Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 2 (2002) / Chapter Skim
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Appendix 4: 1,1-Dichloro-1-Fluoroethane (HCFC-141B)
Appendix 4: 1,1-Dichloro-1-Fluoroethane (HCFC-141B)
Pages 166-210
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From page 166... ...
Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels.
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From page 167... ...
Some experimental exposure durations in both human and animal studies were generally Tong, 4 to 6 h, which lends confidence to using the same value for all exposure durations. The AEGL-l value was based on the observation that exercising healthy human subjects could tolerate exposure to concentrations of 500 or ~ ,000 ppm for 4 h with no adverse effects on lung function, respiratory symptoms, sensory irritation, or cardiac symptoms (Utell et al.
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From page 168... ...
for that of the human, an interspecies UF of 1 was applied. The cardiac sensitization test is highly sensitive as the response to exogenous epinephrine is optimized, so a single intraspecies UF of 3 was applied.
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were located. Animal studies addressed both acute and chronic exposure durations as well as neurotoxicity, genotoxicity, carcinogenicity, and cardiac sensitization.
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bResponse to challenge dose of ep~nephrine (cardiac sensitization test)
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1, 1 -D/CHLORO- 1 -FLUOROETHANE 1 7 1 TABLE 4-2 Chemical and Physical Data Parameter Value Reference Synonyms HCFC-141b CHEMID 1998 1,1 -dichloro- 1 -fluoroethane Freon 141 CFC 141, 141b Refrigerant 141b Molecular formula C2H3Cl2F HSDB 2000 Molecular weight 116.95 HSDB 2000 CAS reg~shy number 1717-00-6 HSDB 2000 Physical state Liquid ECETOC 1994 Color Colorless ECETOC 1994 Solubility In water Approximately 4 g/L ECETOC 1994 Vapor pressure 412mmHg(~25°C HSDB2000 Density, g/cm3 at 20°C 1.24 ECETOC 1994 Melting point - 103.5 ° C ECETOC1994 Boiling point 32°C ECETOC 1994 Odor Weak ethereal ECETOC 1994 Conversion factors 1 ppm= 4.85 mg/m3 ECETOC 1994 1 mg/m3 = 0.206 ppm 2.2. Nonlethal Toxicity The air odor threshold in healthy subj ects is approximately 25 0 ppm (Utell et al.
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From page 172... ...
The chamber concentration was monitored with an infrared analyzer calibrated with a gas chromatograph; the gas chromatograph was calibrated with known amounts of HCFC-141b through a closed-Ioop system. Two volunteers were exposed at one time for an exposure time of 4 h; the exposure included three 20-min exercise periods.
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Exposure concentrations were within 3°/O of targeted concentrations. Clinical chemistry and hematology findings did not differ pre- and postexposure at any concentration.
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Summary icity in humans was located. A single study with eight human volunteers exposed at 0, 250, 500, or 1,000 ppm for 4 or 6 h addressed clinical chemistry and subjective symptoms as well as neurotoxicity, nasal inflammation, respiratory functions, and metabolism (Utell et al.
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Animals were observed for 14 days Ale, and clinical signs, body weights, and food and water consumption were recorded. Twenty-four hour urine samples were collected, and blood samples were collected 48 h postexposure.
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3.2.1. Nonhuman Primates During cardiac sensitization tests, cynomolgus monkeys were exposed at 0, 3,000 (one monkey)
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From page 177... ...
and 11,000 increase in 1995 serum phosphate, Rat >30,000 Rat 2,000-30,000 3 h Rat 29,958 4 h Rat 45,781 42,800 6 h 6h slight body weight loss Prenarcotic signs Hardy et al. 1989b No serum Loizou et al.
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3.2.2. Dogs During cardiac sensitization tests, groups of two purebred male beagle dogs were exposed to concentrations at 0, 2,600, 5,200, ~ 0,000, or 2 ~ ,600 ppm (Mullin 1977)
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~ . l, no deaths occurred in mate and female rats exposed at 29,958 or 45,781 ppm for 4 h or in mate rats exposed at 3 i,730 or 42,800 ppm for 6 h.
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After the 90-d exposure, increased serum cholesterol was observed in female rats exposed at 20,000 ppm, and decreased absolute organ weights and increased relative organ weights (brain, heart, kidneys, lung, liver) were observed in both genders exposed at 20,000 ppm for 90 d.
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Food and water consumption and body weights were monitored. At sacrifice on day 20, maternal organs were examined and uteri were scored for live fetuses, embryonic deaths, implants, corpora lutea, pro- and postimplantation losses, litter weight, and mean fetal weight.
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and an F2 generation was produced. For the Fo generation, body weights, food and water consumption, mating performance, deaths, number of young born, litter Toss, and rearing young to wean
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Sexual maturation was slightly retarded in male pups, which may have been caused by the slightly Tower body weight gain. Adults rats exposed at 20,000 ppm showed an increase in water consumption, slight increase in food consumption, and decrease in body weight.
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At ~ 0,000 ppm, no dogs responded to epinephrine challenge; five of six dogs exposed at 20,000 ppm also showed no response, and the sixth responded with multifocal ventricular ectopic activity followed by fatal ventricular fibrillation. Because the exogenous epinephrine dose used in these studies results in a circulating epinephrine concentration that is up to ten times the physiological level in stressed animals (Chengelis 1997)
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Dog 9,000 10 min Marked cardiac response Hardy et (1/2)
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In vitro, chromosomal aberration assays were positive with Chinese hamster ovary cells but negative with human lymphocytes. In other tests for chromosomal aberrations in Chinese hamster ovary cells, one study showed an increase in gaps but not aberrations when HCFC-14Ib was incorporated as the liquid into the culture medium (Wilmer and De Vogel 1988~; the other study gave positive results using vapor concentrations up to 35% (Bootman and Hodson-Walker 1988~.
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Lethargy, tremors, and body weight loss were observed in mice exposed at 34,000 ppm for 6 h. Exposure of rats to concentrations at 30,000 ppm for 3 h and 11,000 ppm for 6 h resulted in minor liver enzyme and serum biochemical changes, respectively.
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1998~. Although results were mixed in standard assays for genotoxicity (with positive results for chromosomal aberrations only in Chinese hamster ovary cells)
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For all exposure concentrations, the blood concentrations at 55 min were within 80% of the concentrations at 225 min. For volunteers that underwent neurobehavioral testing, circulating HCFC-14Ib concentrations after 6 h at 500 and 1,000 ppm were 1.56 and 3.33,ug/g, respectively.
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From page 190... ...
Although other species have been tested, the dog is the species of choice for the mammalian cardiac sensitization mode} as they serve as a reliable cardiovascular model for humans, possess a large heart size, and can be trained to calmly accept the experimental procedures (Aviado 1994; NRC 1996~. The cardiac sensitization test has been evaluated by NRC (1996)
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From page 191... ...
Although this test is useful for identifying compounds capable of cardiac sensitization, the capacity to establish an effect level is limited. The test is very conservative as the levels of epinephrine administered represent an approximate 10-fold excess over blood concentrations that would be achieved endogenously in dogs (Chengelis 1997)
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From page 192... ...
Only one exposure duration involving lethality was available for the mouse, a mean 30-min I,C50 of approximately 90,000 ppm. Time scaling may not be applicable to halogenated hydrocarbons as blood concentrations of these chemicals do not increase as exposure time is increased beyond 5-10 min (Bakshi et al.
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From page 193... ...
5.2. Summary of Animal Data Relevant to AEGL-1 In the studies that did not involve special procedures such as the cardiac sensitization test, exposures to concentrations up to 30,000 ppm for up to 6 h did not induce clinical signs in mice (VIachos 1988~.
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Only nonsignificant liver and serum biochemical changes occurred in rats exposed at 30,000 ppm for 3 h or ~ 1,000 ppm for 6 h (Table 4-4~. Adjustment of the 6-h, 1 1 ,000-ppm concentration by interspecies and intraspecies UFs of 3 each, for a total of 10, results in essentially the same concentration (1,100 ppm)
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, the end point of cardiac sensitization is relevant to human exposures because humans exposed at high concentrations of some halocarbons can develop cardiac arrhythmias. The supersensitivity of the animal model might argue for application of no uncertainty factors (UFs)
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7.3. Derivation ofAEGL-3 The 9,000-ppm concentration, which appears to be the threshold for death in the dog cardiac sensitization test, was chosen as the basis for the AEGL-3 values.
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Because the cardiac sensitization test is highly sensitive as the response to epinephrine is optimized, a single intraspecies UP of 3 was applied. Cardiac sensitization is concentration dependent; duration of exposure failed to influence the circulating concentration at which this effect occurred.
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Animal studies addressed both acute and chronic exposure durations as well as neurotoxicity, genotoxicity, carcinogenicity, and cardiac sensitiza
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Except for the short-term cardiac sensitization test, most of the study exposure durations were for relatively long periods of time, 4 and 6 h. Using the values derived from longer exposure durations for the shorter durations results in conservative values.
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. Report ALS 1/901565, January 9, 1992, Huntingdon Research Centre Ltd., Huntingdon, Cambridgeshire, England.
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HRC Report ALS 57/942811, Huntingdon Research Centre Ltd., Huntingdon, Cambridgeshire, England. Hardy, C.J., P.C.
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2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals.
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1988. Chromosome analysis of Chinese hamster ovary cells treated in vitro with FC141b.
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Time scaling: Not applied; inadequate data. Based on the rapidity with which blood concentrations approached equilibrium in human subjects, the similarity of lethality values in rats exposed for 4 or 6 h, and the fact that cardiac sensitization, the most sensitive end point in studies with halocarbons, is a concentrationdependent threshold effect, the 6-h value was used for all exposure durations.
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Exercise takes into consideration some of the stress that humans might experience under emergency conditions. Animal studies addressed both acute and chronic exposure durations as well as neurotoxicity, genotoxicity, carcinogenicity, and cardiac sensitization.
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From page 207... ...
; epinephrine dose at 8,ug/kg. The cardiac sensitization test is based on the observation that some halocarbons make the mammalian heart abnormally sensitive to epinephrine, resulting in ectopic beats and/or ventricular fibrillation, which may result in death.
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than that based on cardiac sensitization. Additional animal studies addressed neurotoxicity, reproductive and developmental toxicity, and carcinogenicity.
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. The cardiac sensitization test is based on the observation that some halocarbons make the mammalian heart abnormally sensitive to epinephrine, resulting in ectopic beats and/or ventricular f~brillation, which may result in death.
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From page 210... ...
Therefore, the same concentration was used for all exposure durations. Data adequacy: Humans exposed to halocarbons may develop cardiac arrhythmias.
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