4
1,1-Dichloro-1-fluoroethane (HCFC-141b)1

Acute Exposure Guideline Levels

SUMMARY

Hydrochlorofluorocarbon-141b, or 1,1-dichloro-1-fluoroethane (HCFC141b), has been developed as a replacement for fully halogenated chlorofluorocarbons because its residence time in the atmosphere is shorter, and its ozone depleting potential is lower than that of presently used chlorofluoro-

1  

This document was prepared by the AEGL Development Team comprising Sylvia Talmage (Oak Ridge National Laboratory) and members of the National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances including George Rusch (Chemical Manager) and Robert Benson and Kenneth Still (Chemical Reviewers). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993; NRC 2001).



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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 4 1,1-Dichloro-1-fluoroethane (HCFC-141b)1 Acute Exposure Guideline Levels SUMMARY Hydrochlorofluorocarbon-141b, or 1,1-dichloro-1-fluoroethane (HCFC141b), has been developed as a replacement for fully halogenated chlorofluorocarbons because its residence time in the atmosphere is shorter, and its ozone depleting potential is lower than that of presently used chlorofluoro- 1   This document was prepared by the AEGL Development Team comprising Sylvia Talmage (Oak Ridge National Laboratory) and members of the National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances including George Rusch (Chemical Manager) and Robert Benson and Kenneth Still (Chemical Reviewers). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993; NRC 2001).

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 carbons. HCFC-141b is used in the production of rigid polyurethane and polyisocyanurate or phenolic insulation foams for residential and commercial buildings. It may also be used as a solvent in electronic and other precision cleaning applications. HCFC-141b is of low inhalation toxicity. Uptake and elimination are rapid, and most of the absorbed dose is excreted unchanged in the exhaled air. Its effects have been studied with human subjects and several animal species, including the monkey, dog, rat, mouse, and rabbit. In addition, studies addressing repeated and chronic exposures, genotoxicity, carcinogenicity, neurotoxicity, and cardiac sensitization were also available. At high concentrations, halogenated hydrocarbons may produce cardiac arrhythmias; this sensitive end point was considered in the development of AEGL values. The air odor threshold in healthy subjects is approximately 250 parts per million (ppm) (Utell et al. 1997). The ethereal odor is not unpleasant. Adequate data were available for development of the three AEGL classifications. Inadequate data were available for determination of the relationship between concentration and exposure duration for a fixed effect. However, based on the rapidity with which blood concentrations in humans approached equilibrium, the similarity in lethality values in rats exposed for 4 or 6 hours (h), and the fact that the cardiac sensitization effect is based on a concentration threshold rather than exposure duration, a single AEGL value was used across all time periods for each AEGL classification. Some experimental exposure durations in both human and animal studies were generally long, 4 to 6 h, which lends confidence to using the same value for all exposure durations. The AEGL-1 value was based on the observation that exercising healthy human subjects could tolerate exposure to concentrations of 500 or 1,000 ppm for 4 h with no adverse effects on lung function, respiratory symptoms, sensory irritation, or cardiac symptoms (Utell et al. 1997). The exercise, which tripled the subjects’ minute ventilation, simulates an emergency situation and accelerates pulmonary uptake. Results of the exposure of two subjects for an additional 2 h to the 500-ppm concentration and the exposure of one subject to the 1,000-ppm concentration for an additional 2 h failed to elicit any clear alterations in neurobehavioral parameters. The 4- or 6-h 1,000-ppm concentration is a NOAEL in exercising individuals, there were no indications of response differences among tested subjects, and animal studies indicate that adverse effects occur only at considerably higher concentrations, so the 1,000-ppm value was adjusted by an uncertainty factor (UF) of 1. The intraspecies UF of 1 is supported by the lack of adverse effects in patients with severe

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 chronic obstructive pulmonary disease (COPD) or asthma who were treated with metered-dose inhalers containing chemically similar chlorofluorocarbon propellants. Because blood concentrations of HCFC-141b rapidly achieved a plateau and did not greatly increase after 55 minutes (min) of exposure, the value of 1,000 ppm was applied to all AEGL-1 time periods. An AEGL-1 of 1,000 ppm is supported by an acute animal study in which no adverse effects were observed in rats exposed at 11,000 ppm for 6 h (Brock et al. 1995). Adjustment of the 6-h 11,000-ppm concentration by interspecies and intraspecies UFs of 3 each, for a total UF of 10, results in essentially the same concentration (1,100 ppm) as that derived from the human data. Furthermore, selection of a subchronic NOAEL of 8,000 ppm in rats (Brock et al. 1995) results in a similar value given the differences in duration of exposure and selection of an appropriate UF. The AEGL-2 value was based on the lowest concentration that caused cardiac sensitization in dogs administered exogenous epinephrine and exposed to HCFC-141b at concentrations of 2,600, 5,200, 10,000, or 21,600 ppm for 10 min (Mullin 1977). This value of 5,200 ppm is less than the lowest concentrations that caused death by cardiac arrest (10,000 to 20,000 ppm) (Hardy et al. 1989a). Because the dog heart is a good model 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 an intraspecies UF of 3 was applied. Cardiac sensitization is concentration dependent; duration of exposure does not influence the concentration at which this effect occurs. Because the peak circulating HCFC-141b concentration is the determining factor in cardiac sensitization, and exposure duration is of lesser import, the resulting value of 1,700 ppm was assigned to all time periods. The 1,700-ppm concentration is supported by animal studies in which no effects other than prenarcotic signs and/or narcosis were observed in rats and mice exposed at approximately 30,000 ppm for 4 or 6 h (Vlachos 1988; Hardy et al. 1989b; Brock et al. 1995). Adjustment of the 30,000 ppm concentration by interspecies and intraspecies UFs of 3 each, for a total UF of 10, results in a higher concentration (3,000 ppm) than that derived from the cardiac sensitization data. The AEGL-3 value was based on a concentration of 9,000 ppm, the highest value that resulted in mild to marked cardiac responses but did not cause death in a cardiac-sensitization study with the dog (Hardy et al. 1989a). Because the dog heart is a reliable model 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. Cardiac sensitization is concentration dependent; duration

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 of exposure does not influence the concentration at which this effect occurs. Because the peak circulating HCFC-141b concentration is the determining factor in cardiac sensitization, and exposure duration is of lesser import, the resulting value of 3,000 ppm was assigned to all time periods. The 3,000 ppm concentration is supported by animal studies in which no deaths occurred in rats exposed at 42,800 ppm for 6 h or 45,781 ppm for 4 h (Brock et al. 1995). Adjustment of the 45,781 ppm concentration by interspecies and intraspecies UFs of 3 each, for a total UF of 10, results in a higher concentration (4,600 ppm) than that derived from the cardiac sensitization data. AEGL values are summarized in Table 4–1. 1. INTRODUCTION Hydrochlorofluorocarbons (HCFCs) are replacing chlorofluorocarbons (CFCs) in industry because the substitution of hydrogen for halogen in methane and ethane reduces residence time in the stratosphere compared with completely halogenated compounds and causes less depletion of ozone (Aviado 1994). HCFC-141b has been developed as a replacement for CFCs (Brock et al. 1995). In particular, HCFC-141b is a replacement for CFC-11 (trichlorofluoromethane) and is used in the production of rigid polyurethane and polyisocyanurate or phenolic insulating foams (Millischer et al. 1995). These foams are used in insulation for commercial buildings, in insulation foam boards for residences, in residential wall insulation, or in foam fill for refrigerators. HCFC-141b may also be employed as a solvent replacement for CFC-113 in the removal of soldering flux from printed circuit boards, in precision cleaning of intricate parts, and, in combination with a surfactant, in the removal of trace water from intricate parts. HCFC-141b is produced commercially by the hydrofluorination of 1,1,1-trichloroethane or 1,1-dichloroethylene (ECETOC 1994). It is manufactured by three companies in the United States. In 1992, total world production was 15,000 tons; production was expected to increase to 100,000 tons by 1994 and then be phased out by 2003 (ECETOC 1994). HCFC-141b is a colorless, volatile liquid with a weak, ethereal odor. The vapor is heavier than air and can displace air in confined spaces. Additional chemical and physical properties are listed in Table 4–2. Experimental studies with human subjects and several mammalian species (monkey, dog, rat, mouse, and rabbit) were located. Animal studies addressed both acute and chronic exposure durations as well as neurotoxicity, genotoxicity, carcinogenicity, and cardiac sensitization.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 TABLE 4–1 Summary OF AEGL Values for HCFC-141b (ppm [mg/m3]) Classification 10 min 30 min 1 h 4 h 8 h End Point (Reference) AEGL-1a 1,000 1,000 1,000 1,000 1,000 No effect in humans (Utell et al. 1997) (Nondisabling) (4,850) (4,850) (4,850) (4,850) (4,850) AEGL-2 1,700 1,700 1,700 1,700 1,700 Threshold for cardiac arrhythmia in the dogb (Mullin 1977) (Disabling) (8,245) (8,245) (8,245) (8,245) (8,245) AEGL-3 3,000 3,000 3,000 3,000 3,000 Threshold for severe cardiac response in the dogb (Hardy et al. 1989a) (Lethal) (14,550) (14,550) (14,550) (14,550) (14,550) aThe ethereal odor of HCFC-141b maybe noticeable to some individuals at the 1,000ppm concentration. bResponse to challenge dose of epinephrine (cardiac sensitization test). 2. HUMAN TOXICITY DATA 2.1. Acute Lethality Deaths from exposure to HCFCs have occurred during refrigeration repair and the use of HCFCs as solvents (Aviado 1994). Information on one fatality attributable to the use of HCFC-141b was located. A 40-year-old man was found dead inside a degreasing tank in which pure HCFC-141b was used as the degreasing solvent (Astier and Paraire 1997). The tank was free of liquid at the time. The worker wore no protective clothing. Postmortem examination revealed violaceous coloration and edema of the face. Concentrations of HCFC-141b in tissues and organs were as follows: blood, 14 mg/L; and liver and heart, 29 μg/g. Concentrations in the lungs and spleen were said to be less than those in the blood (no specific values given).

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 TABLE 4–2 Chemical and Physical Data Parameter Value Reference Synonyms HCFC-141b 1,1-dichloro-1-fluoroethane Freon 141 CFC 141, 141b Refrigerant 141b CHEMID 1998 Molecular formula C2H3Cl2F HSDB 2000 Molecular weight 116.95 HSDB 2000 CAS registry 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 412 mm Hg @25°C HSDB 2000 Density, g/cm3 at 20°C 1.24 ECETOC 1994 Melting point −103.5°C ECETOC 1994 Boiling point 32°C ECETOC 1994 Odor Weak ethereal ECETOC 1994 Conversion factors 1 ppm=4.85 mg/m3 1 mg/m3=0.206 ppm ECETOC 1994 2.2. Nonlethal Toxicity The air odor threshold in healthy subjects is approximately 250 ppm (Utell et al. 1997). During a clinical study with exposures at 250, 500, or 1,000 ppm, subjects were asked to record their responses to any perceived odor. At 250, 500, and 1,000 ppm, one, two, and three of eight subjects, respectively, noticed the odor. A subject that responded at 250 and 500 ppm did not notice the odor at 1,000 ppm. In all cases, the odor was rated as mild, which was defined as noticeable but not annoying. 2.2.1. Occupational Exposures According to information compiled by the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) (1994), typical 8-h

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 time-weighted average (TWA) values for different occupations in an HCFC-141b production plant ranged from 1 to 70 ppm. In a research laboratory in which machines using dichlorofluoroethane (isomer not described) as a solvent were operating, grab sample results ranged from 10 to 100 ppm; 8-h TWA values for technicians working in the machine room and a contiguous room were approximately 2 to 9 ppm. 2.2.2. Experimental Studies Eight healthy volunteers (six males and two females, ages 22–30 years) were exposed to concentrations of HCFC-141b at 0 (purified air), 250, 500, or 1,000 ppm in a 43 m3 chamber located at the University of Rochester Medical Center’s Clinical Research Center (Utell et al. 1997).2 Liquid HCFC-141b, 99.88% pure, was metered from a reservoir into a heat-regulated delivery tube where it was vaporized to 50 L/min of diluting air. The vapor was then mixed with 10 m3/min air intake for the exposure chamber and delivered to the chamber through five ceiling defusers. 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-loop system. Two volunteers were exposed at one time for an exposure time of 4 h; the exposure included three 20-min exercise periods. The exposure to air was randomized among the three concentrations, but exposure concentrations were in sequence from lowest to highest. Exposures were separated by at least 1 week (wk). Prior to the first exposure, the subjects underwent a pre-exposure screening, which consisted of a cardiac and respiratory history, physical examination, a baseline electrocardiogram (EKG), blood chemistries with complete blood count, and baseline spirometry. On the day of exposure, subjects filled out a questionnaire involving 17 subjective symptoms. In addition, the following clinical chemistries were obtained: liver function (total bilirubin, lactate dehydrogenase activity, aspartate aminotransferase activity, creatinine), blood parameters (urea nitrogen, total protein, albumin, electrolytes, glucose), complete blood count, spirometry (forced vital capacity [FVC], forced expiratory volume in 1 second [s] [FEV1], and forced expira- 2   This study was reviewed and approved by the Research Subjects Review Board of the University of Rochester. Informed consent was obtained from all subjects.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 tory flow rate at 25% and 75% capacity [FEF25/75]), and EKG (rhythm strips). Blood and exhaled air were collected before exposure, after each exercise period, and immediately postexposure for HCFC-141b concentrations. Nasal lavage (to obtain inflammatory response information) was performed pre-exposure, immediately following exposure, and 24 h after each exposure. The exercise period consisted of 20 min on a bicycle ergometer at a rate sufficient to triple the subjects’ minute ventilation; there were three 20-min exercise periods during each exposure. Two of the subjects were exposed for an additional 2 h during which time they underwent computerized neurobehavioral testing. Exposure concentrations were within 3% of targeted concentrations. Clinical chemistry and hematology findings did not differ pre- and postexposure at any concentration. Baseline EKGs were normal and responded appropriately during exercise. There were no differences between air and HCFC-141b exposures. FEV1 and FEV1/FVC did not change significantly after exposure. Increases in FVC of 2.5% from baseline immediately after the 500 ppm exposure and 4.4% from baseline 24 h after the 1,000 ppm exposure are considered clinically insignificant. The number of polymorphonuclear neutrophils in nasal lavage fluid was greater pre-exposure than postexposure, which may have been a result of pre-exposure washout. There was no evidence of nasal inflammation. Subjective symptoms such as headache appeared unrelated to exposures. No symptoms consistent with respiratory affects were reported during exposures. Concentrations of metabolites in blood, urine, and expired air are discussed in Section 4.1 (Disposition and Metabolism Considerations). Results of neurobehavioral tests are discussed below. 2.3. Neurotoxicity In the study with human volunteers (Section 2.2.2) (Utell et al. 1997), two of the subjects were exposed at 0 or 500 ppm for 6 h, and computerized neurobehavioral testing was performed during the last 2 h. One subject also completed neurobehavioral testing during the last 2 h of the 6-h exposure to 1,000 ppm. The neurobehavioral testing was composed of two parts. The first part was a work simulation test that involved simultaneous monitoring of memory, calculation, and visual and auditory activities; the second part involved response time during a cognitive test of arithmetic processing, procedural memory, memory of letter sequence, and visual-spatial processing.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 In the first part, scores were generally higher (i.e., performance improved) for one subject at 500 ppm compared with 0 ppm, and there was a slightly higher value at 1,000 ppm compared with 500 ppm. Scores were generally lower for the other subject. Changes in scores were minimal for the response times during the cognitive tests. Subjective mood descriptions prior to and after the test indicated a “decreased activity level” but no changes related to fatigue, happiness, depression, anger, or fear. 2.4. Developmental and Reproductive Toxicity No studies were located regarding reproductive or developmental effects in humans after inhalation exposure to HCFC-141b. 2.5. Genotoxicity No information on genotoxicity in humans was located. In vitro, chromosome aberration assays were negative with human lymphocytes at vapor concentrations of 1.25% to 35% v/v; incubation times ranged from 3 to 24 h (Millischer et al. 1995). 2.6. Carcinogenicity No information on carcinogenicity in humans was located. 2.7. Summary 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. 1997). There were no significant differences in respiratory and nonrespiratory symptoms and no changes in lung function or nasal lavage parameters before and after exposure. A battery of neurotoxicity tests, undertaken by two of the subjects, failed to show clear pre- and postexposure differences; however, there were too few subjects to make rigorous comparisons. No information on developmental and reproductive toxicity, chronic exposures, or carcinogenicity in humans was located.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality Acute lethality data are summarized in Table 4–3. 3.1.1. Rats Groups of five male and five female Sprague-Dawley rats were exposed (whole-body) to concentrations at 0 (air), 29,958, 45,781, 68,143, or 77,215 ppm for 4 h in a 115 L chamber (de Rooij 1989; Brock et al. 1995). Atmospheres were generated by heating the HCFC-141 b and diluting the vapor with clean air. The pressure of the supply generator provided a flow rate of 25 L/min. Several samples were collected during each exposure, and the concentrations were measured by gas chromatography and flame ionization. Animals were observed for 14 days (d), 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. At death or termination of the study, lungs, liver, and kidneys were examined microscopically. Mortalities for males were 0/5, 0/5, 4/5, and 5/5 for the respective exposures; respective mortalities for females were 0/5, 0/5, 1/5, and 5/5 (time of death was not provided). Calculated LC50 values for male and female rats were 58,931 and 64,991 ppm, respectively; the combined LC50 was 61,647 ppm. Reduced motor activity, shallow breathing with rapid respiration, and anesthesia were observed at concentrations greater than 29,000 ppm. Above 50,000 ppm, tremors, incoordination, and convulsions were noted in some animals. Clinical signs and respiratory changes in survivors resolved by the next day. Lung-to-body weight ratios were increased in the highest dose group. No treatment-related microscopic changes were observed. Groups of six male Chr-CD rats were exposed to concentrations at 31,700, 42,800, 50,200, 55,270, 72,400 or 95,950 ppm for 6 h in 20 L chambers (Brock et al. 1995). Atmospheres were generated as above with continuous monitoring by gas chromatography. Clinical signs and body weights were recorded during a 14-d observation period; no histological examinations were performed. Deaths were observed at concentrations at 50,200 ppm and above. Mortalities at the 31,700-, 42,800-, 50,200-, 55,270-, 72,400-, and 95,950-ppm concentrations were 0/6, 0/6, 1/6, 2/6, 6/6 and 6/6. The calculated LC50 was 56,700 ppm (time of death was not provided). Clinical signs were similar to those in the above study.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 TABLE 4–3 Summary of Acute Lethal Inhalation Data in Laboratory Animals Species Concentration (ppm) Exposure Time Effecta Reference Rat de Rooij 1989; Brock et al. 1995 male 58,931 4 h LC50 female 64,991 4 h LC50 combined 61,647 4 h LC50 Rat (male) 56,700 6 h LC50 Brock et al. 1995 Mouse 100,000 30 min LC50 Davies et al. 1976 Mouse 80,000 30 min 60% mortality Vlachos 1988 aObserved 14 d postexposure. Sources: de Rooij 1989; Brock et al. 1995. 3.1.2. Mice Davies et al. (1976) reported unpublished data on concentrations resulting in lethality and narcosis and found a 30-min LC50 of 100,000 ppm in Alderley Park mice. The time of death was not stated. In a second study, groups of five male and five female Crl:CD-1(ICR)BR mice were exposed to concentrations at 9,700, 20,000, 30,000, 40,000, or 80,000 ppm for 6 h during preliminary testing (Vlachos 1988). A concentration of 80,000 ppm resulted in 60% mortality (3/5 males and 3/5 females) within 30 min. According to de Rooij (1989), clinical signs were consistent with those of an anesthetic agent. The proximate cause of death was deep anesthesia. 3.2. Nonlethal Toxicity Results of acute exposures are summarized in Table 4–4. These studies and studies involving longer-term exposures are discussed below. 3.2.1. Nonhuman Primates During cardiac sensitization tests, cynomolgus monkeys were exposed at 0, 3,000 (one monkey), 5,000 (two monkeys), or 10,000 ppm (two monkeys)

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 9. REFERENCES AIHA (American Industrial Hygiene Association). 1998. Environmental Exposure Level Guide: 1,1-dichloro-1-fluoroethane. Fairfax, VA. Alexander, D.J. 1995. Safety of propellants. J. Aerosol Med. 8 (Suppl. 1):S29–S33. Aster, A. and F.Paraire. 1997. Fatal intoxication with 1,1-dichloro-1-fluoroethane. N. Engl. J. Med. 337:940. Aviado, D.M. 1994. Fluorine-containing organic compounds. In Patty’s Industrial Hygiene and Toxicology, Fourth Ed., Vol. II, Part B, John Wiley & Sons, NY, pp. 1188–1220. Bakshi, K, B.M.Wagner, W.K.Anger, C.E.Feigley, W.Generoso, I.Greaves, R. Snyder, G.N.Wogan, and G.S.Yost. 1998. Toxicity of alternatives to chlorofluorocarbons: HFC-134a and HCFC-123. Inhal. Toxicol. 10:963–967. Boorman, G.A., S.L.Eustis, M.R.Elwell, C.A.Montgomery, Jr., and W.F.MacKenzie. 1990. Pathology of the Fischer Rat: Reference and Atlas. New York: Academic Press, Inc., p. 413. Bootman, J. and G.Hodson-Walker. 1988. In vitro assessment of the clastogenic activity of CFC 141b in cultured Chinese hamster ovary (CHO-K1) cells (88/PSV007/214). Life Science Laboratory, EYE, Suffolk, England (Cited in ECETOC 1994). Bootman, J., G.Hodson-Walker, S.Cracknell, and C.A.Dance. 1988a. Assessment of clastogenic action on bone marrow erythrocytes in the micronucleus test. 4874–89/LSR.PVSO 29, Life Science Research Laboratory, EYE, Suffolk, England (Cited in ECETOC 1994). Bootman, J., G.Hodson-Walker, and J.M.Lloyd. 1988b. CFC141b: Investigation of mutagenic activity at the HGPRT locus in a Chinese hamster V79 cell mutation system. 88/PSV005/257, Life Science Research Laboratory, EYE, Suffolk, England (Cited in ECETOC 1994). Brock, W.J., H.J.Trochimowicz, R.J.Millischer, C.Farr, T.Kawano, and G.M. Rusch. 1995. Acute and subchronic toxicity of 1,1-dichloro-1-fluoroethane (HCFC-141b). Fd. Chem. Toxicol. 33:483–490. CHEMID (Chemical Identification File). 1998. National Library of Medicine, National Institutes of Health on-line data base. Chengelis, C.P. 1997. Epinephrine sensitivity of the canine heart: A useful test. In R.Snyder, K.S.Bakshi, and B.M.Wagner, Abstracts of the Workshop on Toxicity of Alternatives to Chlorofluorocarbons. Inhal. Toxicol. 9:775–810. Coombs, D.W., C.J.Hardy, C.Meyer-Aspell, D.R.Algate, S.E.Begg, and D.J.Lewis. 1992. HCFC 141b—Potential neurobehavioral and neuropathological effects of exposure of rats to vapour (6 h a day, 5 days a week over a 16-week period). Report ALS 1/901565, January 9, 1992, Huntingdon Research Centre Ltd., Huntingdon, Cambridgeshire, England. (Cited in ECETOC 1994) Davies, R.H., R.D.Babnall, W.Bell, and W.G.M.Jones. 1976. The hydrogen bond

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 proton donor properties of volatile halogenated hydrocarbons and ethers and their mode of action in anaesthesia. Int. J. Quantum Chem., Quantum Biol. Symp. No. 3, 171–185. de Rooij, C.H. 1989. The toxicity of HCFC-141b. Proceedings of the 1989 European Meeting of the Toxicology Forum, Toulouse, France, September 18–22, pp. 204–216. ECETOC (European Centre for Ecotoxicology and Toxicology of Chemicals). 1994. Joint assessment of commodity chemicals no. 29:1,1-dichloro-1-fluoroethane (HCFC-141b) CAS No 1717–00–6. ECETOC, 4 Avenue E. Van nieuwenhuyse (Bte 6) 1160—Brussels, Belgium. Eger, E.I. No date. Report on arrhythmogenic and other effects of CH3CFCl2. Report to AlliedSignal Inc, Morristown, NJ. Hardy, C.J. 1994. HCFC-1717: Assessment of cardiac sensitisation potential in dogs. HRC Report ALS 57/942811, Huntingdon Research Centre Ltd., Huntingdon, Cambridgeshire, England. Hardy, C.J., P.C.Kieran, and I.J.Sharman. 1994. Assessment of the cardiac sensitisation potential (CSP) of a range of halogenated alkanes. Toxicologist 14:378. Hardy, J.C., I.J.Sharman, and D.O.Chanter. 1989a. Assessment of cardiac sensitisation potential in dogs and monkeys. Comparison of I-141b and F11. PWT 86/89437, Huntingdon Research Centre Ltd., Huntingdon, Cambridgeshire, England. Hardy, J.C., G.C.Jackson, R.S.Rad, D.J.Lewis, and C.Gopinath. 1989b. Acute inhalation toxicity study in rats (PWT95/881676), Huntingdon Research Centre Ltd., Huntingdon, Cambridgeshire, England (Cited in ECETOC 1994). Harris, J.W. and M.W.Anders. 1991. In vivo metabolism of the hydrochlorofluorocarbon 1,1-dichloro-1-fluoroethane (HCFC-141b). Biochem. Pharmacol. 41:R13– R16. Hino, Y, K.Yamasaki, and K.Schiraishi. 1992. Twenty-eight-day repeated inhalation toxicity study of HCFC 141b in rats. Report B 18–0005, Hita Research Laboratory Chemical Biotesting Center, Chemicals Inspection and Testing Institute, Japan. Hodson-Walker, G. and K.May. 1988. CFC141b: Assessment of its ability to cause lethal DNA damage in strains of Escherichia coli. 88PSV008/258, Life Science Research Ltd., EYE, Suffolk, England (Cited in ECETOC 1994). HSDB (Hazardous Substances Data Bank). 2000. MEDLARS Online Information Retrieval System, National Library of Medicine, retrieved 9/6/00. Janssen, P.J.M. 1989. Acute inhalation study to investigate the respiratory irritating properties of FC141b in male rats. Doc. No. 56645/41/89, DUPHAE, B.V. Weesp., The Netherlands (Cited in ECETOC 1994). Loizou, G.D. and M.W.Anders. 1993. Gas-uptake pharmacokinetics and biotransformation of 1,1-dichloro-1-fluoroethane (HCFC-141b). Drug Metab. Disp. 21:634–713. Loizou, G.D., N.I.Eldirdiri, and L.J.King. 1996. Physiologically based pharmacoki-

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 netics of uptake by inhalation of a series of 1,1,1-trihaloethanes: correlations with various physicochemical parameters. Inhal. Toxicol. 8:1–19. Millischer, R.-J., C.G.de Rooij, G.M.Rusch, C.H.Farr, R.Ben-Dyke, C.J.Hardy, D.J.Lewis, and G.Hodson-Walker. 1995. Evaluation of the genotoxicity potential and chronic inhalation toxicity of 1,1-dichloro-1-fluoroethane (HCFC-141b). Fd. Chem. Toxicol. 6:491–500. Mullin, L.S. 1977. Cardiac sensitisation. Haskell Laboratory Report 957–77, E.I. duPont de Nemours and Co., Newark, DE. NRC (National Research Council). 1993. Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. NRC (National Research Council). 1996. Toxicity of Alternatives to Chlorocarbons: HFC-134a and HCFC-123. Washington, DC: National Academy Press. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press. Reinhardt, C.F., A.Azar, M.E.Maxfield, P.E.Smith, and L.S.Mullin. 1971. Cardiac arrhythmias and aerosol “sniffing.” Arch. Environ. Health 22:265–279. Rusch, G.M., R.-J.Millischer, C.de Rooij, A.J.Brooker, E.Hughes, and D.Coombs. 1995. Inhalation teratology and two-generation studies with 1,1-dichloro-1-fluoroethane (HCFC-141b). Fd. Chem. Toxicol. 33:285–300. Smith, D.L., S.L.Aikman, L.J.Coulby, J.Sutcliffe, and B.J.O’Conner. 1994. The attenuation of methacholine-induced bronchoconstriction by salmeterol; comparison between an alternative metered dose inhaler propellant GR106642X and chlorofluorocarbons 11 and 12. Eur. Resp. J. 7 (Suppl. 18):318s. Taggart, S.C.O., A.Custovic, D.H.Richards, and A.Woodcock. 1994. An alternative metered dose inhaler propellant GR106642X: comparison to chlorofluorocarbon 11 and 12 in the attenuation of histamine-induced bronchoconstriction by salbutamol. Eur. Resp. J. (Suppl. 18):400s. Trochimowicz, H.J. 1997. Experience with the epinephrine sensitivity test for arrhythmia induction. In R.Snyder, K.S.Bakshi, and B.M.Wagner, Abstracts of the Workshop on Toxicity of Alternatives to Chlorofluorocarbons. Inhal. Toxicol. 9:775–810. Trochimowicz, H.J., C.F.Reinhardt, L.S.Mullin, and B.W.Karrh. 1997. The effect of myocardial infarction on the cardiac sensitization potential of certain halocarbons. J. Occup. Med. 18:26–30. Tong, Z., M.J.Utell, P.E.Morrow, G.M.Rusch, M.W.Anders. 1998. Metabolism of 1,1-dichloro-1-fluoroethane (HCFC-141b) inhuman volunteers. Drug Metab. Disp. 26:711–713. Utell, M.J., M.W.Anders, P.E.Morrow. 1997. Clinical inhalation studies with HCFC-141b. Final report: December 4, 1997. MA-RR-97–2406, Departments of Medicine, Environmental Medicine, and Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 Ventresca, G.P. 1995. Clinical pharmacology of HFA 134a. J. Aerosol Med. 8:S35– S39. Vlachos, D.A. 1988. Mouse Bone Marrow Micronucleus Assay of FC-141b. Haskell Laboratory Report No. 746–88. E.I. du Pont de Nemours and Company, Inc., Newark, DE. Wilmer, J.W.G.M. and N.De Vogel. 1988. Chromosome analysis of Chinese hamster ovary cells treated in vitro with FC141b. TNO Report No. V88.156/271236, TNO-CIVO Institutes, 3700 AJ. Zeist, The Netherlands. Woodcock, A. 1995. Continuing patient care with metered-dose inhalers. J. Aerosol Med. 8 (Suppl. 2):S5–S10.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 Appendix

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 DERIVATION SUMMARY FOR ACUTE EXPOSURE GUIDELINE LEVELS FOR 1,1-DICHLORO-1-FLUOROETHANE (HCFC-141b) (CAS No. 1717–00–6) AEGL-1 10 min 30 min 1 h 4 h 8 h 1,000 ppm 1,000 ppm 1,000 ppm 1,000 ppm 1,000 ppm Key reference: Utell, M.J., M.W.Anders, and P.E.Morrow. 1997. Clinical inhalation studies with HCFC-141b. Final report: December 4, 1997. MA-RR-97–2406, Departments of Medicine, Environmental Medicine, and Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY. Test species/Strain/Number: Eight healthy human subjects Exposure route/Concentrations/Durations: Inhalation: 0, 250, 500, 1,000 ppm for 4 h (eight subjects); two subjects were exposed at 500 ppm for 6 h; and 1 subject was exposed at 1,000 ppm for 6 h. Subjects exercised for three 20-min periods during each exposure. Effects: No effects at any concentration for any subject. End point/Concentration/Rationale: The highest tested concentration of 1,000 ppm for 4 or 6 h was used as the basis for the AEGL-1. This concentration was a NOAEL for irritation and cardiac, lung, and respiratory effects. Uncertainty factors/Rationale: Total uncertainty factor: 1 Interspecies: Not applicable; human subjects tested. Intraspecies: 1—This no-effect concentration for eight healthy, exercising individuals was far below concentrations causing effects in animals. At this low concentration there was no indication of differences in sensitivity among the subjects. Studies with structurally related chemicals administered in metered-dose inhalers to patients with respiratory diseases show that these chemicals produce no adverse effects. Modifying factor: Not applied. Animal to human dosimetric adjustment: Not applicable; human data used. 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 concentration-dependent threshold effect, the 6-h value was used for all exposure durations.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 Data adequacy: The key study was well designed, conducted, and documented. 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. In animal studies, concentrations up to 11,000 ppm for up to 6 h did not produce adverse effects. Adjustment of the 11,000-ppm concentration by interspecies and intraspecies uncertainty factors of 3 each, for a total of 10, results in essentially the same concentration (1,100 ppm) as that derived from the human data.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 AEGL-2 10 min 30 min 1 h 4 h 8 h 1,700 ppm 1,700 ppm 1,700 ppm 1,700 ppm 1,700 ppm Key reference: Mullin, L.S. 1977. Cardiac sensitisation. Haskell Laboratory Report 957–77, E.I. du Pont de Nemours and Co., Newark, DE. Test species/Strain/Sex/Number: male beagle dogs (1–2 per exposure group) Exposure route/Concentrations/Durations: Inhalation: 2,600, 5,200, 10,000, and 21,600 ppm for 10 min (the cardiac sensitization test is a 10-min test); epinephrine dose at 8 μg/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. The dose of administered epinephrine results in blood levels that may be approximately ten times endogenous levels and is close to the threshold for inducing cardiac effects in the absence of the test chemical. Effects: No cardiac effects at 2,600 ppm; cardiac response in 1/10 dogs at 5,200 ppm; death of 1/10 dogs at 10,000 ppm. End point/Concentration/Rationale: The concentration of 5,200 ppm was chosen as the basis for the AEGL-2. This concentration is the threshold for cardiac sensitization in the dog. Uncertainty factors/Rationale: Total uncertainty factor: 3 Interspecies: 1—The cardiac sensitization model with the dog heart is considered a good model for humans. Intraspecies: 3—The test is optimized; there is a built in safety factor because of the greater-than-physiological dose of epinephrine administered. In addition, there are no data indicating individual differences in sensitivity. Modifying factor: Not applied. Animal to human dosimetric adjustment: Not applicable. Time scaling: Not applied. The cardiac sensitization response is a concentration-dependent threshold effect; dogs exposed for longer durations to similar chemicals responded in a similar manner. Therefore, the same concentration was used for all exposure durations. Data adequacy: Humans exposed to halocarbons may develop cardiac arrhythmias. The cardiac sensitization test with the dog is a good model because the test is highly sensitive (i.e., the exogenous dose of epinephrine is at much greater than physiological levels). The concentration of 1,700 ppm is far below

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 the highest 6-h non-narcotic concentration in mice (30,000 ppm). Adjustment of the 30,000-ppm concentration by interspecies and intraspecies uncertainty factors of 3 each, for a total of 10, would result in a higher concentration (3,000 ppm) than that based on cardiac sensitization. Additional animal studies addressed neurotoxicity, reproductive and developmental toxicity, and carcinogenicity.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 AEGL-3 10 min 30 min 1 h 4 h 8 h 3,000 ppm 3,000 ppm 3,000 ppm 3,000 ppm 3,000 ppm Key reference: Hardy, J.C., I.J.Sharman, and D.O.Chanter. 1989a. Assessment of cardiac sensitisation potential in dogs and monkeys. Comparison of I-141b and F11. PWT 86/89437, Huntingdon Research Centre Ltd., Huntingdon, Cambridgeshire, England. Test species/Strain/Sex/Number: male beagle dogs (1–2 per exposure group) Exposure route/Concentrations/Durations: Inhalation: 2,600, 5,200, 10,000, and 21,600 ppm; epinephrine dose at 8 μg/kg (Mullin 1977). Inhalation: 9,000–20,000 ppm; epinephrine dose at 10 μg/kg (Hardy et al. 1989a). 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. Effects are monitored with electrocardiograms (EKG). The dose of administered epinephrine results in blood levels that may be approximately ten times endogenous levels and is close to the threshold for inducing cardiac effects in the absence of the test chemical. Effects: No cardiac effects at 2,600 ppm; cardiac response at ≥5,200 ppm (Mullin 1977). Marked cardiac response at 9,000 ppm; death at 20,000 ppm (Hardy et al. 1989a). End point/Concentration/Rationale: The concentration of 9,000 ppm was chosen as the basis for the AEGL-3 because it was the highest tested concentration that did not result in lethality in the cardiac sensitization test. Uncertainty factors/Rationale: Total uncertainty factor: 3 Interspecies: 1—The cardiac sensitization model with the dog heart is considered a good model for humans. Intraspecies: 3—The test is optimized; there is a built in safety factor because of the greater-than-physiological dose of epinephrine administered. In addition, there are no data indicating individual differences in sensitivity. Modifying factor: Not applied. Animal to human dosimetric adjustment: Not applicable.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 Time scaling: Not applied. The cardiac sensitization response is a concentration-dependent threshold effect; dogs exposed to similar chemicals for longer durations responded in a similar manner. Therefore, the same concentration was used for all exposure durations. Data adequacy: Humans exposed to halocarbons may develop cardiac arrhythmias. The cardiac sensitization test with the dog is a good model because the test is highly sensitive (i.e., the exogenous dose of epinephrine is at much greater than physiological levels). The concentration of 3,000 ppm is far below the highest 4–6 h nonlethal concentration of 45,781 ppm in studies with laboratory animals. Adjustment of the 45,781 ppm concentration by interspecies and intraspecies uncertainty factors of 3 each, for a total of 10, results in a higher concentration (4,600 ppm) than that derived from the cardiac sensitization data. Using repeated exposures, 8,000 ppm was a NOAEL and 20,000 ppm was a LOAEL for developmental effects associated with maternal toxicity in rats. Additional studies addressed neurotoxicity and carcinogenicity.