and deviation to the right in a blind walk. Rosenbaum (1939) presented the industrial experiences of EDC in Russia in the 1930s and 1940s. Without specifying the exact exposure concentrations, Rosenbaum reported that occupational exposures of 90 workers to EDC at below 25 ppm could produce bradycardia, fatigue, insomnia, and headache, but no effects on the blood. Kozik (1957) studied workers in the aircraft industry in Russia. These workers applied glue containing EDC as a solvent to large rubber sheets. On the basis of the data presented by Kozik, the National Institute of Occupational Safety and Health (NIOSH) estimated that, in the first half of the shift, the time-weighted average (TWA) exposure concentrations of EDC were 28 ppm during glue application and 16 ppm during the period the glue dried (NIOSH, 1976). In the second half of the shift, the TWA exposure concentration of EDC was 11 ppm. Therefore, the EDC TWA exposure concentration for the entire shift

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 was 15 ppm (NIOSH, 1976). Comparing the morbidity data between the gluers and the machinists, who were not exposed to EDC, Kozik (1957) reported that the EDC exposure increased both the number of cases of acute GI disorders per 100 workers and the number of workdays lost to acute GI disorders per 100 workers. Kozik also measured the hand-eye coordination speed of the gluers and machinists at the start and end of the workday for 14 d in 17 gluers and 10 machinists (as controls). The speed did not differ among the groups. However, more errors were made in the test by the EDC-exposed gluers test than by the nonexposed machinists (error rates of 30% for the gluers and 10% for the machinists). Brzozowski et al. (1954) studied 118 agricultural workers who used EDC as a fumigant in Poland. These workers were exposed to EDC at a TWA concentration of about 15 ppm and at a maximum concentration of 60 ppm, but they were also subjected to cutaneous exposure due to EDC spilled on their skin and clothes and due to the use of EDC to wash their skin. In 90 of 118 workers, Brzozowski et al. (1954) also detected redness of the conjunctiva and pharynx, burning sensation of the eye, bronchial symptoms, weakness, metallic taste in the mouth, headache, nausea, liver pain, tachycardia, and cough. Among the studies reported by Cetnarowicz (1959), Byers (1945), Rosenbaum (1939) , Kozik (1957), and Brzozowski et al. (1954), the data of Brzozowski et al. are not used to derive an acceptable concentration (AC) for CNS and GI symptoms because of the confounding effect of cutaneous exposures. The data of the other four studies used to derive a LOAEL for the symptoms are listed in Table 6-3. TABLE 6-3 Symptoms of Occupational EDC Poisoning EDC Concentration, ppm Symptoms Produced in Workers Reference Slightly > 100 CNS and GI symptoms Byers, 1945 70 Less severe than > 100 ppm Byers, 1945 < 25 CNS symptoms Rosenbaum, 1939 15 CNS and GI symptoms and signs Kozik, 1957

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 tive than the lethality end point. SMACs derived to prevent these toxic end points will also prevent lethality. For each toxic end point, an acceptable concentration (AC) is estimated for a given exposure duration. In the end, the lowest AC for each exposure duration is chosen to be the SMAC for that duration. CNS Effects Based on the report by Kozik (1957), 15 ppm is the lowest-observed-adverse-effect level (LOAEL) for CNS effects (e.g., increased errors in a hand-eye coordination test) in workers exposed to EDC. The severity of CNS effects is assumed to be related to the concentration of EDC in the blood. Because Reitz et al. (1980) showed that the blood concentration of EDC in rats reached equilibrium in 2 h during an inhalation exposure at 150 ppm, it is highly likely that the concentration of EDC in the blood also reached equilibrium within several hours of occupational exposure of workers in the studies performed by Kozik (1957). Therefore, the occupational LOAEL of 15 ppm should be a LOAEL for any EDC exposure lasting from 24 h to 180 d. Because the occupational LOAEL is good for 24 h, it should be valid for a 1-h exposure. An extrapolation factor of 10 is used to estimate the NOAEL from the occupational LOAEL. The LOAEL of 15 ppm is based on a large population of workers (Kozik, 1957); therefore, no adjustment for "small n" is needed. 1-h, 24-h, 7-d, 30-d, and 180-d ACs for CNS depression = occupational LOAEL × 1/NOAEL factor = 15 ppm × 1/10 = 1.5 ppm. Gastrointestinal Symptoms The LOAEL for GI symptoms is also 15 ppm based on the study of Kozik (1957) in Russian workers. Unlike CNS symptoms, it is not certain whether GI symptoms are totally dependent on blood concentration. As a result, time adjustment is needed to extrapolate from the occupa-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 tional LOAEL to a continuous exposure of 7, 30, or 180 d. Kozik did not report how many months or years the Russian workers in his study were exposed to EDC; therefore, the time adjustment is done on a per workweek basis. Due to the uncertainty on the number of hours worked per week in the 1940s and 1950s by Russian workers, the number of work hours is prudently assumed to be 40 h/w. 7-d, 30-d, and 180-d AC for GI symptoms = occupational LOAEL × 1/LOAEL factor × time adjustment = 15 ppm × 1/10 × (40 h/w)/(24 h/d × 7 d/w) = 15 ppm × 1/10 × 0.24 = 0.36 ppm. Without a better approach, the 1-h and 24-h ACs for GI symptoms are conservatively estimated to be the same as the 7-d AC of 0.36 ppm. Liver Toxicity According to the study of Spencer et al. (1951), a 1-h exposure of rats to EDC at 1200 ppm would not produce any liver injuries. So the 1-h AC is derived using 1200 ppm as the NOAEL. 1-h AC for liver toxicity = 1-h NOAEL × 1/species factor = 1200 ppm × 1/10 = 120 ppm. The 7-d, 30-d, and 180-d ACs for liver toxicity also are derived using the data of Spencer et al. (1951). The NOAEL for liver toxicity was determined to be 100 ppm in rats and guinea pigs exposed 7 h/d, 5 d/w, for 15 or 30 w. 180-d AC for liver toxicity = 30-w NOAEL × 1/species factor × time adjustment = 100 ppm × 1/10 × (7 h/d × 5 d/w × 30 w)/(24 h/d × 180 d) = 100 ppm × 1/10 × 0.24 = 2.4 ppm.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 30-d AC for liver toxicity = 15-w NOAEL × 1/species factor × time adjustment = 100 ppm × 1/10 × (7 h/d × 5 d/w × 15 w)/(24 h/d × 30 d) = 100 ppm × 1/10 × 0.73 = 7.3 ppm. For the 24-h and 7-d ACs, the conservative approach of not adjusting for the exposure time is taken. 24-h and 7-d ACs for liver toxicity = 15-w NOAEL × 1/species factor = 100 ppm × 1/10 = 10 ppm. Impaired Host Defense A 3-h exposure to EDC as low as 5 ppm was reported to increase the mortality of mice challenged with Streptococcus via inhalation (Sherwood et al., 1987). Repetitive exposures of mice to 2.5 ppm, 3 h/d, for 5 d failed to affect the host defense against bacterial challenges. Based on the SMAC subcommittee report (NRC, 1992), no interspecies extrapolation factor is needed to derive ACs for the prevention of impaired host defense against pulmonary bacterial infections. However, an uncertainty factor of 3 is used because microgravity is known to impair cell-mediated immunity in astronauts (Taylor, 1993). 1-h, 24-h, 7-d, 30-d, and 180-d ACs for host defense impairment = 5-h NOAEL × 1/microgravity factor = 2.5 ppm × 1/3 = 0.8 ppm. Carcinogenesis Although EDC has been shown to produce tumors only in a gavage study (Ward, 1980) and not in an inhalation study (Maltoni et al., 1980), the carcinogenicity findings were considered by NIOSH (1978) in recommending an exposure limit of 1 ppm and the Occupational

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Safety and Health Administration (OSHA) (U.S. Department of Labor, 1989) in promulgating a permissible exposure limit (PEL) of 1 ppm. EPA (1990) also derived an inhalation tumor risk from the data of the gavage study. It is important that the SMACs prevent unacceptable risks of tumor development. Even though there is uncertainty about the validity of data extrapolation from gavage and inhalation exposures, the tumor data from the gavage study are used to derive ACs. The 2-5 times difference between gavage and inhalation exposure in peak blood concentrations of EDC and DNA binding in several potential target organs (Reitz et al., 1982) is small compared with the 2 orders of magnitude difference between the statistical sensitivity of an animal bioassay and the tumor risk accepted by the National Aeronautics and Space Administration (NASA). In other words, a negative finding in an animal bioassay in which 50 rodents per group inhaled EDC does not guarantee that inhaled EDC would not produce a significant tumor response if 10,000 rodents were used. Because EDC given by gavage was carcinogenic in about 50 rodents and because the effective dose of EDC given by inhalation was only 2-5 times lower than that given by gavage (Ward, 1980; Reitz et al., 1982), there is a possibility that inhaled EDC is carcinogenic at a risk level of greater than 1 in 10,000. In contrast, Baertsch et al. (1991) advocated not using the gavage data to estimate the carcinogenic potency of continuous inhalation exposure at a low concentration. Their position was based on their comparison of the amount of EDC absorbed and the amount of DNA binding in the liver and lung in female F344 rats exposed to EDC at 80 ppm for 4 h (i.e., continuous low exposure) or at 4400 ppm for a few minutes (i.e., peak exposure). They showed that the amount of EDC metabolized, which was a measure of the amount of EDC absorbed, in the 12 h after the exposure was 3 times higher in the peak-exposure group than the low-exposure group. The amount of DNA binding in the liver was about 110 times higher in the peak-exposure group than in the low-exposure group. Similarly, the amounts of DNA binding in the lung differed by about 90 times in the two groups. Unfortunately, Baertsch et al. (1991) did not include a gavage-exposure group in their study, so it is difficult to disregard the carcinogenic potential of inhaled EDC on the basis of their data alone. The only conclusion from their study was that DNA binding of EDC depends on the concentration and time exposure profile.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Based on the gavage data of the National Cancer Institute (Ward, 1980) and assuming that equivalent amounts of EDC inhaled per day would produce the same tumor responses, EPA (1990), using a linearized multistage model, estimated that an airborne EDC concentration of 4 µg/m3 would yield an excess tumor risk of less than 1/10,000 in a continuous lifetime exposure of humans. Based on the approach of the NRC (1992) (assuming that the carcinogenesis of EDC is a three-step process, the earliest age of exposure is 30 y, and the average life span of an astronaut is 70 y), an adjustment factor of 3728, 871, or 146.7 is needed to compress the lifetime exposure at 4 µg/m3 into a much shorter continuous exposure of 7, 30, or 180 d, yielding the same tumor risk. Some genotoxic carcinogens are known to produce tumors even after a single exposure (Williams and Weisburger, 1985). EDC is genotoxic. Consequently, its carcinogenicity has to be considered in setting the 24-h SMAC. For a 24-h exposure, an adjustment factor of 26,082 is calculated by using the NRC (1992) approach. With these adjustment factors, the EDC exposure concentrations for 24 h, 7 d, 30 d, and 180 d can be calculated and are as follows: Exposure Duration Concentration with a 10-4 Tumor Risk 24 h 26 ppm 7 d 4 ppm 30 d 1 ppm 180 d 0.2 ppm Establishment of SMACs All the ACs derived above are tabulated to show the minimum AC for each exposure duration of interest. The 1-h, 24-h, 7-d, and 30-d SMACs are all set at 0.4 ppm on the basis of the ACs for protecting against GI symptoms. Based on an exposure concentration that will yield a tumor risk of 1/10,000, 0.2 ppm is selected to be the 180-d SMAC.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 TABLE 6-7 Acceptable Concentrations     Uncertainty Factors     To NOAEL     Microgravity Acceptable Concentrations, ppm Effect, Data, Reference Species Species Time 1 h 24 h 7 d 30 d 180 d CNS effects   LOAEL, 15 ppm, occupational exposure (Kozik, 1957) Human 10 - - - 1.5 1.5 1.5 1.5 1.5 GI symptoms   LOAEL, 15 ppm, occupa-tional exposure (Kozik, 1957) Human 10 - 160/40 - 0.4 0.4 0.4 0.4 0.4 Liver toxicity   NOAEL, 1200 ppm, 1 h (Spencer et al., 1951) Rat - 10 - - 120 - - - - NOAEL, 100 ppm, 7 h/d, 5d/w, 15 or 30 w (Spencer et al., 1951) Rat - 10 - - - 10 10 - - NOAEL, 100 ppm, 7 h/d, 5 d/w, 15 or 30 w (Spencer et al., 1951) Rat - 10 HR - - - - 2.4 7.3 Impaired host defense   NOAEL, 2.5 ppm, 3 h/d, 5 d (Sherwood et al., 1987) Mouse - - - 3 0.8 0.8 0.8 0.8 0.8 Carcinogenesis   Bioassay data (Ward, 1980) Rat, mouse - - NRCa - - 26 4 1 0.2 SMACs           0.4 0.4 0.4 0.4 0.2 a NRC (1992). —, Data not considered applicable to the exposure time; HR, Haber's rule.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 REFERENCES ACGIH. 1991. Ethylene dichloride. In Documentation of the Threshold Limit Values and Biological Exposure Indices, 6th Ed. American Conference of Governmental Industrial Hygienists, Cincinnati, Ohio. Anders, M. W., and J. C. Livesey. 1980. Metabolism of 1, 2-dihaloethanes. Pp. 331-341 in Banbury Report 5. Ethylene Dichloride: A Potential Health Risk? B. Ames, P Infante, and R. Reitz, eds. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory. Baertsch, A., W. K. Lutz, and C. Schlatter. 1991. Effect of inhalation exposure regimen on DNA binding potency of 1, 2-dichloroethane in the rat. Arch. Toxicol. 65:169-176. Bonnet, P., J.-M. Francin, D. Gradiski, G. Raoult, and D. Zissu. 1980. Determination of the median lethal concentration of the main chlorinated aliphatic hydrocarbons in the rat. Arch. Mal. Prof. Med. Trav. Secur. Soc. 41:317-321. Borisova, M. K. 1957. Experimental data for determination of the maximum allowable concentration of dichloroethane in the atmosphere. Gig. Sanit. 22:13-19. Borisova, M. K. 1960. Data for the determination of maximum permissible concentrations of ethylene dichloride in atmospheric air. Predel'no Dopustimye Konts. Atmos. Zagryaz. 4:61-74. Brass, K. 1949. Concerning a lethal dichloroethane poisoning. Dtsch. Med. Worchenschr. 74:553-554. Brem, H., A. B. Stein, and H. S. Rosenkranz. 1974. The mutagenicity and DNA-modifying effect of haloalkanes. Cancer Res. 34:2576-2579. Brondeau, M. T., P. Bonnet, J. P. Guenier, and J. de Geaurriz. 1983. Short-term inhalation test for evaluating industrial hepatotoxicants in rats. Toxicol. Lett. 19:139-146. Brzozowski, J., J. Czajka, T. Dutkiewicz, I. Kesy, and J. Wojcik. 1954. Work hygiene and the health condition of workers occupied in combating the Leptinotarsa decemlineata with HCN and dichloroethane. Med. Pr. 5:89-98. Byers, D. H. 1945. Chlorinated solvents—In common wartime use. Ind. Med. 12:440-443. Cetnarowicz, J. 1959. Experimental and clinical studies on effects of dichloroethane. Folia Med. Cracov. 1:169-192.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Cheever, K. L., J. M. Cholakis, A.M. El-Hawari, R. M. Kovatch, and E. K. Weisburger. 1990. Ethylene dichloride: The influence of disulfiram or ethanol on oncogenicity, metabolism, and DNA covalent binding in rats. Fundam. Appl. Toxicol. 14:243-261. D'Souza, R. W., W.R. Francis, and M. E. Andersen. 1988. Physiological model for tissue glutathione depletion and increased resynthesis after ethylene dichloride exposure. J. Pharmacol. Exp. Ther. 245: 563-568. EPA. 1990. 1, 2-Dichloroethane. In Integrated Risk Information System. Environmental Criteria and Assessment Office, U.S. Environmental Protection Agency, Cincinnati, Ohio. Finkel, A. J., A. Hamilton, and H. L. Hardy. 1983. Aromatic hydrocarbons. P. 246 in Hamilton and Hardy's Industrial Toxicology. Boston: John Wright PSG. Guerdjikoff, C. 1955. Acute and Chronic Occupational Intoxication by Symmetric Dichloroethane. Doctoral thesis. Faculty of Medicine, University of Geneva, Geneva, Switzerland. Hadengue, A., and R. Martin. 1953. A case of fatal poisoning by dichloroethane. Soc. Med. Leg. 33:247-249. Heppel, L. A., P. A. Neal, K. M. Endicott, and V. T. Porterfield. 1944. Toxicology of dichloroethane—I. Effect on the cornea. Arch. Ophthalmol. 32:391-394. Heppel, L. A., P. A. Neal, T. L. Perrin, K. M. Endicott, and V. T. Porterfield. 1946. The toxicology of 1, 2-dichloroethane (ethylene dichloride). J. Ind. Hyg. Toxicol. 28:113-120. Hofmann, H. T., H. Birnstiel, and P. Jobst. 1971. On the inhalation toxicity of 1,1- and 1,2-dichloroethane. Arch. Toxikol. 27:248-265. IARC. 1979. 1, 2-Dichloroethane. Pp. 429-448 in IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Vol. 20. Lyon, France: International Agency for Research on Cancer. IPCS. 1987. 1, 2-Dichloroethane. Environmental Health Criteria 62. International Programme on Chemical Safety. Geneva, Switzerland: World Health Organization. Jordie, A. 1944. Industrial poisonings due to symmetrical 1, 2-dichloroethane. Z. Unfallmed. Berufskr. 37:131-136. Kozik, I. 1957. Problems of occupational hygiene in the use of dichloroethane in the aviation industry. Gig. Tr. Prof. Zabol. 1: 32-38.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Rapoport, I. A. 1960. The reaction of genic proteins with 1,2-dichloroethane. Dokl. Biol. Sci. 134:745-747. Reitz, R. H., T. R. Fox, J. Y. Domoradzki, J. F. Quast, P. Langvardt, and P. G. Watanabe. 1980. Pharmacokinetics and macromolecular interactions of ethylene dichloride: Comparison of oral and inhalation exposures. Pp. 135-148 in Banbury Report 5. Ethylene Dichloride: A Potential Health Risk? B. Ames, P Infante, and R. Reitz, eds. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory. Reitz, R. H., T. R. Fox, J. C. Ramsey, J. F. Quast, P. Langvardt, and P. G. Watanabe. 1982. Pharmacokinetics and macromolecular interactions of ethylene dichloride in rats after inhalation or gavage. Toxicol. Appl. Pharmacol. 62:190-204. Rosenbaum, N. D. 1939. Use of dichloroethane in industry from the standpoint of occupational hygiene. Pp. 109-113 in Dichloroethane. Moscow, Russia. Rosenbaum, N. D. 1947. Ethylene dichloride as an industrial poison. Gig. Sanit. 12:17-21. Sherwood, R. L., W. O'Shea, P. T. Thomas, H. V. Ratajczak, C. Aranyi, and J. A. Graham. 1987. Effects of inhalation of ethylene dichloride on pulmonary defenses of mice and rats. Toxicol. Appl. Pharmacol. 91:491-496. Spencer, H. C., V. K. Rowe, E. M. Adams, D. D. McCollister, and D. D. Irish. 1951. Vapor toxicity of ethylene dichloride determined by experiments on laboratory animals. AMA Arch. Ind. Hyg. 4:482-493. Storer, R. D., and R. B. Conolly. 1985. An investigation of the role of microsomal oxidative metabolism in the in vivo genotoxicity of 1, 2-dichloroethane. Toxicol. Appl. Pharmacol. 77:36-46. Storer, R. D., N. M. Jackson, and R. B. Conolly. 1984. In vivo genotoxicity and acute hepatotoxicity of 1, 2-dichloroethane in mice: Comparison of oral, intraperitoneal, and inhalation routes of exposure. Cancer Res. 44:4267-4271. Taylor, G. R. 1993. Immune changes during short-duration missions. J. Leukocyte Biol. 54:202-208. Troisi, F. M. and D. Cavallazzi. 1961. A fatal case of poisoning from inhalation of dichloroethane vapours. Med. Lavoro 52:612-618. U.S. Department of Labor. 1995. Air Contaminants—Permissible Ex-

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