Toxicity of Alternatives to Chlorofluorocarbons: HFC-134a and HCFC-123 (1996)

The 1987 Montreal Protocol on Substances that Deplete the zone Layer (and its later versions) called for the phasing out of both chlorofluorocarbons (CFCs) and bromofluorocarbons (BFCs). Specifically, the treaty called for the discontinuation of production of CFCs and some related compounds (e.g., carbon tetrachloride and methyl chloroform) by January 1, 1996. Production of the Halon gases was discontinued January 1, 1994. However, the protocol does not apply to the use of existing stocks of CFCs or Halon gases.

CFCs continue to be used in large amounts in refrigeration, metal and electronics cleaning, mobile air conditioning, and sterilization. Until recently, the Halon gases were used extensively in fighting fires and were the major components of fire extinguishants. Because CFCs and Halon gases have been produced and used in such large quantities, any chemical that takes a substantial

portion of their market must have relatively low risk associated with its production, use, and disposal, as well as minimal or no toxicity and minimal impact on the environment.

In response to current concerns over the release of CFCs and BFCs into the atmosphere, their effect on the ozone layer, and upcoming restrictions on their availability, industry has been searching for substitute chemicals that will perform the same functions as the CFCs and BFCs without adversely affecting human health or the environment.

Two of the chemical classes under consideration for replacing CFCs are hydrochlorofluorocarbons (HCFCs) and hydrofluorocarbons (HFCs). HCFCs contribute to the destruction of stratospheric ozone, but to a much lesser extent than CFCs. Use of HCFCs as transitional refrigerants will allow industry to phase out the production of CFCs and will offer environmental benefits over the continued use of CFCs. Because they contain hydrogen, HCFCs break down more easily in the atmosphere than do CFCs. Therefore, HCFCs have less ozone depletion potential, in addition to less global-warming potential.

HFCs do not contain chlorine and do not contribute to destruction of stratospheric ozone. However, some HFCs have a significant global-warming potential. Although a few HFCs have been in use for some time, the potential for HFCs as a replacement for CFCs has grown rapidly over the last several years. The U.S. Environmental Protection Agency (EPA) is concerned that rapid expansion of the use of some HFCs could contribute to global warming. Nonetheless, use of HFCs offers lower overall risk than use of CFCs as well as a reduction in the time needed to eliminate CFC use.

The U.S. Navy, as an extensive user of refrigeration equipment, is in the process of replacing CFC refrigerants used aboard ships

and submarines. Due to a concern for potential reproductive, developmental, and neurobehavioral effects from exposure to HFCs, the Navy's Bureau of Medicine asked the National Research Council (NRC) to review the toxicity data on HFC-134a, a prime candidate for the replacement of Freon 12 (dichlorofluoromethane). 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 has 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 Air Force, the 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.

The NRC assigned these tasks to the Committee on Toxicology (COT), which established the Subcommittee to Review Toxicity of Alternatives to Chlorofluorocarbons. The subcommittee reviewed applicable scientific documents, including reports prepared by EPA that assessed the toxicological data on potential CFC substitutes—HFCs and HCFCs. This report presents the subcommittee's assessment of (1) the toxicity of specific substitutes (1,1,1,2-tetrafluoroethane (HFC-134a) and 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123)), (2) the various methods used to quantify the toxicological effects of CFCs and their substitutes, including proposed EEGLs and CEGLs, and a model used to evaluate and quantify the risks of cardiac sensitization from exposure to CFCs and their substitutes, and (3) data gaps and future research needs.

An EEGL is defined as a ceiling guidance level for single emer-

gency exposures, usually lasting from 1 hr to 24 hr—an occurrence expected to be infrequent in the lifetime of a person. “Emergency” connotes a rare and unexpected situation with potential for significant loss of life, property, or mission accomplishment if not controlled. An EEGL can also be set for much shorter periods, such as 1-min or 5-min exposures. An EEGL, a single ceiling or upper number for a particular exposure period, specifies and reflects the subcommittee 's interpretation of available information in the context of an emergency.

An EEGL is acceptable only in an emergency, when some risks or some discomfort must be endured to prevent greater risks (such as fire, explosion, or massive release). Even in an emergency, exposure should be limited to a defined short period. Exposure at the EEGL might produce such effects as increased respiratory rate from increased carbon dioxide exposure, headache or mild centralnervous-system effects from carbon monoxide exposure, or respiratory-tract or eye irritation from ammonia, phosgene, or sulfur dioxide exposure. The EEGL is intended to prevent irreversible harm. Even though some reduction in performance is permissible, it should not prevent proper responses to the emergency (such as shutting off a valve, closing a hatch, removing a source of heat or ignition, or using a fire extinguisher). For example, in normal work situations, a degree of upper-respiratory-tract irritation or eye irritation causing discomfort would not be considered acceptable; during an emergency, it would be acceptable if it did not cause irreversible harm or seriously affect judgment or performance. The EEGL for a substance represents the subcommittee's judgment based on evaluation of experimental and epidemiological data, mechanisms of injury, and, when possible, operating conditions in which emergency exposure might occur, as well as consideration of DOD goals and objectives.

Acute toxicity is the primary basis for establishing an EEGL. However, even brief exposure to some substances might have the potential to increase the risk of cancer or other delayed effects. If

the substance under consideration is carcinogenic, a cancer risk assessment is performed with the aim of providing an estimate of the exposure that would not lead to an excess risk of cancer greater than 1 in 10,000 exposed persons. The acceptable risk selected for military exposures is based on considerations of policy and objectives of DOD.

In estimating the EEGL for a substance that has multiple biological effects, all end points—including reproductive (in both sexes), developmental, carcinogenic, neurotoxic, respiratory, and other organ-related effects —are evaluated, and the most important is selected. If confidence in the available data is low or if important data are missing, appropriate safety factors are used and the rationale for their selection is stated. Generally, EEGLs have been developed for exposure to single substances, although emergency exposures often involve complex mixtures of substances and thus have a potential for toxic synergism. In the absence of other information, guidance levels for complex mixtures can be developed from EEGLs by assuming as a first approximation that the toxic effects are simply additive—thus implying a proportional reduction in EEGLs for each of the constituents of a mixture.

The CEGL is a ceiling guidance level set to avoid adverse health effects, either immediate or delayed, of prolonged exposures and to avoid degradation in crew performance that might endanger the objectives of a particular mission as a consequence of continuous exposure for up to 90 days. In contrast with EEGLs, which are intended to guide exposures during emergencies (exposures that, although not acceptable under normal operating conditions, should not cause serious or permanent effects), CEGLs are intended to provide guidance for operations lasting up to 90 days in closed environments such as in a submarine.

This report consists of the following: Chapter 2 contains an evaluation of the suitability of the current method for detecting and quantifying the risk of cardiac sensitization from exposure to CFCs and their substitutes. Chapter 3 reviews the toxicity data on HFC-134a and recommends 1-hr and 24-hr EEGLs and a 90-day CEGL. Chapter 4 evaluates the adequacy of the 1-min EEGL proposed by Air Force toxicologists for exposure to HCFC-123. Supporting documentation on HCFC-123 is contained in Appendix A and attachment 1, attachment 2, attachment 3 and attachment 4. That information was generated either by the Air Force toxicologists or the manufacturer of HCFC-123. The subcommittee reviewed but did not participate in the preparation of Appendix A and its attachments.