Summary

IN ACCORDANCE WITH the Montreal Protocol on Substances That Deplete the Ozone Layer, which calls for phasing out the use of chlorofluorocarbons (CFCs), the U.S. Navy proposes to replace CFC refrigerants aboard its submarines with hydrofluorocarbons HFC-236fa and HFC-404a. To protect submariners from adverse health effects resulting from exposure to accidental releases of those compounds, the Navy plans to set emergency exposure guidance levels (EEGLs) and continuous exposure guidance levels (CEGLs) for them.

An EEGL is defined as a concentration of a substance in air that is judged to be acceptable for the performance of specific tasks during rare emergency conditions lasting for periods of 1-24 hr. EEGLs are intended to prevent irreversible harm and degradation in crew performance. Temporary discomfort, such as eye or upper-respiratory-tract irritation, is permissible as long as there is no effect on judgment, performance, or ability to respond to an emergency.

To protect submariners from exposures that are longer than 24 hr, CEGLs are set to provide a ceiling guidance level for up to 90 days of continuous exposure to a substance. The intent of a CEGL is to avoid any adverse health effects, either immediate or delayed, associated with prolonged exposures and to avoid any degradation in performance. Some conditions, such as a slight headache, which might be acceptable for short periods in emergency situations, are not permissible for longer-term exposures.

The Navy proposes to use the same exposure guidance levels for HFC-



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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a Summary IN ACCORDANCE WITH the Montreal Protocol on Substances That Deplete the Ozone Layer, which calls for phasing out the use of chlorofluorocarbons (CFCs), the U.S. Navy proposes to replace CFC refrigerants aboard its submarines with hydrofluorocarbons HFC-236fa and HFC-404a. To protect submariners from adverse health effects resulting from exposure to accidental releases of those compounds, the Navy plans to set emergency exposure guidance levels (EEGLs) and continuous exposure guidance levels (CEGLs) for them. An EEGL is defined as a concentration of a substance in air that is judged to be acceptable for the performance of specific tasks during rare emergency conditions lasting for periods of 1-24 hr. EEGLs are intended to prevent irreversible harm and degradation in crew performance. Temporary discomfort, such as eye or upper-respiratory-tract irritation, is permissible as long as there is no effect on judgment, performance, or ability to respond to an emergency. To protect submariners from exposures that are longer than 24 hr, CEGLs are set to provide a ceiling guidance level for up to 90 days of continuous exposure to a substance. The intent of a CEGL is to avoid any adverse health effects, either immediate or delayed, associated with prolonged exposures and to avoid any degradation in performance. Some conditions, such as a slight headache, which might be acceptable for short periods in emergency situations, are not permissible for longer-term exposures. The Navy proposes to use the same exposure guidance levels for HFC-

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a 236fa and HFC-404a that it established for two chlorofluorocarbons (CFC-12 and CFC-114): a 1-hr EEGL of 2,000 parts per million (ppm), a 24-hr EEGL of 1,000 ppm, and a 90-day CEGL of 100 ppm. The Navy also proposes to apply those guidance levels to HFC-23, a combustion product of HFC-236fa. HFC-23 is formed when escaped HFC-236fa is passed through a submarine's carbon monoxide and hydrogen burners. STATEMENT OF TASK The National Research Council (NRC) was asked to conduct an independent evaluation of the Navy's proposed exposure guidance levels for HFC-236fa, HFC-23, and HFC-404a. The NRC assigned this task to the Committee on Toxicology (COT), which convened the Subcommittee on Exposure Guidance Levels for Selected Hydrofluorocarbons, a multidisciplinary group of experts. The subcommittee was asked to review the available toxicity data on the three HFCs and to determine the scientific validity of the Navy's proposed EEGLs and CEGLs. The evaluation was to include an assessment of the relevance of animals studies for evaluating risks to humans, the completeness of the data base, the target organs of toxicity, and the appropriateness of the methods used to derive the guidance levels (e.g., correctly adjusting for exposure durations and the use of uncertainty factors). The subcommittee was asked to review the three HFCs only in the context of use aboard submarines —vessels with male personnel only. The subcommittee was also asked to identify any deficiencies in the data base on each HFC and to make recommendations for future research. Although products other than HFC-23 are formed during combustion of HFC-236fa or HFC-404a, HFC-23 was the only combustion product the subcommittee was asked to consider. APPROACH TO THE STUDY The subcommittee conducted a critical analysis of the available toxicity data on each of the HFCs and used the data to calculate possible EEGLs and CEGLs according to the guidelines outlined in the NRC' s 1986 report Criteria and Methods of Preparing Emergency Exposure Guidance Level (EEGL), Guidance Level (CEGL) Documents. The subcommittee also reviewed the Navy's toxicity assessments of the HFCs and used information provided in a 1996 report of

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a the NRC titled Toxicity of Alternatives to Chlorofluorocarbons: HFC-134a and HCFC-123, which provides a toxicity assessment and establishes EEGLs and CEGLs for HFC-134a, a component of HFC-404a CONCLUSIONS AND RECOMMENDATIONS Table S-1 presents a comparison of the EEGLs and CEGLs recommended by the subcommittee with those proposed by the Navy. The subcommittee concludes that the guidance levels proposed by the Navy are unnecessarily conservative. In all cases, the subcommittee's recommended levels are greater than those proposed by the Navy. The reason for the difference is that the Navy did not use data on the HFCs to calculate the proposed exposure guidance levels, but rather proposed to use the same guidance levels established for chlorofluorocarbons CFC-12 and CFC-114. The subcommittee believes there are adequate data on the individual HFCs to calculate scientifically valid exposure guidance levels. TABLE S-1 Submarine Exposure Guidance Levels Exposure NRC Levels,a ppm Navy Levels,b ppm HFC-236fa 1-hr EEGL 10,000 2,000 24-hr EEGL 2,000 1,000 90-day CEGL 350 100 HFC-23 1-hr EEGL 20,000 2,000 24-hr EEGL 5,000 1,000 90-day CEGL 500 100 HFC-404a 1-hr EEGL 12,900 2,000 24-hr EEGL 4,300 1,000 90-day CEGL 800 100 aCalculated on the basis of the available data. bThe proposed exposure guidance levels are the same as those previously established for chlorofluorocarbons CFC-12 and CFC-114.

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a HFC-236fa On the basis of the available data on HFC-236fa, the subcommittee recommends a 1-hr EEGL of 10,000 ppm, a 24-hr EEGL of 2,000 ppm, and a 90-day CEGL of 350 ppm. The 1-hr EEGL is based on a cardiac sensitization study in which the no-observed-adverse-effect level (NOAEL) for HFC-236fa in dogs was 100,000 ppm for a 5-min exposure. The NOAEL was divided by an uncertainty factor of 10 to account for interspecies variability, yielding a value of 10,000 ppm for exposures up to 1 hr. A 14-week toxicity study in rats was used to determine the 24-hr EEGL for HFC-236fa. In the study, a NOAEL of 20,000 ppm was identified on the basis of decrements in “alerting response” (the response to a sudden auditory stimulus). The subcommittee had reservations about using alerting response as a toxicity end point, because effects were transient, responses were subjectively evaluated (and are known to vary among strains and individual animals), and it is unclear whether such effects are applicable to humans. However, in the absence of other data regarding effects caused by HFC-236fa, alerting response was considered to be the most appropriate available end point. A 24-hr EEGL of 2,000 ppm was determined by dividing the NOAEL of 20,000 ppm by an uncertainty factor of 10 to account for interspecies variability. The 14-week toxicity study in rats was also considered to be the most relevant study for calculating the 90-day CEGL. The NOAEL of 20,000 ppm was divided by an uncertainty factor of 10 to extrapolate from animals to humans to yield a value of 2,000 ppm. That value was adjusted to account for the discontinuous exposure regimen used in the study by multiplying 2,000 ppm by 1/4 (to account for exposure for 6 hr per day) and by 5/7 (to account for exposure five times per week), which yielded a 90-day CEGL of 350 ppm. If HFC-236fa is considered for use on vessels with female crew members, the 24-hr EEGL and 90-day CEGL might have to be reconsidered on the basis of maternal toxicity. A developmental toxicity study in rats reported reduced weight gain and decrements in alerting response in pregnant animals exposed at 20,000 ppm. That is the same concentration as the NOAEL in the 14-week toxicity study used to calculate the 24-hr EEGL and the 90-day CEGL. Uncertainties exist with regard to the effects that HFC-236fa might have on human performance. End points of narcosis and decrements in alerting response have been observed in laboratory animals, but it is unclear whether human performance would be similarly affected. Because HFC-236fa was

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a relatively nontoxic in laboratory studies and because similar HFCs, such as HFC-23 and HFC-134a, have been shown to have low toxicity in humans, the subcommittee recommends that tests be conducted with humans to determine whether HFC-236fa affects performance skills, such as motor coordination and alertness. HFC-23 The subcommittee believes that data on HFC-23 support a 1-hr EEGL of 20,000 ppm, a 24-hr EEGL of 5,000 ppm, and a 90-day CEGL of 500 ppm. The basis for the 1-hr EEGL was a human exposure study in which subjects were intermittently exposed to HFC-23 (eight exposures of 3 min each with 2-min intervals of exposure to air only). The NOAEL for the study was 200,000 ppm. To account for the discontinuous exposure, the NOAEL was divided by a factor of 10, resulting in a 1-hr EEGL of 20,000 ppm. For the 24-hr EEGL, a developmental toxicity study was used. Although such a developmental study is not necessarily the most appropriate study for deriving a 24-hr exposure guidance level, when considering the all-male population aboard submarines, that study had the most relevant exposure duration (a total of 90 hr), and no maternal or fetal effects were observed at the highest dose tested of 50,000 ppm. The NOAEL was divided by a factor of 10 to account for interspecies differences, resulting in an exposure guidance level of 5,000 ppm. The basis for the 90-day CEGL of 500 ppm was a 90-day continuous exposure study in dogs, in which the NOAEL was 5,000 ppm. That value was divided by an uncertainty factor of 10 to account for interspecies variability. HFC-404a HFC-404a is a gaseous mixture of three halocarbons—52% HFC-143a, 44% HFC-125, and 4% HFC-134a. The subcommittee believes that the most appropriate way to calculate exposure guidance levels for HFC-404a is the method used by the American Conference of Governmental Industrial Hygienists to calculate threshold limit values for special cases when the exposure of concern is a liquid mixture and the atmospheric composition is assumed to be similar to that of the original material (i.e., on a time-weighted-average exposure basis, all the liquid mixture eventually evaporates). In this case, when the percent composition by weight of the liquid mixture is

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a known, the exposure guidance levels (EGLs) can be determined using the following equation: where f is the fraction of each particular component. The component 's corresponding EGL is expressed in units of milligrams per cubic meter (mg/m3). To use this equation, it was necessary to calculate the exposure guidance levels for the individual components of HFC-404a. Exposure Guidance Levels for Components of HFC-404a The three halocarbons that comprise HFC-404a are HFC-143a, HFC-125, and HFC-134a. For component HFC-143a, the subcommittee estimated a 1-hr EEGL of 25,000 ppm on the basis of a cardiac sensitization study in dogs. The NOAEL for the study was 250,000 ppm, and an uncertainty factor of 10 was applied to account for interspecies variability. For the 24-hr EEGL, a 4-week toxicity study in rats was used; the highest tested concentration of 40,000 ppm was the NOAEL. To extrapolate from animals to humans, the NOAEL was divided by an uncertainty factor of 10, yielding a 24-hr EEGL of 4,000 ppm. A 90-day toxicity study in rats was used to calculate the 90-day CEGL for HFC-143a. The NOAEL for the study was 40,000 ppm, which was divided by 10 to account for interspecies variability; the resulting value of 4,000 ppm was adjusted to account for the study's discontinuous exposure regimen by multiplying it by 1/4 (to account for exposure for 6 hr per day) and by 5/7 (to account for exposure five times per week), which yielded a 90-day CEGL of 700 ppm. For component HFC-125, a cardiac sensitization study in dogs was used to derive a 1-hr EEGL. The NOAEL for the study was 75,000 ppm, and an uncertainty factor of 10 was applied to account for interspecies variability, yielding a 1-hr EEGL of 7,500 ppm. The subcommittee calculated a 24-hr EEGL of 5,000 ppm on the basis of a 4-week toxicity study in rats. The highest tested concentration of 50,000 ppm was the NOAEL, and that value was divided by an uncertainty factor of 10 to account for interspecies differences. For the 90-day CEGL, a 90-day toxicity study in rats was used. The NOAEL for that study was 50,000 ppm, and an uncertainty factor of 10 was applied for to account for interspecies differences. To account for the discontinuous exposure regimen used in the study, 5,000 ppm was multiplied

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SUBMARINE EXPOSURE GUIDANCE LEVELS FOR SELECTED HYDROFLUOROCARBONS: HFC-236fa, HFC-23, and HFC-404a by 1/4 (to account for exposure for 6 hr per day) and by 5/7 (to account for exposure five times per week), resulting in a 90-day CEGL of 900 ppm. In 1996, the COT reviewed the available toxicity data on HFC-134a and proposed a 1-hr EEGL of 4,000 ppm, a 24-hr EEGL of 1,000 ppm, and a 90-day CEGL of 900 ppm. Since that review, additional data on HFC-134 have become available. One of the new studies was an ascending-concentration safety study in humans, in which subjects were exposed to HFC-134a at concentrations up to 8,000 ppm for 1 hr with no adverse effects. The subcommittee believes that, on the basis of that study, a 1-hr EEGL of 8,000 ppm for HFC-134a is justified. For the 24-hr EEGL, the subcommittee used a 13-week toxicity study in rats, in which the highest concentration tested of 50,000 ppm was the NOAEL. Dividing the NOAEL by an uncertainty factor of 10 to account for interspecies variability yielded a 24-hr EEGL of 5,000 ppm. That exposure level is higher than the EEGL of 1,000 ppm recommended by the NRC in 1996. The reason for the difference is that in 1996 the NRC was determining exposure levels for use aboard Navy ships with female crew members and, therefore, based the NOAEL of 10,000 ppm on a developmental study in which fetal toxicity was observed. However, fetal toxicity is not as a relevant an end point for setting an exposure level for use on submarines, which have no female crew members. For the 90-day toxicity study, the subcommittee agreed with the NRC's earlier proposal of 900 ppm. That exposure level was based on a 2-year toxicity study, in which the NOAEL was 50,000 ppm. That value was divided by an uncertainty factor of 10 and then adjusted for the discontinuous exposure regimen used in the study by multiplying it by 1/4 (to account for exposure 6 hr per day) and by 5/7 (to account for exposure five times per week). Exposure Guidance Levels for HFC-404a Using the equation presented earlier and the exposure levels calculated above for the individual components of HFC-404a, the 1-hr EEGL, 24-hr EEGL, and 90-day CEGL for HFC-404a were calculated to be 12,900 ppm, 4,300 ppm, and 800 ppm, respectively.

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