Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants Volume 3 (1996) / Chapter Skim
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B6: 1,2-Dichloroethane
B6: 1,2-Dichloroethane
Pages 135-170
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B6 ~ 2-Dichioroethane King Lit Wong9 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-dichIoroethane (EDC)
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Another pathway involves direct conjugation with glutathione to form S-~2-chIoroethyi) -glutathione, which could either form glutathione episulfonium ion or react with glutathione to form ethane and hydrogen chloride.
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o g o cn ~ ~ ID o c, c]
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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~.
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(1946) compared the sensitivities of rats, rabbits, guinea pigs, cats, and dogs to acute EDC exposures.
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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.
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stated that repeated exposures to EDC at 75-125 ppm could result in acute poisonings with the development of dizziness, headache, weakness, mucosai irritation, nausea, and vomiting. TABLE 6-2 EDC Exposure Conditions Without Adverse Effects Exposure Concentration, ppm 12,000 3000 1000 300 200 Exposure Duration, h 0.1 0.3 1.5 3.0 7.0
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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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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. Subchron~c and Chronic Exposures Miscellaneous Symptoms The symptoms of subchronic EDC intoxication resemble those of nonfatal acute EDC poisoning, consisting mainly of CNS and G1: symptoms.
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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.
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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, Symptoms Produced ppm in Workers Reference Slightly > 100 CNS and GI symptoms Byers, 1945 70 Less severe than Byers, 1945 <25 15 > 100 ppm CNS symptoms CNS and GI symptoms Kozil`, 1957 and signs Rosenbaum, 1939
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Therefore, the TWA exposure concentration of 15 ppm found to cause GT disorders and CNS impairment by Kozik (1957) is selected as the LOAEL for GT and CNS symptoms.
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(1946) , who exposed rats and guinea pigs to EDC at 0, 100, 200, or 400 ppm, 7 in/d, 5 d/w, for 2-8 w, subchronic EDC exposures at 400 ppm definitely produced fatty liver in rats and guinea pigs.
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The high-dose female mice received 250 mg/kg per exposure day for ~ w, 400 mg/kg per exposure day for 3 w, and 300 mg/kg per exposure day for 67 w, followed by 12 w of no exposure. in male rats, EDC produced signif~cant increases in squamous cell carcinoma of the forestomach and hemangiosarcomas of the circulatory system; in female rats EDC exposure significantly increased the incidence of mammary adenocarcinoma.
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rats after EDC was given by Savage at 150 mg/kg was about 5 times higher than that observed when EDC was given by inhalation at 150 ppm for 6 h. Moreover, the amounts of DNA binding in the liver, spleen, kidney, and stomach after Savage were about double or triple those after a 6-h inhalation exposure.
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There were no adverse effects on mean litter size, fetal body weight, fetal crown-rump length, and incidence of resorptions, indicating that EDC is not toxic to the embryo and fetus. A similar exposure of pregnant rats to EDC at 300 ppm killed two-thirds of the rats, so the teratogenicity of that exposure concentration cannot be evaluated.
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The derivation involves consideration of the important toxic end points: CNS effects, G} symptoms, liver toxicity, impaired host resistance, and carcinogenesis. The acute lethality end point is not used, because toxic end points, such as CNS and GI symptoms and internal injuries, should be more sensi
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(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~.
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(1951~. The NOAEL for liver toxicity was determined to be 100 ppm in rats and guinea pigs exposed 7 in/d, 5 d/w,fori5Or30w.
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24-h and 7-d ACs for liver toxicity 15-w NOAEL x I/species factor 100 ppm x 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~.
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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)
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approach. With these adjustment factors, the EDC exposure concentrations for 24 h, 7 d, 30 d, and IS0 d can be calculated and are as follows: Exposure Duration 24 h 7 d 30 d 180 d Concentration with a lo-4 Tumor Risk 26 ppm 4 ppm 1 ppm 0.2 ppm Establishment of SMACs All the ACs derived above are tabulated to show the minimum AC for each exposure duration of interest.
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1991. Effect of inhalation exposure regimen on DNA binding potency of I,2-dichIoroethane in the rat.
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for tissue glutathione depletion and increased resynthesis after ethylene dichloride exposure.
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Pp. 87-89 in Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants.
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1980. Pharmacokinetics and macromolecular interactions of ethylene dichloride: Comparison of oral and inhalation exposures.
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Reitz, eds. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory.
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