Executive Summary

In 1987, the Montreal Protocol on Substances That Deplete the Ozone Layer and its later versions called for phasing out chlorofluorocarbons (CFCs) (e.g., CFC-12, CFC-113, and CFC-114) and bromofluorocarbons (BFCs) (e.g., Halon gases). CFCs are still being used in large amounts in refrigeration, metal and electronics cleaning, mobile air conditioning, and sterilization. Until recently, Halon gases were the major components of fire extinguishants and were used extensively in fighting fires. Because CFCs and Halon gases have been produced and used in large quantities, any chemical that replaces them on a large scale must have relatively low risks associated with its production, use, and disposal, as well as minimal toxicity and impact on the environment.

Two of the chemical classes under consideration for replacing CFCs are hydrochlorofluorocarbons (HCFCs) and hydrofluoro-



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Toxicity of Alternatives to Chlorofluorocarbons: HFC-134a and HCFC-123 Executive Summary In 1987, the Montreal Protocol on Substances That Deplete the Ozone Layer and its later versions called for phasing out chlorofluorocarbons (CFCs) (e.g., CFC-12, CFC-113, and CFC-114) and bromofluorocarbons (BFCs) (e.g., Halon gases). CFCs are still being used in large amounts in refrigeration, metal and electronics cleaning, mobile air conditioning, and sterilization. Until recently, Halon gases were the major components of fire extinguishants and were used extensively in fighting fires. Because CFCs and Halon gases have been produced and used in large quantities, any chemical that replaces them on a large scale must have relatively low risks associated with its production, use, and disposal, as well as minimal toxicity and impact on the environment. Two of the chemical classes under consideration for replacing CFCs are hydrochlorofluorocarbons (HCFCs) and hydrofluoro-

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Toxicity of Alternatives to Chlorofluorocarbons: HFC-134a and HCFC-123 carbons (HFCs). HCFCs break down more easily in the atmosphere than do CFCs. HCFCs have less stratospheric-ozone-depletion potential and less global-warming potential. Use of HCFCs as transitional refrigerants will enable industry to phase out the production of CFCs and will offer environmental benefits over the continued use of CFCs. HFCs do not contain chlorine or contribute to destruction of stratospheric ozone. However, some HFCs might contribute to global warming. Although a few HFCs have been in use for some time, their potential use as replacements for CFCs has grown rapidly over the past several years. Concern has been raised that rapid expansion of the use of some HFCs might contribute to global warming. Nonetheless, use of HFCs not only offers lower overall risk to the environment than use of CFCs but also offers a reduction in the time needed to eliminate use of CFCs. The U.S. Department of Defense (DOD) needs exposure guidance levels for the alternatives to CFCs for emergencies and for continuous exposures of up to 90 days. Therefore, the Navy's Bureau of Medicine asked the National Research Council (NRC) to review the toxicity data on HFC-134a, a prime candidate for replacing CFC-12 (dichlorofluoromethane), which is used in refrigeration systems and medical aerosols. The Navy also asked the NRC to recommend 1-hr and 24-hr emergency exposure guidance levels (EEGLs) and a 90-day continuous exposure guidance level (CEGL) for HFC-134a and identify appropriate research to fill data gaps. Similarly, the Air Force requested that the NRC evaluate the adequacy of the 1-min EEGL proposed by Air Force toxicologists for exposure to HCFC-123. HCFC-123 is a proposed substitute for Halon 1211, the fire extinguishant currently used by the Air Force. In addition to the requests made by the Navy and the Air Force, the U.S. Environmental Protection Agency (EPA) asked the NRC to assess the suitability of current methods for detecting and quantifying the risk of cardiac sensitization from exposure to CFCs and their substitutes.

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Toxicity of Alternatives to Chlorofluorocarbons: HFC-134a and HCFC-123 The NRC assigned the project to the Committee on Toxicology (COT), which established the Subcommittee to Review Toxicity of Alternatives to Chlorofluorocarbons. The subcommittee prepared this report. ASSESSMENTOF MODELFOR CARDIAC SENSITIZATION Inhalation of some chlorinated hydrocarbons, such as CFCs and volatile anesthetics, can make the mammalian heart abnormally sensitive to epinephrine, resulting in cardiac arrhythmias and possibly death. The phenomenon is referred to as cardiac sensitization and can be experimentally induced by most halocarbons (e.g., carbon tetrachloride and chloroform) and some hydrocarbons (e.g., cyclopropane and n-hexane). The subcommittee evaluated the suitability of the available dog cardiac-sensitization test developed by the DuPont Company for quantifying the risk of cardiac sensitization from exposure to CFCs and other related chemicals. In the cardiac-sensitization test, dogs are intravenously administered epinephrine at doses of 5-12 µg/kg and monitored for cardiac arrhythmias for 5 min. If no arrhythmias occur, the animals are exposed to the test chemical. After 5 min of exposure, the dog is given a second challenge injection of epinephrine, and the exposure to the test chemical is continued for an additional 5 min. The criterion for cardiac sensitization is the induction of ventricular fibrillation as monitored by an electrocardiogram. The test has been used to study the cardiac-sensitization potential of many chemicals. The subcommittee concludes that the dog cardiac-sensitization test is effective in determining the potential of chemicals to sensitize the myocardium to epinephrine-induced arrhythmias. Although the dog cardiac-sensitization test is performed under conditions that are optimized for the induction of arrhythmias in animals, humans exposed to high concentrations of some halocarbons develop arrhythmias. Therefore, uncertainty factors are necessary when performing risk assess-

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Toxicity of Alternatives to Chlorofluorocarbons: HFC-134a and HCFC-123 ment for humans. The subcommittee recommends that the mechanism of cardiac sensitization be determined and that a more sensitive test be developed that permits adequate safety evaluation of halocarbons that will replace the currently used CFCs. This topic will be addressed in greater detail in 1996 in a workshop on toxicity of alternatives to CFCs, which is being organized by the NRC's Committee on Toxicology. EXPOSURE GUIDANCE LEVELSFOR HFC-134A The 1-hr EEGL recommended by the subcommittee for HFC-134a is 4,000 parts per million (ppm). This recommendation is based on a no-observed-adverse-effect level (NOAEL) of 40,000 ppm, which was identified in cardiac-sensitization tests of male beagles exposed to HFC-134a at concentrations of 40,000, 80,000, 160,000, and 320,000 ppm and simultaneously injected with epinephrine. Cardiac sensitization was observed in dogs exposed at the three highest concentrations but not at the lowest concentration of 40,000 ppm. Fetotoxic effects, such as a slight retardation of skeletal ossification, were observed in rats and rabbits at lower concentrations than those producing cardiac sensitization in dogs, but the NOAELs (20,000 ppm for rabbits exposed for 78 hr and 10,000 ppm for rats exposed for 240 hr) identified in the rat and rabbit tests cannot be used to establish a 1-hr EEGL because the animals were exposed to HFC-134a for much longer periods. (HFC-134a was not teratogenic or embryotoxic with exposures at concentrations up to 50,000 ppm.) Using the NOAEL of 40,000 ppm identified in dog cardiac-sensitization studies, the subcommittee determined the 1-hr EEGL to be 4,000 ppm (40,000 ppm divided by an uncertainty factor of 10 to allow for interspecies variability). Because blood concentrations of halogenated hydrocarbons are not likely to increase when exposure time is increased beyond 5-10 min, the NOAEL identified for cardiac sensitization following a 10-min exposure can be used without time extrapolation to set a 1-hr EEGL.

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Toxicity of Alternatives to Chlorofluorocarbons: HFC-134a and HCFC-123 The recommended 24-hr EEGL is based on the fetotoxicity effects (slight retardation of skeletal ossification) observed in rats. Using a NOAEL of 10,000 ppm in rats, the subcommittee determined the 24-hr EEGL to be 1,000 ppm (10,000 ppm divided by an uncertainty factor of 10 to allow for interspecies variability). The maternal toxicity effects observed in rabbits were not used to determine the 24-hr EEGL because the effects observed were limited to body-weight changes, which the subcommittee did not judge to be an important adverse effect. The recommended 90-day CEGL is based on a 2-year chronic toxicity study conducted in male rats exposed to HFC-134a at concentrations of 2,500, 10,000, or 50,000 ppm for 6 hr/day, 5 days/wk. The study identified 50,000 ppm as the NOAEL. An increase in testicular weight and benign Leydig tumors occurred at that dose. However, the subcommittee did not judge the increase in testicular weight to be an adverse effect. In addition, the increase in Leydig tumors is not applicable to humans because they are related to some unique aspect of rodent metabolism; therefore, the subcommittee identified 50,000 ppm as the NOAEL. Using the NOAEL of 50,000 ppm, the subcommittee determined the 90-day CEGL to be 900 ppm (50,000 ppm divided by an uncertainty factor of 10 to account for interspecies variability, a factor of 4 for a 24-hr/day exposure vs. a 6-hr/day exposure, and a factor of 5/7 for a 7-days/wk exposure vs. a 5-days/wk exposure). The subcommittee's proposed 1-hr and 24-hr EEGLs and the 90-day CEGL recommendations for HFC-134a are as follows: Proposed Recommendations for HFC-134a by the Subcommittee Exposure Concentration, ppm 1-hr EEGL 4,000 24-hr EEGL 1,000 90-day CEGL 900

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Toxicity of Alternatives to Chlorofluorocarbons: HFC-134a and HCFC-123 Although the recommended 24-hr EEGL of 1000 ppm and 90-day CEGL of 900 ppm are similar, they are based on different end points or target toxicities. The similarity of the exposure guidance levels recommended for 24-hr and 90-day exposures is consistent with the fact that blood concentrations of CFCs or their substitutes reach maximal levels within minutes of the onset of exposure, and continued exposure for many hours or days does not increase blood concentrations further or lead to the buildup of the chemical in the body. EXPOSURE GUIDANCE LEVELFOR HCFC-123 For HCFC-123, the end points of pharmacological or adverse effects considered for establishing an EEGL are cardiac sensitization, anesthesia or CNS-related effects, malignant hyperthermia, and hepatotoxicity. Cardiac sensitization was chosen as the most sensitive end point because of the potent sensitizing effect of this chemical and similar chemicals in epinephrine-challenged dogs. The EC50 (concentration required to produce cardiac sensitization in 50% of the animals) for HCFC-123 was determined in dog studies to be 1.9% (19,000 ppm) for a 5-min exposure. The Air Force toxicologists recommended that the EC50 of 19,000 ppm be the 1-min EEGL for HCFC-123. However, the subcommittee believes that 1,900 ppm (19,000 ppm divided by an uncertainty factor of 10 for interspecies variability) should be considered the human no-observed-effect level (NOEL) for a 1-min exposure to HCFC-123 on the basis of the dog cardiac-sensitization model. Therefore, the subcommittee recommends that the 1-min EEGL of 19,000 ppm proposed by the Air Force be lowered to 1,900 ppm.