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1,1,1,2-Tetrafluoroethane (HFC-134a)1

Acute Exposure Guideline Levels

SUMMARY

Hydrofluorocarbon-134a or 1,1,1,2-Tetrafluoroethane (HFC-134a) has been developed as a replacement for fully halogenated chlorofluorocarbons because, compared with chlorofluorocarbons, its residence time in the atmo-

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 AEGL values 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 3 1,1,1,2-Tetrafluoroethane (HFC-134a)1 Acute Exposure Guideline Levels SUMMARY Hydrofluorocarbon-134a or 1,1,1,2-Tetrafluoroethane (HFC-134a) has been developed as a replacement for fully halogenated chlorofluorocarbons because, compared with chlorofluorocarbons, its residence time in the atmo- 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 AEGL values 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 sphere is shorter and its ozone depleting potential is insignificant. HFC-134a is used in refrigeration and air conditioning systems, as a blowing agent for polyurethane foams, and as a propellant for medical aerosols. Yearly production is estimated at 175,000 tons. HFC-134a is a colorless gas with a faint ethereal odor that may go unnoticed by most individuals. HFC-134a has a very low acute inhalation toxicity. Both uptake and elimination are rapid, but uptake is low, and most of the compound is exhaled unchanged. Consequences of acute HFC-134a inhalation have been studied with human subjects and several animal species, including the monkey, dog, rat, and mouse. Considerable inhalation data from controlled studies with healthy human subjects as well as patients with respiratory diseases are available. 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 end point was considered in development of AEGL values. Adequate data were available for development of the three AEGL classifications. Inadequate data were available for determination of the relationship between concentration and time for a fixed effect. Based on the observations that (1) blood concentrations in humans rapidly approach equilibrium with negligible metabolism and tissue uptake and (2) the end point of cardiac sensitization is a blood-concentration related threshold phenomenon, the same concentration was used across all AEGL time periods for the respective AEGL classifications. The AEGL-1 concentration was based on a 1-hour (h) no-effect concentration of 8,000 parts per million (ppm) in healthy human subjects (Emmen et al. 2000). This concentration was without effects on pulmonary function, respiratory parameters, the eyes (irritation), or the cardiovascular system. Because this concentration is considerably below that causing any adverse effect in animal studies, an intraspecies uncertainty factor (UF) of 1 was applied. The intraspecies UF of 1 is supported by the absence of adverse effects in therapy tests with patients with severe chronic obstructive pulmonary disease and adult and pediatric asthmatics who were tested with metered-dose inhalers containing HFC-134a as the propellant. Because blood concentrations in this study approached equilibrium following 55 minutes (min) of exposure and effects are determined by blood concentrations, the value of 8,000 ppm was made equivalent across all time periods. The AEGL-1 of 8,000 ppm is supported by the absence of adverse effects in experimental animals that inhaled considerably higher concentrations. No adverse effects were observed in rats exposed at 81,000 ppm for 4 h (Silber and Kennedy 1979) or in rats exposed

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 repeatedly at 50,000 or 100,000 ppm for 6 h/day (d). Adjustment of the 81,000 ppm value by interspecies and intraspecies UFs of 3 each, for a total of 10, results in essentially the same concentration (8,100 ppm) as the AEGL-1 based on human data. The AEGL-2 concentration was based on the no-effect concentration of 40,000 ppm for cardiac sensitization in dogs (Hardy et al. 1991). The cardiac sensitization model with the dog is considered an appropriate model for humans. Because the dog heart is considered an appropriate model for the human heart, an interspecies UF of 1 was applied. Because the cardiac sensitization test is highly sensitive as the response to exogenous epinephrine is optimized, an intraspecies UF of 3 was applied to account for sensitive individuals. Cardiac sensitization is concentration-dependent; duration of exposure does not influence the concentration at which this effect occurs. Using the reasoning that peak circulating concentration is the determining factor in HFC-134a cardiac sensitization, and exposure duration is of lesser importance, the resulting value of 13,000 ppm was applied to all time periods. The AEGL-3 concentration was based on a concentration of 80,000 ppm, which caused marked cardiac toxicity but no deaths in dogs (Hardy et al. 1991). The cardiac sensitization model with the dog is considered an appropriate model for humans; therefore, an interspecies UF of 1 was applied. Because the cardiac sensitization test is highly sensitive as the response to epinephrine is optimized, an intraspecies UF of 3 was applied to account for sensitive individuals. Cardiac sensitization is concentration-dependent; duration of exposure does not influence the concentration at which this effect occurs. Using the reasoning that peak circulating concentration is the determining factor in HFC-134a cardiac sensitization, and exposure duration is of lesser importance, the resulting value of 27,000 ppm was applied to all time periods. Values are summarized in Table 3–1. 1. INTRODUCTION Hydrofluorocarbons (HFCs) 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 therefore causes less depletion of ozone. The contribution of radicals formed by the atmospheric degradation of 1,1,1,2-tetrafluoroethane (HFC-134a) to ozone depletion is insignificant and its global

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 TABLE 3–1 Summary of AEGL Values for HFC-134a (ppm [mg/m3]) Classification 10 min 30 min 1 h 4 h 8 h End Point (Reference) AEGL-1 8000 8000 8000 8000 8000 No effects— humans (Emmen et al. 2000) (Nondisabling) (34,000) (34,000) (34,000) (34,000) (34,000) AEGL-2 13,000 13,000 13,000 13,000 13,000 No effect, cardiac sensitization— dogsa (Hardy et al. 1991) (Disabling) (55,250) (55,250) (55,250) (55,250) (55,250) AEGL-3 27,000 27,000 27,000 27,000 27,000 Marked effect, cardiac sensitization—dogsa (Hardy et al. 1991) (Lethal) (114,750) (114,750) (114,750) (114,750) (114,750) aResponse to challenge dose of epinephrine (cardiac sensitization test). warming potential is much lower than that of CFCs (Ravishankara et al. 1994; ECETOC 1995). HFC-134a has been developed as a replacement for fully halogenated chlorofluorocarbons and for partially halogenated hydrochlorofluorocarbons. Its primary use is in refrigeration and air conditioning systems in which it is used alone or as a component of blends. It has been used as a blowing agent for polyurethane foams and as a propellant for medical aerosols (ECETOC 1995; Harrison et al. 1996). On August 15, 1996, the U.S. Food and Drug Administration (FDA) approved the use of metered-dose inhalers containing HFC-134a as the propellant. These metered-dose inhalers are used in the treatment and prevention of bronchospasm in patients 12 years (y) of age and older with reversible obstructive airway disease (FDA 1996). As of June, 1999, the age of treatment with HFC-134a containing inhalants was lowered from 12 y to 4 y. The same dosage is recommended for children and adults. HFC-134a is produced commercially by (1) the hydrofluorination of trichloroethylene via 1-chloro-1,1,1-trifluoroethane, (2) isomerization and hydrofluorination of 1,1,2-trichloro-1,2,2-trifluoroethane to 1,1-dichloro-1,2,2,2-tetrafluoroethane followed by hydrodechlorination, and (3) hydrofluorination of tetrachloroethylene to 1-chloro-1,2,2,2-tetrafluoroethane and subsequent hydrodechlorination to tetrafluoroethane (ECETOC 1994). It is manufactured by four companies in the United States and 13 companies worldwide. World production capacity was estimated at 175,000 tons/y in the

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 early 1990s (ECETOC 1995). Production is estimated to reach 300,000 tons/y by 2020. HFC-134a is a nonflammable, colorless gas or liquified gas with a faint ethereal odor. The odor, characterized as weak and nonirritating (Shulman and Sadove 1967), may not be noticeable for most individuals and thus will not serve as a warning property. The vapor is heavier than air and can displace air in confined spaces (ECETOC 1995). Additional chemical and physical properties are listed in Table 3–2. Experimental studies with human subjects and several mammalian species (monkey, dog, rat, mouse, and rabbit) were located. Animal studies addressed neurotoxicity, genotoxicity, carcinogenicity, and cardiac sensitization and were conducted over acute, subchronic, and chronic exposure durations. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality Although deaths from exposure to CFCs have occurred during refrigeration repair, its use as solvents, and its use and abuse as aerosol propellant (Aviado 1994), no data specific to HFCs were located. 2.2. Nonlethal Toxicity Eight healthy human volunteers, four males and four females, ages 20–24, were exposed individually (whole body) to concentrations at 0 (air), 1,000, 2,000, 4,000, or 8,000 ppm for 1 h in a 13.6 m3 room (Emmen and Hoogendijk 1998; Emmen et al. 2000).2 Each subject was exposed at each concentration in a partially blind ascending order of concentration. With the exception of one 14-d interval, each exposure was separated by a period of 7 d. Chlorofluorocarbon-12 (CFC-12) was used as a reference compound. No mention was made of the ability of the test subjects to recognize the odor of either test chemical. Prior to and during exposures, blood pressure and cardiac rate and rhythm (EKG) were monitored. Pulmonary function, as indi- 2   The protocol was approved by the Medical Ethics Testing Committee of The Netherlands Organization. Subjects signed an informed consent form.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 TABLE 3–2 Chemical and Physical Data Parameter Value Reference Synonyms HFC-134a 1,1,1,2-tetrafluoroethane HFA-134a HCFC 134a R-134a ECETOC 1995, HSDB 2000 Molecular formula C2H2F4 ECETOC 1995 Molecular weight 102.03 HSDB 2000 CAS registry number 811–97–2 HSDB 2000 Physical state Gas or liquified gas ECETOC 1995 Color colorless ECETOC 1995 Solubility in water 1 g/L ECETOC 1995 Vapor pressure 4,730 mm Hg @25°C HSDB 2000 Vapor density 3.52 ECETOC 1995 Melting point −108°C ECETOC 1995 Boiling point −26°C ECETOC 1995 Odor Faint ethereal ECETOC 1995 Conversion factors 1 ppm=4.25 mg/m3 1 mg/m3=0.24 ppm ECETOC 1995 cated by peak expiratory flow, was measured before and after exposures. Blood samples were taken prior to, during, and after exposure. Clinical chemistry and hematology parameters were also recorded before and after exposure. The test chemical was vaporized and introduced into the air supply of the exposure chamber via a calibrated rotameter; the atmospheres were monitored with a gas monitor. Five samples were taken from each of six locations in the exposure chamber. Atmospheres were within a few percent of nominal concentrations; the mean oxygen concentration was approximately 20.5%. No significant or consistent differences were found between air exposure and test chemical exposure for clinical observations, blood pressure, heart rate, peak expiratory flow, or EKG recordings. During blood sampling and blood pressure measurements, all subjects showed sinus arrhythmia before and after exposure.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 A Mobitz type I heart block was present in one subject before, during, and after exposure. Medical personnel did not consider this a risk, and the informed subject completed the study without any evidence of adverse effect. CFCs are used as propellants in metered-dose inhalers for the treatment of asthma. To that end, HFC-134a has been tested with human subjects using single or repeated inhalations. A number of studies are cited here as examples of direct inhalation from such devices (up to 90% of the aerosol from metereddose inhalers may consist of the propellant). In a 28-d, double-blind parallel study, two groups of eight healthy nonsmoking male subjects, ages 18–55, inhaled either HFC-134a propellant from a pressurized metered-dose inhaler (HFC 134a as propellant, ethanol as co-solvent, and oleic acid as surfactant) or chlorofluorocarbon propellants, CFC-11 or CFC-12 (Harrison et al., 1996). All subjects gave written informed consent. Subjects received either four inhalations four times per day for 14 d or eight inhalations four times per day for 14 d; after 14 d the subjects were given the alternate propellant. Subjects held their breath for 10 seconds (s) after each inhalation and waited 30 s between inhalations. Blood pressure, heart rate, and EKGs were recorded; pulmonary function tests were administered immediately before and 20 min after the first exposure on each day; blood was taken for clinical chemistry determinations at this time on various days. No clinically significant differences from baseline occurred in blood pressure, heart rate, EKGs, pulmonary functions, hematology, or serum chemistry. One subject had an elevated eosinophil count throughout the study. The most frequently reported subjective adverse effect was headache, reported by four subjects in each propellant group. Twelve healthy subjects showed no adverse clinical or pulmonary function response to inhalation of HFC-134a (Donnell et al. 1995), but three subjects reported coughing or nausea and vomiting. Coughing occurred in one subject after dosing from an inhaler that contained HCF-134a but no bronchodilator medication, and the other events occurred prior to cumulative dosing and approximately 21 h after the previous dosing regime. The relationship of these events to HFC-134a exposures is unknown. When radiolabeled HFC-134a was delivered by metered dose inhalers to healthy subjects and patients with severe chronic obstructive pulmonary disease (COPD), there were no adverse effects in either group as monitored by vital signs, pulmonary function tests, EKG, and liver function. No symptoms or complaints of upper respiratory tract irritation were recorded (Ventresca 1995). In preclinical trials, there were no significant acute or long-term neurobehavioral effects from exposure to four to eight metered-dose inhalations, four to 16 times per day (Bennett 1991; Engle 1991; Graepel and Alexander 1991).

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 As part of an extensive toxicological assessment of HFC-134a, metereddose inhalers using HFC-134a as a propellant have been tested with adult and pediatric asthmatic patients (Woodcock 1995). In a single-dose, double-blind, placebo-controlled study, 20 adult patients (mean age, 27 y) with mild to moderate asthma were exposed to a therapeutic agent (salmeterol, a β2 agonist) with currently used chlorofluorocarbons or HFC-134a as the propellant prior to challenge with methacholine, a bronchoconstricting agent (Smith et al. 1994). All subjects completed the study without significant side effects. The therapeutic agent was equally protective against methacholine challenge regardless of propellant. In a similar study with 24 male and female asthmatic patients (mean age, 37 y), the efficacy of salbutamol delivered with either HFC-134a or two currently used chlorofluorocarbons was tested (Taggart et al. 1994). The challenge agent was histamine. Again, there were no significant side effects. There was no difference in the level of protection of the therapeutic agent whether it was delivered with HFC-134a or the currently used chlorofluorocarbons. In a third study, which used pediatric asthmatic subjects (mean age, 10 y), salbutamol delivered by HFC-134a or the currently used CFCs was equally protective against histamine-induced bronchoconstriction (Woodcock 1995). In a randomized, double-blind, placebo-controlled, multicenter trial of several hundred adult asthmatic patients requiring inhaled β-adrenergic bronchodilators for symptom control, metered-dose inhalers with HFC-134a had a safety profile similar to the currently marketed product formulated with a CFC (Tinkelman et al. 1998). Patients with other serious concomitant diseases were excluded from the study. The study lasted 12 weeks (wk). Although several adverse events, such as vomiting and tachycardia, were increased over those in patients receiving the drug with CFC propellant (7% vs. 2% in patients receiving the CFC propellant), overall incidences for adverse events did not differ among patients receiving the drug with either propellant or receiving HFC-134a without the drug. 2.3. Neurotoxicity No signs of central or peripheral neurologic involvement were reported following inhalation exposure to HFC-134a (Donnell et al. 1995; Woodcock 1995; Harrison et al. 1996; Tinkelman et al. 1998).

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 2.4. Developmental and Reproductive Toxicity No studies were located regarding reproductive or developmental effects in humans after inhalation exposure to HFC-134a. 2.5. Genotoxicity No information on genotoxicity in humans was located. In vitro, a cytogenic assay with human lymphocytes was negative (Collins et al. 1995). Vapor concentrations ranged from 5% to 100% volume per volume (v/v), and the incubation period was 3 h in both the presence and absence of metabolic activation. 2.6. Carcinogenicity No information on the carcinogenic potential of HFC-134a in humans was located. 2.7. Summary In a study with human volunteers exposed at concentrations up to 8,000 ppm for 1 h, no adverse effects on pulmonary function, clinical chemistry, hematology parameters, or heart rate or rhythm were observed. When HFC134a was delivered directly to the respiratory tract with metered-dose inhalers, no adverse effects, as indicated by clinical signs, respiratory tract irritation, or heart rhythm, were reported. The occurrences of headache, coughing, or nausea in some of the subjects that tested metered-dose inhalers are difficult to interpret but were not limited to HFC-134a exposure. Healthy subjects, as well as patients with COPD and asthma, were included in the test protocols, and no differences between the response of these populations could be discerned. No information on developmental and reproductive effects or carcinogenicity in humans was located. A single in vitro genotoxicity test with human lymphocytes was negative.

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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 3–3. The only species tested in these studies was the rat. In the rat, a 15-min LC50 of >800,000 ppm and a 4-h LC50 of >500,000 ppm have been reported (Collins 1984; Alexander 1995). These high concentrations required oxygen supplementation (19% v/v) to prevent anoxia of the test animals. The 30-min LC50 was 750,000 ppm (Rissolo and Zapp 1967). In another study, groups of six rats were exposed at time-weighted average (TWA) concentrations of 81,100, 205,200, 359,300, 566,700, 646,700, or 652,700 ppm for 4 h (Silber and Kennedy 1979a). The lowest lethal concentration was 566,700 ppm, which resulted in the deaths of five of six rats during the exposure period. Two of six rats exposed at 652,700 ppm also died. No deaths were recorded following exposure to the three lower concentrations, and no adverse effects were reported at the concentration of 81,000 ppm. Signs observed during exposures in these studies included lethargy, rapid respiration, trembling, tearing, foaming at the nose, pallor, and weight loss in survivors during the first 24 h of the recovery period. Surviving rats appeared normal within 5 min after cessation of exposure, and no abnormalities were present in surviving rats necropsied 14 d postexposure. 3.2. Nonlethal Toxicity Results of acute HFC-134a exposures are summarized in Table 3–4. Many of these studies are reviewed in Alexander and Libretto (1995). 3.2.1. Nonhuman Primates Exposure at 500,000 ppm induced narcosis in rhesus monkeys within 1 min (Shulman and Sadove 1967). Respiratory depression accompanied by multiple premature ventricular contractions occurred when concentrations exceeded 60%. Blood pressure was said to be increased, but the actual data were not reported.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 TABLE 3–3 Summary of Acute Lethal Inhalation Data in Laboratory Animals Species Concentration (ppm) Exposure Time Effect Reference Rat >800,000 15 min LC50 Collins 1984 Rat 750,000 30 min LC50 Rissolo and Zapp 1967 Rat 566,700 4 h Lowest lethal concentration Silber and Kennedy 1979a Rat >500,000 4 h LC50 Collins 1984 3.2.2. Dogs Concentrations at 700,000 and 800,000 ppm for 3 to 5 h induced deep anesthesia in dogs, usually within 1 min (Shulman and Sadove 1967). Respirations remained spontaneous, and blood pressure remained normal. Light anesthesia was induced at concentrations of 500,000 to 600,000 ppm. Emergence time was usually less than 2 min. The effect of HFC-134a on the histamine-induced bronchial constriction of anesthetized male beagle dogs was studied (Nogami-Itoh et al. 1997). Bronchial constriction in the dogs was induced by the intravenous administration of histamine. The β2-agonist, salbutamol, in metered-dose inhalers was used for treatment of the constriction. When HFC-134a was tested as the propellant for the salbutamol treatment (one to four puffs of 100 or 200 μg of the drug), there was no effect of the HFC-134a on the salbutamol treatment compared with other CFC propellants. HFC-134a added to the formulation had no influence on histamine-induced bronchoconstriction, blood pressure, or heart rate in the anesthetized dogs. Alexander et al. (1995b) exposed a group of four male and four female beagles to a nominal 12% HFC-134a (120,000 ppm) by means of a face mask. The measured concentration was 118,278 ppm. Two control groups consisting of three males and three females each were used, an atmospheric-air control group and a group exposed to medical-grade air mixed with an additional 12% nitrogen to simulate the depleted oxygen level of the HFC-134a-exposed group. The HFC-134a was approximately 99.3% pure and was specially prepared to contain all likely related hydrocarbons that might be formed during production. The dogs were exposed for 1 h/d for 1 y in order to simulate

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 FDA (U.S. Food and Drug Administration). 2000. On-line search: http://www.fda.gov/cder/da/da896.htm. Retrieved September 12, 2000. Finch, J.R., E.J.Dadey, S.L.Smith, L.I.Harrison, and G.A.Digenis. 1995. Dynamic monitoring of total-body absorption by 19F-NMR spectroscopy: one hour ventilation of HFA-134a in male and female rats. Magn. Reson. Med. 33:409–413. German Research Association (Deutsche Forschungsgemeinschaft). 1999. List of MAK and BAT Values, 1999. Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area, Report No. 35. Federal Republic of Germany: Wiley-VCH. Graepel, P. and D.J.Alexander. 1991. CFC replacements: safety testing, approval for use in metered dose inhalers. J. Aerosol Med. 4:193–200. Hardy, C.J., I.J.Sharman, and G.C.Clark. 1991. Assessment of cardiac sensitisation potential in dogs: comparison of HFA 134a and A12. Report No. CTL/C/2521. Huntingdon Research Centre, Huntingdon, Cambridgeshire. 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. Harrison, L.I. 1996. Pharmacokinetics of HFA-134a: a preliminary report. Am. J. Therap. 3:763–765. Harrison, L.I., D.Donnell, J.L.Simmons, B.P.Ekholm, K.M.Cooper, and P.J.Wyld. 1996. Twenty-eight-day double-blind safety study of an HFA-134a inhalation aerosol system in healthy subjects. J. Pharm. Pharmacol. 48:596–600. Hext, P.M. 1989. 90-day inhalation toxicity study in the rat. ICI Report No. CTL/P/2466. Central Toxicology Laboratory, Imperial Chemical Industries, Alderley Park, Macclesfield, Cheshire, U.K. (Cited in NRC 1996). Hodge, M.C.E., M.Kilmartin, R.A.Riley, T.M.Weight, and J.Wilson. 1979. Arcton 134a: teratogenicity study in the rat. ICI Report no. CTL/P/417. Central Toxicology Laboratory, Alderly Park, Macclesfield, Cheshire, U.K. HSDB (Hazardous Substances Data Bank). 2000. MEDLARS Online Information Retrieval System, National Library of Medicine, retrieved 9/6/00. Larsen, E.R. 1966. 1,1,1,2-Tetrafluoroethane anaesthetic. U.S. Patent Number 3,261,748, July 19, 1966. LMES (Lockheed Martin Energy Systems, Inc.). 1998. Material Safety Reference Sheet, Online database, retrieved 2/3/98. Longstaff, E., M.Robinson, C.Bradbrook, J.A.Styles, and I.E.H.Purchase. 1984. Genotoxicity and carcinogenicity of fluorocarbons: Assessment by short-term in vitro tests and chronic exposure in rats. Toxicol. Appl. Pharmacol. 72:15–31. Lu, M., and R.Staples. 1981. 1,1,1,2-Tetrafluoroethane (FC-134a): embryo-fetal toxicity and teratogenicity study by inhalation in the rat. Report No. 317–81. Haskell Laboratory, Wilmington, DE. (Cited in NRC 1996). Ministry of Social Affairs and Employment (SDU Uitgevers). 2000. Nationale MAC (Maximum Allowable Concentration) List, 2000. The Hague, The Netherlands. Monte, S.Y., I.Ismail, D.N.Mallett, C.Matthews, and R.J.N.Tanner. The minimal metabolism of inhaled 1,1,1,2-tetrafluoroethane to trifluoroacetic acid in man as

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 determined by high sensitivity 19F nuclear magnetic resonance spectroscopy of urine samples. J. Pharmaceut. Biomed. Anal. 12:1489–1493. Mullin, L.S. and R.W.Hartgrove. 1979. Cardiac sensitization. Report No. 42–79, Haskell Laboratory, Wilmington, DE. (Cited in ECETOC 1995) Mullin, L.S., C.F.Reinhardt, and R.E.Hemingway. 1979. Cardiac arrhythmias and blood levels associated with inhalation of Halon 1301. Am. Ind. Hyg. Assoc. J. 40:653–658. Nogami-Itoh, M., I.Yakuo, D.M.Hammerbeck, R.I.Miller, and K.Takeyama. 1997. The equivalent bronchodilator effects of salbutamol formulated in chlorofluorocarbon and hydrofluoroalkane-134a metered dose inhalers on the histamine-induced pulmonary response in dogs. Pharmaceut. Res. 14:208–212. 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 Chlorofluorocarbons: 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. Olson, M.J., C.A.Reidy, and J.T.Johnson. 1990a. Defluorination of 1,1,1,2tetrafluoroethane (R-134a) by rat hepatocytes. Biochem. Biophys. Res. Comm. 166:1390–1396. Olson, M.J., C.A.Reidy, J.T.Johnson, and T.C.Pederson. 1990b. Oxidative defluorination of 1,1,1,2-tetrafluoroethane by rat liver microsomes. Drug Metab. Dispos. 18:992–998. Olson, M.J. and S.E.Surbrook, Jr. 1991. Defluorination of the CFC-substitute 1,1,1,2-tetrafluoroethane: comparison in human, rat and rabbit hepatic microsomes. Toxicol. Lett. 59:89–99. Pike, V.W., F.I.Aigbirhio, C.A.J.Freemantle, B.C.Page, C.G.Rhodes, S.L.Waters, T.Jones, P.Olsson, G.P.Ventresca, R.J.N.Tanner, M.Hayes, and J.M.B. Hughes. 1995. Disposition of inhaled 1,1,1,2-tetrafluoroethane (HFA134a) in healthy subjects and in patients with chronic airflow limitation. Drug Metab. Disp. 23:832–839. Ravishankara, A.R., A.A.Turnipseed, N.R.Jensen, S.Barone, M.Mills, C.J.Howard, and S.Solomon. Do hydrofluorocarbons destroy stratospheric ozone? Science 263:71–75. 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. Ritchie, G.D., E.C.Kimmel, L.E.Bowen, J.E.Reboulet, and J.Rossi, III. 2001. Acute neurobehavioral effects in rats from exposure to HFC 134a or CFC 12. Neurotoxicology 22:233–248. Riley, R.A., I.P.Bennett, I.S.Chart, C.W.Gore, M.Robinson, and T.M.Weight.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 1979. Arcton-134a: Subacute toxicity to the rat by inhalation. ICI Report No. CTL/P/463. Central Toxicology Laboratory, Alderly Park, Macclesfield, Cheshire, U.K. (Cited in NRC 1996). Rissolo, S.B., and J.A.Zapp. 1967. Acute inhalation toxicity. Report No. 190–67. Haskell Laboratory Wilmington, DE. (Cited in NRC 1996). Shulman, M., and M.S.Sadove. 1967. 1,1,1,2-Tetrafluoroethane: an inhalation anesthetic agent of intermediate potency. Anaesthesia & Analgesia 46:629–633. Silber, L.S., and G.L.Kennedy. 1979a. Acute inhalation toxicity study of tetrafluoroethane (FC 134a). Haskell Laboratory, Report No. 422–79, DuPont de Nemours and Company, Newark, DE. Silber, L.S., and G.L.Kennedy. 1979b. Subacute inhalation toxicity of tetrafluoroethane (FC 134a). Haskell Laboratory, Report No. 228–79, DuPont de Nemours and Company, Newark, DE, cited in ECETOC, 1995. 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. Surbrook, S.E., and M.J.Olson. 1992. Dominant role of cytochrome P-450 2E1 in human hepatic microsomal oxidation of the CFC-substitute 1,1,1,2-tetrafluoroethane. Drug Metab. Dispos. 20:518–524. 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. Tinkelman, D.G., E.R.Bleecker, J.Ramsdell, B.P.Ekholm, N.M.Klinger, G.L. Colice, and H.B.Slade. 1998. Proventil HFA and Ventolin have similar safety profiles during regular use. Chest 113:290–296. 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., A.Azar, J.B.Terrill, and L.S.Mullin. 1974. Blood levels of fluorocarbon related to cardiac sensitization: Part II. Am. Ind. Hyg. Assoc. J. 35:632–639. Trochimowicz, H.J., C.F.Reinhardt, L.S.Mullin, and B.W.Karrh. 1976. The effect of myocardial infarction on the cardiac sensitization potential of certain halocarbons. J. Occup. Med. 18:26–30. Ventresca, G.P. 1995. Clinical pharmacology of HFA 134a. J. Aerosol Med. 8:S35– S39. Vinegar, A., G.W.Jepson, R.S.Cook, J.D.McCafferty, III, and M.C.Caracco. Human inhalation of Halon 1301, HFC-134a and HFC-227ea for collection of pharmacokinetic data. AL/OE-TR-1997–0116, Occupational and Environmental

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 Health Directorate, Toxicology Division, Wright-Patterson AFB, OH. Wickramaratne, G.A. 1989a. HCF-134a: Teratogenicity Inhalation Study in the Rabbit. ICI Report No. CTL/P/2504. Central Toxicology Laboratory, Alderly Park, Macclesfield, Cheshire, U.K. (Unpublished). Wickramaratne, G.A. 1989b. HCF-134a: Embryotoxicity Inhalation Study in the Rabbit. ICI Report No. CTL/P/2380. Central Toxicology Laboratory, Alderly Park, Macclesfield, Cheshire, U.K. (Unpublished). 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 1,1,1,2-TETRAFLUOROETHANE (HCF-134a) (CAS No. 811–97–2) AEGL-1 10 min 30 min 1 h 4 h 8 h 8,000 ppm 8,000 ppm 8,000 ppm 8,000 ppm 8,000 ppm Key reference: Emmen, H.H., and E.M.G.Hoogendijk. 1998. Report on an ascending dose safety study comparing HFA-134a with CFC-12 and air, administered by whole-body exposure to healthy volunteers. MA-250B-82–306, TNO Report V98.754, The Netherlands Organization Nutrition and Food Research Institute, Zeist, The Netherlands. Test species/Strain/Number: Eight healthy adult human subjects Exposure route/Concentrations/Durations: Inhalation: 0, 1,000, 2,000, 4,000, 8,000 ppm for 1 h. Effects: No effects on tested parameters of blood pressure, heart rate, electrocardiogram (EKG) rhythms, or lung peak expiratory flow. End point/Concentration/Rationale: The highest no-effect concentration of 8,000 ppm for 1 h was used as the basis for the AEGL-1. This concentration is considerably below the threshold for effects in animal studies. For example, anesthetic effects occur at a concentration of approximately 200,000 ppm. Uncertainty factors/Rationale: Total uncertainty factor: 1 Interspecies: Not applicable, human subjects used. Intraspecies: 1—this no-effect concentration for eight healthy individuals was far below concentrations causing effects in animals. At this low exposure concentration there was no indication of differences in sensitivity among the subjects. This uncertainty factor is supported by the lack of effects in COPD and adult and pediatric asthmatic patients treated with metered-dose inhalers containing HFC-134a as a propellant. Modifying factor: Not applicable. Animal to human dosimetric adjustment: Not applied, human subjects used. Time scaling: Not applied. Effects such as cardiac sensitization have been correlated with blood concentrations. Several studies have shown that blood concentrations of halocarbons do not increase greatly with time after 15 min of exposure. The key study showed that at each exposure concentration, blood

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 concentrations were approaching equilibrium after 55 min of exposure. Therefore, susceptibility to effects are predicted to remain the same as exposure time increases beyond 1 h. Data adequacy: The key study was well designed and conducted and documented a lack of effects on heart and lung parameters as well as clinical chemistry. Pharmacokinetic data were also collected. The compound was without adverse effects when tested as a component of metered-dose inhalers on patients with COPD. Animal studies covered acute, subchronic, and chronic exposure durations and addressed systemic toxicity as well as neurotoxicity, reproductive and developmental effects, cardiac sensitization, genotoxicity, and carcinogenicity. The values are supported by a study with rats in which no effects were observed during a 4-h exposure to 81,000 ppm. Adjustment of the 81,000 ppm concentration by an interspecies and intraspecies uncertainty factors of 3 each, for a total of 10, results in essentially the same value (8,100 ppm) as that from the human study.

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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 13,000 ppm 13,000 ppm 13,000 ppm 13,000 ppm 13,000 ppm Key reference: Hardy, C.J., I.J.Sharman, and G.C.Clark. 1991. Assessment of cardiac sensitisation potential in dogs: comparison of HFA 134a and A12. Report No CTL/C/2521, Huntingdon Research Centre, Cambridgeshire, U.K. Test species/Strain/Sex/Number: Male beagle dogs, six total. Exposure route/Concentrations/Durations: Inhalation: 40,000, 80,000, 160,000, or 320,000 ppm for 10 min (the cardiac sensitization test is a 10-min exposure test). The test is based on the principle that halocarbons make the mammalian heart abnormally sensitive to epinephrine. Epinephrine is administered prior to and during test exposures at doses that are up to ten times higher than levels secreted by die human adrenal gland in time of stress. Doses of epinephrine were adjusted for each individual dog so that administration of epinephrine without the test chemical produced a threshold response. Effects: Concentration (ppm) Response   40,000 No response 80,000 Marked response (2/6) 160,000 Convulsions (1/4) 320,000 Marked response (2/3); convulsions (1/3) A marked response is considered an effect; number of dogs affected per number of dogs tested in parenthesis. Dogs that responded at one concentration were not tested at higher concentrations. End point/Concentration/Rationale: The no-effect concentration of 40,000 ppm was chosen as the basis for the AEGL-2 because the next higher concentration of 80,000 ppm produced a serious effect. 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 is no data indicating individual differences in sensitivity.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 Modifying factor: Not applicable. Animal to human dosimetric adjustment: Not applied. As noted, the cardiac sensitization model with the dog heart is considered a good model for humans. Time scaling: Not applied. Cardiac sensitization is an exposure and blood concentration related threshold effect. Several studies have shown that blood concentrations of halocarbons do not increase greatly with time after 15–55 min of exposure, and exposure duration did not influence the concentration at which the effect occurred. Data adequacy: The key study was well conducted and documented. Supporting data include both human and animal studies. Animal studies covered acute, subchronic, and chronic exposure durations and addressed systemic toxicity as well as neurotoxicity, reproductive and developmental effects, cardiac sensitization, genotoxicity, and carcinogenicity. Other effects in animal studies occurred at much higher concentrations or with repeated exposures; the latter are not relevant for setting short-term exposures. No effects other than narcosis occurred in rats and mice exposed at 200,000 ppm for various periods of time. Adjustment by a total UF of 10 results in a higher value (20,000 ppm) than from the cardiac sensitization test with dogs.

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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 27,000 ppm 27,000 ppm 27,000 ppm 27,000 ppm 27,000 ppm Key reference: Hardy, C.J., I.J.Sharman, and G.C.Clark. 1991. Assessment of cardiac sensitisation potential in dogs: comparison of HFA 134a and A12. Report No CTL/C/2521, Huntingdon Research Centre, Cambridgeshire, U.K. Test species/Stain/Sex/Number: Male beagle dogs, six total. Exposure route/Concentrations/Durations: Inhalation: 40,000, 80,000, 160,000, or 320,000 ppm for 10 min (the cardiac sensitization test is a 10-min exposure test). The test is based on the principle that halocarbons make the mammalian heart abnormally sensitive to epinephrine. Epinephrine is administered prior to and during test exposures at doses that are up to ten times higher than levels secreted by the human adrenal gland in time of stress. Doses of epinephrine were adjusted for each individual dog so that administration of epinephrine without the test chemical produced a threshold response. Effects: Concentration (ppm) Response   40,000 No response 80,000 Marked response (2/6) 160,000 Convulsions (1/4) 320,000 Market response (2/3); convulsions (1/3) A marked response is considered an effect; number of dogs affected per number of dogs tested in parenthesis. Dogs that responded at one concentration were not tested at higher concentrations. End point/Concentration/Rationale: The concentration at 80,000 ppm was chosen as the basis for the AEGL-3 because it produced a serious, life-threatening cardiac arrhythmia in two of six dogs. No dogs died at this or the two higher concentrations, although one of four dogs suffered convulsions at 160,000 ppm, and one of three dogs suffered convulsions at 320,000 ppm. 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 is no data indicating individual differences in sensitivity.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 Modifying factor: Not applicable. Animal to human dosimetric adjustment: Not applied. As noted, the cardiac sensitization model with the dog heart is considered a good model for humans. Time scaling: Not applied. Cardiac sensitization is an exposure and blood concentration related threshold effect. Several studies have shown that blood concentrations of halocarbons do not increase greatly with time after 15–55 min of exposure, and exposure duration did not influence the concentration at which the effect occurred. Data adequacy: The study was well conducted and documented. Supporting data include both human and animal studies. Animal studies covered acute, subchronic, and chronic exposure durations and addressed systemic toxicity as well as neurotoxicity, reproductive and developmental effects, cardiac sensitization, genotoxicity, and carcinogenicity. Other effects in animal studies occurred at much higher concentrations or with repeated exposures; the latter are not relevant for setting short-term exposures. No deaths occurred in several species of animals exposed for various periods of time to concentrations less than those requiring supplemental oxygen (approximately 700,000 ppm).