Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 18 (2014)

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1 Bromine Chloride1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin- guished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could 1 This document was prepared by the AEGL Development Team composed of Sylvia Talmage (Oak Ridge National Laboratory), Heather Carlson-Lynch (SRC, Inc.), Chemi- cal Manager Marquea King (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). 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) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifi- cally valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 13 

14 Acute Exposure Guideline Levels experience notable discomfort, irritation, or certain asymptomatic, nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopula- tions, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic respons- es, could experience the effects described at concentrations below the corre- sponding AEGL. SUMMARY Bromine chloride is a red-brown liquid. It is formed when bromine and chlorine react reversibly in the liquid and vapor phases. When equimolar amounts of the halogens are reacted, about 60% of the mixed halogens are pre- sent as bromine chloride (about 40% is dissociated). The interhalogen com- pounds are very reactive and hydrolyze readily. Bromine chloride is used as a water-treatment biocide and in organic syn- thesis involving addition across olefinic double bonds to produce bromochloro compounds and for aromatic brominations, where an aromatic bromide and hy- drogen chloride are produced. Bromine chloride also has application as a bro- minating agent in the preparation of fire-retardant chemicals, pharmaceuticals, high-density brominated liquids, agricultural chemicals, dyes, and bleaching agents. No data relevant to deriving AEGL-1 values for bromine chloride were found. Thus, AEGL-1 values are not recommended. Relevant data for deriving AEGL-2 values for bromine chloride were also not found. However, in accordance with the standing operating procedures for developing AEGL values (NRC 2001), AEGL-2 values were determined by dividing the AEGL-3 values by 3, because the dose-response curve for bromine chloride is steep (0% lethality at 40 ppm and almost 100% lethality at 120 ppm). 

Bromine Chloride 15 For AEGL-3 values, the point-of-departure was the threshold for lethality estimated from a study by Dow Chemical (1977). In that study, the mortality rate in rats exposed to bromine chloride at 20, 40, 80, or 120 ppm for 7 h was 0/6, 0/6, 1/6, and 5/6, respectively. Benchmark concentration analysis was used to estimate the no-observed-adverse-effect level (NOAEL) for lethality (NRC 2001). The 7-h BMCL05 (benchmark concentration, 95% lower confidence limit with 5% response) was 39.4 ppm. A total uncertainty factor of 10 was applied; a factor of 3 for interspecies differences and a factor of 3 for intraspecies variabil- ity. The effects of direct-acting irritants like bromine chloride are not expected to differ significantly between species or among individuals (NRC 2001). In addition, a modifying factor of 3 was applied to account for the sparse data on bromine chloride and the uncertainty in the exposure concentrations in the Dow Chemical study. Time scaling was performed using the equation Cn × t = k. Data on bromine chloride were inadequate to derive an empirical value for n, so de- fault values of n = 3 for extrapolating to shorter durations and n = 1 for extrapo- lating to longer durations were used (NRC 2001). Because of the uncertainty associated with time scaling a 7-h point-of-departure to a 10-min value, the 10- min AEGL-3 value was set equal to the 30-min value. The AEGL values for bromine chloride are presented in Table 1-1. 1. INTRODUCTION Bromine chloride is a red-brown liquid (Lang 2006). It is formed when bromine and chlorine react reversibly in the liquid and vapor phases. When equimolar amounts of the halogens are reacted at room temperature, about 60% of the mixed halogens are present as bromine chloride (about 40% is dissociat- ed) (Dagani et al. 2000). TABLE 1-1 AEGL Values for Bromine Chloride End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 NRa NRa NRa NRa NRa Insufficient data. (nondisabling) AEGL-2 1.1 ppm 1.1 ppm 0.83 ppm 0.53 ppm 0.37 ppm One-third of the (disabling) (5.2 (5.2 (3.9 (2.5 (1.7 AEGL-3 values. mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 3.2 ppm 3.2 ppm 2.5 ppm 1.6 ppm 1.1 ppm Threshold for (lethal) (15 (15 (12 (7.6 (5.2 lethality in the rat mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (Dow Chemical Co. 1977). a Not recommended. Absence of an AEGL-1 value does not imply that exposures below the AEGL-2 value are without adverse effects. 

16 Acute Exposure Guideline Levels The physical properties of mixed halogens are generally intermediate be- tween those of the component halogens (Lang 2006; Frim and Ukeles 2011); however, mixed halogens are polar while single halogen molecules are not (Cot- ton and Wilkinson 1980). Bromine chloride is a strong oxidizing agent (Dagani et al. 2000). In general, interhalogen compounds are more chemically reactive than elemental halogens due to the weakness of the interhalogen bond (Cotton and Wilkinson 1980; Barrie et al. 2012). Among the diatomic interhalogens, bromine chloride is the least stable, dissociating reversibly to its elemental com- ponents (Cotton and Wilkinson 1980; Lang 2006). The mixed halogen compounds readily hydrolyze (Cotton and Wilkinson 1980). Bromine chloride and its dissociation products may react with water to form a variety of weak and strong acids, including hydrochloric, hypochloric, hydrobromic, and hypobromous acids. The relative proportions of the products depend on pH, but have little dependence on temperature (Liu and Margerum 2001). The following equations show some of the primary reactions (Liu and Margerum 2001; Frim and Ukeles 2011): 2BrCl ↔ Br2 + Cl2 BrCl + H2O ↔ HCl + HOBr Cl2 + H2O ↔ HOCl + HCl Br2 + H2O ↔ HOBr + HBr Ions (e.g., Br-, Cl-) may also exist in equilibrium with the molecules pre- sented above (Liu and Margerum 2001). As a result of the numerous chemical species that may be formed on contact with water, a release of bromine chloride into the atmosphere may result in human exposure to mixtures of varying com- position, depending on the environmental humidity and its pH; physiologic sources of moisture (e.g., sweat, moisture in the upper respiratory tract) may also create localized exposures to mixtures including hydrolysis products. The vapor density of bromine chloride has not been determined; however, on the basis of molecular weight (115.36 g/mol), bromine chloride vapor is ap- proximately four times heavier than dry air (average molecular weight of 28.96 g/mol at standard temperature and pressure). The chemical and physical proper- ties of bromine chloride are presented in Table 1-2. Bromine chloride is used as a water-treatment biocide. Its advantages over chlorine include activity over a wider pH range, more rapid disinfection, effec- tiveness at lower residual concentrations, and lower aquatic toxicity (Frim and Ukeles 2011). Bromine chloride is used in organic synthesis involving addition across olefinic double bonds to produce bromochloro compounds, and for aro- matic brominations, where an aromatic bromide and hydrogen chloride are pro- duced. Bromine chloride is also used as a brominating agent in the preparation of fire-retardant chemicals, pharmaceuticals, high density brominated liquids, agricultural chemicals, dyes, and bleaching agents (Frim and Ukeles 2011). 

Bromine Chloride 17 TABLE 1-2 Chemical and Physical Properties of Bromine Chloride Parameter Value References Synonyms Bromochloride HSDB 2011 CAS registry no. 13863-41-7 HSDB 2011 Chemical formula BrCl HSDB 2011 Molecular weight 115.36 HSDB 2011 Physical state Red-brown liquid at ≤5ºC HSDB 2011 Melting point -66ºC HSDB 2011 Boiling point 5ºC (decomposes) HSDB 2011 Solubility in water Reacts with water HSDB 2011 Density (water =1) 2.32 g/L at 25ºC IPCS 2009 Vapor pressure 2.368 kPa (17.8 mm Hg) at 25ºC IPCS 2009 3 Conversion factors 1 ppm = 4.72 mg/m 1 mg/m3 = 0.212 ppm 2. HUMAN TOXICITY DATA No human data on the odor threshold, lethal concentrations, developmen- tal toxicity, reproductive toxicity, genotoxicity, or carcinogenicity of bromine chloride were found. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality A single, unpublished study of the acute lethality of bromine chloride was found (Dow Chemical Co. 1977). Groups of six male Sprague-Dawley rats were exposed in a 19-L glass cylinder to bromine chloride at nominal concentrations of 550, 960, 2,110, or 2,925 ppm for 7 h. The vapor was metered from a cylinder containing liquid bromine chloride and mixed with clean air before entering the chamber. Flow rates for the vapor and clean air were used to estimate the nomi- nal concentrations. The investigators reported that the vapor had been analyzed and showed 70% chloride and 30% bromine (molar fraction); it is unclear where the sample was taken or how it was analyzed. Relative humidity in the exposure chamber was not reported, but a diagram of the exposure chamber showed that the air supply passed through a desiccant (Drierite scrubber) before entering the chamber, suggesting that the humidity was probably low. A separate experiment was conducted to measure the actual chamber con- centrations, because the rats appeared to have survived exposure at concentra- tions far above “working tolerance levels.” Six rats were exposed to bromine 

18 Acute Exposure Guideline Levels chloride at a nominal concentration of 1,100 ppm (estimated on the basis of the mass of bromine chloride liquid lost from the cylinder and air flow rate) for 5 h. Air samples were taken from the gas inlet and from the top, middle, and bottom of the chamber, once per hour; the heights of the three chamber sample inlets were not reported. The air samples were scrubbed through a solution of potassi- um iodide (1 g/50 mL) and a known amount of 0.025 N sodium thiosulfate (quantity not reported) until the scrubbing solution exhibited a yellow color in- dicating free iodine; subsequently, the samples were titrated iodometrically to a starch-iodide end point. Total halogen concentration in ppm was reported; the investigators indicated that the halogen concentration was calculated using an assumption of 70% Cl and 30% Br. The halogen concentration estimates pre- sented in Table 1-3 show that the concentration in the bottom of the chamber was roughly twice the concentrations of the middle and top of the chamber. The investigators estimated the actual exposure concentrations of bromine chloride in the acute lethality study as 4% of the nominal values. That estimate appears to be based on the average concentration in the top and middle cham- bers (approximately 42-45 ppm) divided by the nominal concentration (1,100 ppm). The actual concentrations were estimated to be 20, 40, 80, and 120 ppm (nominal concentrations of 550, 960, 2,110, and 2,925 ppm, respectively). In the lethality study, the behavior of the rats was consistent with the ob- served vapor stratification, as rats tried to breathe the air in the top of the cham- ber. The report did not indicate the frequency or duration of rearing behavior, nor the dimensions of the inhalation chamber; thus, it is unclear whether the rats were exposed primarily to vapor concentrations corresponding to the bottom, middle, or top of the chamber. However, the estimated concentrations may be conservative, as only the concentrations in the top and middle of the chamber, which were lower than those in the bottom of the chamber, were used in the calculations. Furthermore, because chlorine gas is less dense (vapor density of 1.4 [NRC 2004a]) than bromine (vapor density of 3.5 [NRC 2010]) or bromine chloride (estimated vapor density of approximately 4), the upper portions of the chamber may have contained more chlorine gas than other constituents. All rats exhibited respiratory problems during and after exposure. At all concentrations, rats lost considerable body weight and recovery to normal was slow. The death of a single rat exposed to bromine chloride at 80 ppm occurred 3 days after exposure; deaths at 120 ppm occurred during the exposure. The primary cause of death was severe upper- and lower-respiratory tract irritation. Mortality and observations over a 14-day period after exposure are presented in Table 1-4. 3.2. Developmental and Reproductive Toxicity No data on the developmental or reproductive toxicity of bromine chloride were found. 

Bromine Chloride 19 TABLE 1-3 Analytic Measurements of Bromine Chloride in the Test Chamber Concentration (ppm) in Chamber Where Sample Was Takena Time of Sample (h) Gas inlet Top Middle Bottom 1 529 78a 58 96 2 527 53 44 86 3 544 40 32 98 4 507 37 40 86 5 502 32 40 88 6 530 – – – Average 523 48 (41, excluding sample 1) 43 91 a Nominal concentration was 1,100 ppm. b Study authors believed that this sample was potentially contaminated by the initial inlet sample. Source: Adapted from Dow Chemical Co. 1977. TABLE 1-4 Mortality Data and Observations from a Study of Rats Exposed to Bromine Chloride Nominal Estimated actual concentration concentration Exposure (ppm) (ppm) Duration Mortality Observations 550 20 7h 0/6 Respiratory distress, bloody eyes and noses, yellow fur, and weight loss with slow recovery. 960 40 5h 0/6 Extreme respiratory irritation, bloody eyes and noses, and yellow fur. 960 40 7h 0/6 Respiratory distress, bloody eyes and noses, yellow fur, and weight loss with slow recovery. 2,110 80 7h 1/6 Death on day 3 after exposure; severe respiratory-tract irritation, yellow fur, and considerable weight loss with slow recovery in remaining rats. 2,925 120 7h 5/6 Deaths during exposure; severe upper- and lower-respiratory tract irritation and subsequent mouth breathing. Yellow fur and extreme weight loss with slow recovery in surviving rat. Source: Adapted from Dow Chemical Co. 1977. 

20 Acute Exposure Guideline Levels 3.3. Genotoxicity No data on the genotoxicity of bromine chloride were found. 3.4. Chronic Toxicity and Carcinogenicity No data on the chronic toxicity or carcinogenicity of bromine chloride were found. 3.5. Summary A single study on the lethality of bromine chloride was found. Groups of six male Sprague-Dawley rats were exposed at concentrations of 20, 40, 80, or 120 ppm for 7 h (Dow Chemical Co. 1977). Mortality rates at those concentra- tions were 0/6, 0/6, 1/6, and 5/6, respectively. All rats experienced respiratory problems during and after the exposure. No data on developmental toxicity, re- productive toxicity, genotoxicity, and chronic toxicity or carcinogenicity of bromine chloride were found. 4. SPECIAL CONSIDERATIONS 4.1. Metabolism and Disposition No information on the metabolism or disposition of bromine chloride in humans or animals is available. 4.2. Mechanism of Toxicity Halogens are contact irritants. Death in the single study of bromine chlo- ride was due to severe irritation of the upper- and lower-respiratory tract (Dow Chemical Co. 1977), providing evidence for the direct contact mode of action. 4.3. Structure-Activity Relationships In the atmosphere, bromine chloride is expected to exist in equilibrium with its dissociation and hydrolysis products, including chlorine, bromine, hy- drogen chloride, and hydrogen bromide. Although the data on bromine chloride is sparse, information is available on the toxicity of its dissociation and hydroly- sis products, all of which exhibit similar direct-contact irritation modes of ac- tion. Table 1-5 shows LC50 (lethal concentration, 50% lethality) values for the four compounds in the mouse and rat, along with the 7-h rat LC50 for bromine chloride. The LC50 values suggest that chlorine and bromine are more toxic than the hydrogenated forms, and that chlorine may be somewhat more toxic than 

Bromine Chloride 21 bromine. In addition, time-scaling the 1-h rat LC50 values for chlorine using the equation Cn × t = k (n =2 [NRC 2004a]) results in estimated 7-h LC50 values of 110-170 ppm, compared with the LC50 of 98 ppm for bromine chloride estimated from the study by Dow Chemical Co. (1977). Thus, on the basis of sparse (and uncertain) data, the lethality of bromine chloride appears to be comparable to that of chlorine. 4.4. Other Relevant Information 4.4.1. Species Variability No data on species variability in response to bromine chloride were found. For other halogens, the mouse appeared to be slightly more sensitive than the rat (see Table 1-5). 4.4.2. Susceptible Populations No data on populations susceptible to the effects of bromine chloride were found. Individuals with respiratory diseases or individuals under stress may be more susceptible to the effects of bromine chloride. TABLE 1-5 Comparison of LC50 Values for Bromine Chloride and Its Dissociation and Hydrolysis Products Chemical 30 min 1h 2h 3h 6h 7h Mouse Chlorinea 127 137 <170 <10 - ~250 b Bromine 174 – 240 >40 <22 >750 c Hydrogen chloride 2,600 1,108 – – – – d Hydrogen bromide – 814 – – – – Rat Bromine chloride – – – – – 98d a Chlorine 700 293-455 – – – – b Bromine – – – – – – c Hydrogen chloride 4,700 3,124 – – – – e f Hydrogen bromide >1,300 2,858 – – – – a NRC 2004a. b NRC 2010. c NRC 2004b. d Dow Chemical Co. 1977; based on estimated actual exposure concentrations. e Stavert et al. 1991. f MacEwen and Vernot 1972. 

22 Acute Exposure Guideline Levels 4.4.3. Concentration-Exposure Duration Relationship No data on concentration-exposure duration relationships for bromine chloride were found. 4.4.4. Concurrent Exposure Issues No data on concurrent exposure issues for bromine chloride were found. 5. DATA ANALYSIS FOR AEGL-1 5.1. Human Data Relevant to AEGL-1 No data on human exposure to bromine chloride were found. 5.2. Animal Data Relevant to AEGL-1 No animal data on bromine chloride relevant to developing AEGL-1 val- ues were found. 5.3. Derivation of AEGL-1 Values No data relevant to deriving AEGL-1 values for bromine chloride were available. Therefore, AEGL-1 values are not recommended. 6. DATA ANALYSIS FOR AEGL-2 6.1. Human Data Relevant to AEGL-2 No data on human exposure to bromine chloride were found. 6.2. Animal Data Relevant to AEGL-2 Seven-hour exposures of rats to analytically-determined concentrations of bromine chloride at 20, 40, 80, or 120 ppm resulted in mortality rates of 0/6, 0/6, 1/6, and 5/6, respectively (Dow Chemical Co. 1977). Severe clinical signs and respiratory problems were observed at all concentrations. Those effects are more severe than those defined by AEGL-2 values. 6.3. Derivation of AEGL-2 Values No data relevant to deriving AEGL-2 values for bromine chloride were available. The dose-response curve for bromine chloride is steep, with 0, 17, and 

Bromine Chloride 23 83% mortality at 40, 80, and 120 ppm, respectively (Dow Chemical Company 1977). In accordance with NRC (2001) guidelines for chemicals with steep dose-response curves, the AEGL-2 values were derived by dividing the AEGL-3 values by 3 (see Section 7.3). AEGL-2 values for bromine chloride are presented in Table 1-6; the calculations are presented in Appendix A and a category graph of AEGL values and toxicity data is presented in Appendix B. 7. DATA ANALYSIS FOR AEGL-3 7.1. Human Data Relevant to AEGL-3 No data on human exposure to bromine chloride were found. 7.2. Animal Data Relevant to AEGL-3 Seven-hour exposures of rats to estimated concentrations of bromine chlo- ride at 20, 40, 80, or 120 ppm resulted in mortality rates of 0/6, 0/6, 1/6, and 5/6, respectively (Dow Chemical Co. 1977). Severe clinical signs and respiratory problems were observed at all concentrations. The death at 80 ppm occurred 3 days after exposure. 7.3. Derivation of AEGL-3 Values Benchmark concentration analysis was applied to the Dow Chemical Co. (1977) data to estimate the NOAEL for lethality (NRC 2001). The data yielded a 7-h BMCL05 of 39.4 ppm and BMC01 of 60.2 ppm (see Appendix C). The BMCL05 of 39.4 ppm was selected as the point-of-departure. A total uncertainty factor of 10 was applied; a factor of 3 for interspecies differences and a factor of 3 for intraspecies variability. The effects of direct-acting irritants like bromine chloride are not expected to differ significantly between species or among indi- viduals (NRC 2001). A modifying factor of 3 was applied to account for the sparse data on bromine chloride and the uncertainty in the exposure concentra- tions in the Dow Chemical study. Time scaling was performed using the equa- tion Cn × t = k. Data on bromine chloride were inadequate to derive an empirical value for n, so default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations were used (NRC 2001). Because of the uncertainty associated with time scaling a 7-h point-of-departure to a 10-min value, the 10-min AEGL-3 value was set equal to the 30-min value. AEGL-3 values for bromine chloride are presented in Table 1-7; the calculations are pre- sented in Appendix A and a category graph of AEGL values and toxicity data is presented in Appendix B. 

24 Acute Exposure Guideline Levels 8. SUMMARY OF AEGLS 8.1. AEGL Values and Toxicity End Points AEGL values for bromine chloride are presented in Table 1-8, and a summary of the derivations is provided in Appendix D. 8.2. Other Standards and Guidelines There are no other standards or guidelines for bromine chloride. AEGL values for the dissociation and hydrolysis products of bromine chloride (includ- ing chlorine, bromine, hydrogen chloride, and hydrogen bromide) are presented in Table 1-9 for comparison with the values derived for bromine chloride. The comparison suggests that the AEGLs for bromine chloride, which are lower than those of chlorine, should be protective. Although bromine appears to be some- what less toxic than chlorine (see Table 1-5), the AEGL-3 values for bromine are lower than those for chlorine as a consequence of the less robust database on bromine. 8.3. Data Adequacy and Research The database on bromine chloride is sparse. Only a single, unpublished acute lethality study is available (Dow Chemical Co. 1977). The exposure con- centrations in the study are uncertain as a result of vapor stratification in the chamber and lack of concentration measurements during the study. The AEGL values derived for bromine chloride are supported by comparison to AEGL val- ues for its dissociation and hydrolysis products. However, additional studies of the acute toxicity of bromine chloride, with analysis of actual exposure concen- trations and speciation of the compounds in the exposure chamber, should be conducted to refine the AEGL-3 values and provide data relevant to AEGL-2 and AEGL-1 end points. Additional studies comparing the acute toxicity of bromine chloride with that of its dissociation and hydrolysis products would also be beneficial. TABLE 1-6 AEGL-2 Values for Bromine Chloride 10 min 30 min 1h 4h 8h 1.1 ppm 1.1 ppm 0.83 ppm 0.53 ppm 0.37 ppm (5.2 mg/m3) (5.2 mg/m3) (3.9 mg/m3) (2.5 mg/m3) (1.7 mg/m3) TABLE 1-7 AEGL-3 Values for Bromine Chloride 10 min 30 min 1h 4h 8h 3.2 ppm 3.2 ppm 2.5 ppm 1.6 ppm 1.1 ppm (15 mg/m3) (15 mg/m3) (12 mg/m3) (7.6 mg/m3) (5.2 mg/m3) 

Bromine Chloride 25 TABLE 1-8 AEGL Values for Bromine Chloride Exposure Duration Classification 10 min 30 min 1h 4h 8h AEGL-1 NRa NRa NRa NRa NRa (nondisabling) AEGL-2 1.1 ppm 1.1 ppm 0.83 ppm 0.53 ppm 0.37 ppm (disabling) (5.2 mg/m3) (5.2 mg/m3) (3.9 mg/m3) (2.5 mg/m3) (1.7 mg/m3) AEGL-3 3.2 ppm 3.2 ppm 2.5 ppm 1.6 ppm 1.1 ppm (lethal) (15 mg/m3) (15 mg/m3) (12 mg/m3) (7.6 mg/m3) (5.2 mg/m3) a Not recommended. Absence of an AEGL-1 value does not imply that exposures below the AEGL-2 value are without adverse effects. TABLE 1-9 AEGL Values for Bromine Chloride and Its Dissociation and Hydrolysis Products Exposure Duration Classification 10 min 30 min 1h 4h 8h Bromine Chloride AEGL-1 NRa NRa NRa NRa NRa AEGL-2 1.1 ppm 1.1 ppm 0.83 ppm 0.53 ppm 0.37 ppm AEGL-3 3.2 ppm 3.2 ppm 2.5 ppm 1.6 ppm 1.1 ppm Chlorine (NRC 2004a) AEGL-1 0.50 ppm 0.50 ppm 0.50 ppm 0.50 ppm 0.50 ppm AEGL-2 2.8 ppm 2.8 ppm 2.0 ppm 1.0 ppm 0.70 ppm AEGL-3 50 ppm 28 ppm 20 ppm 10 ppm 7.1 ppm Bromine (NRC 2010) AEGL-1 0.033 ppm 0.033 ppm 0.033 ppm 0.033 ppm 0.033 ppm AEGL-2 0.55 ppm 0.33 ppm 0.24 ppm 0.13 ppm 0.095 ppm AEGL-3 19 ppm 12 ppm 8.5 ppm 4.5 ppm 3.3 ppm Hydrogen Chloride (NRC 2004b) AEGL-1 1.8 ppm 1.8 ppm 1.8 ppm 1.8 ppm 1.8 ppm AEGL-2 100 ppm 43 ppm 22 ppm 11 ppm 11 ppm AEGL-3 620 ppm 210 ppm 100 ppm 26 ppm 26 ppm Hydrogen Bromide (NRC 2014) AEGL-1 1.0 ppm 1.0 ppm 1.0 ppm 1.0 ppm 1.0 ppm AEGL-2 250 ppm 83 ppm 40 ppm 10 ppm 5 ppm AEGL-3 740 ppm 250 ppm 120 ppm 31 ppm 15 ppm a Not recommended. Absence of an AEGL-1 value does not imply that exposures below the AEGL-2 value are without adverse effects. 

26 Acute Exposure Guideline Levels 9. REFERENCES Barrie, M.D., D.L. Dahlstrom, E. Goswami, and R. Kaetzel. 2012. The halogens. Pp. 1033-1108 in Patty’s Industrial Hygiene and Toxicology, 6th Ed., E. Bingham, and B. Cohrssen, eds New York: Wiley. Cotton, F.A., and G. Wilkinson. 1980. Advanced Inorganic Chemistry: A Comprehensive Text, 4th Ed. New York: John Wiley and Sons. Dagani, M.J., H.J. Barda, T.J. Benya, and D. C. Sanders. 2000. Bromine compounds. In Ullmann’s Encyclopedia of Industrial Chemistry, New York: John Wiley and Sons. Dow Chemical Co. 1977. Evaluation of Acute Inhalation Toxicity of Bromine Chloride in Rats. Dow Report No. 77 2993. Submitted to EPA by Dow Chemical Company, Midland, MI, with Cover Letter Dated 05/28/92. EPA Document No. 88-920002267. Frim, R., and S.D. Ukeles. 2011. Bromine, inorganic compounds. In Kirk-Othmer Ency- clopedia of Chemical Technology. New York: John Wiley and Sons. IPCS (International Programme on Chemical Safety). 2009. Bromine chloride (CAS Reg. No. 13863-41-7). International Chemical Safety Card 1713. International Pro- gramme on Chemical Safety and the Commission of the European Communities [online]. Available: http://www.ilo.org/dyn/icsc/showcard.display?p_lang=en&p_ card_id=1713 [accessed June 20, 2014]. HSDB (Hazardous Substances Data Bank). 2011. Bromine Chloride. TOXNET Toxicol- ogy Data Network, U.S. National Library of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/ [accessed June 20, 2014]. Lang, J.P. 2006. Chlorine, bromine, iodine, and astatine: Inorganic chemistry. In Ency- clopedia of Inorganic Chemistry. New York: John Wiley and Sons. Liu, Q., and D.W. Margerum. 2001. Equilibrium and kinetics of bromine chloride hy- drolysis. Environ. Sci. Technol. 35(6):1127-1133. MacEwen, J.D., and E.H. Vernot. 1972. Toxic Hazards Research Unit Annual Technical Report: 1972. AMRL-TR-72-62, AD 755 358, Aerospace Medical Research La- boratory, Wright-Patterson Air Force Base, OH [online]. Available: http://www. dtic.mil/dtic/tr/fulltext/u2/755358.pdf [accessed June 20, 2014]. NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na- tional Academy Press. NRC (National Research Council). 2004a. Chlorine. Pp. 11-76 in Acute Exposure Guide- line Levels for Selected Airborne Chemicals, Vol. 4. Washington, DC: The Na- tional Academies Press. NRC (National Research Council). 2004b. Hydrogen chloride. Pp. 77-122 in Acute Ex- posure Guideline Levels for Selected Airborne Chemicals, Vol. 4. Washington, DC: The National Academies Press. NRC (National Research Council). 2010. Bromine. Pp. 13-45 in Acute Exposure Guide- line Levels for Selected Airborne Chemicals, Vol. 9. Washington, DC: The Na- tional Academies Press. NRC (National Research Council). 2014. Hydrogen bromide. Pp. 429-457 in Acute Ex- posure Guideline Levels for Selected Airborne Chemicals, Vol. 17. Washington, DC: The National Academies Press. 

Bromine Chloride 27 Stavert, D.M., D.C. Archuleta, M.J. Behr, and B.E. Lehnert. 1991. Relative acute toxici- ties of hydrogen fluoride, hydrogen chloride, and hydrogen bromide in nose- and pseudo-mouth-breathing rats. Fundam. Appl. Toxicol. 16(4):636-655. 

28 Acute Exposure Guideline Levels APPENDIX A DERIVATION OF AEGL VALUES Derivation of AEGL-1 Values Data on bromine chloride were insufficient to derive AEGL-1 values; therefore, AEGL-1 values are not recommended. Derivation of AEGL-2 Values The AEGL-2 values for bromine chloride were derived by dividing the AEGL-3 values by 3. 10-min AEGL-2: 3.2 ppm ÷ 3 = 1.1 ppm 30-min AEGL-2: 3.2 ppm ÷ 3 = 1.1 ppm 1-h AEGL-2: 2.5 ppm ÷ 3 = 0.83 ppm 4-h AEGL-2: 1.6 ppm ÷ 3 = 0.53 ppm 8-h AEGL-2: 1.1 ppm ÷ 3 = 0.37 ppm Derivation of AEGL-3 Values Key study: Dow Chemical Co. 1977. Evaluation of Acute Inhalation Toxicity of Bromine Chloride in Rats. Dow Report No. 77 2993. Submitted to EPA by Dow Chemical Company, Midland, MI, with Cover Letter Dated 05/28/92. EPA Document No. 88-920002267. Toxicity end point: Lethality threshold, BMCL05 of 39.4 ppm for a 7-h exposure (see Appendix C) Time scaling: Cn × t = k; default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations (NRC 2001) (39.4 ppm ÷ 30)3 × 7 h = 15.85707 ppm-h (39.4 ppm/30)1 × 7 h = 9.19333 ppm-h Uncertainty factors: Total uncertainty factor: 10 Interspecies: 3, because the mechanism of action of direct-acting irritants is not expected to differ greatly among species. 

Bromine Chloride 29 Intraspecies: 3, because the mechanism of action of direct-acting irritants is not expected to differ greatly among individuals. Modifying factor: 3, to account for sparse database and uncertainty associated with the exposure concentrations in the key study. Calculations: 10-min AEGL-3: Set equal to the 30-min AEGL-3 value of 3.2 ppm, because of the uncertainty associate with time-scaling a 7-h point-of-departure to a 10-min value. 30-min AEGL-3: (15.85707 ppm-h ÷ 0.5 h)1/3 C = 3.2 ppm 1-h AEGL-3: (15.85707 ppm-h ÷ 1 h)1/3 C = 2.5 ppm 4-h AEGL-3: (15.85707 ppm-h ÷ 4 h)1/3 C = 1.6 ppm 8-h AEGL-3: (9.19333 ppm-h ÷ 8 h) C = 1.1 ppm 

30 Accute Exposure Guideline Levels AP PPENDIX B CATEG GORY PLOT FOR BROMIN NE CHLORID DE FIGUR RE B-1 Category y plot of toxicity data and AEGL L values for brom mine chloride. E B-1 Data Useed in Category Plot TABLE P for Brominne Chloride Source Species ppmm Minutes Category AEGL-2 1.1 10 AEGL AEGL-2 1.1 30 AEGL AEGL-2 0.83 60 AEGL AEGL-2 0.53 240 AEGL AEGL-2 0.37 480 AEGL AEGL-3 3.2 10 AEGL AEGL-3 3.2 30 AEGL AEGL-3 2.5 60 AEGL AEGL-3 1.6 240 AEGL AEGL-3 1.1 480 AEGL Dow Cheemical Co. 1977 Rat 20 420 2, respiratory disstress Rat 40 420 2, respiratory disstress Rat 40 300 2, extreme respirratory irritation Rat 80 420 SL (1/6) Rat 120 420 SL (5/6) For cateegory: 0 = no effeect, 1 = discomfo ort, 2 = disablingg, SL = some lethhality, 3 = lethalitty. 

Bromine Chloride 31 APPENDIX C DERIVATION OF BENCHMARK CONCENTRATION FOR BROMINE CHLORIDE Probit Model. (Version: 3.2; Date: 10/28/2009) Input Data File: C:/Users/hclynch.ESC1/Documents/BMDS 220/Data/lnp_Dax_Setting.(d) Gnuplot Plotting File: C:/Users/hclynch.ESC1/Documents/BMDS 220/Data/lnp_Dax_Setting.plt Wed Sep 11 12:38:40 2013 BMDS_Model_Run The form of the probability function is: P[response] = Background + (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), where CumNorm(.) is the cumulative normal distribution function Dependent variable = Effect Independent variable = Dose Slope parameter is not restricted Total number of observations = 3 Total number of records with missing values = 0 Maximum number of iterations = 250 Relative Function Convergence has been set to: 1e-008 Parameter Convergence has been set to: 1e-008 User has chosen the log transformed model Default Initial (and Specified) Parameter Values Background = 0 Intercept = -9.28868 Slope = 2.05319 Asymptotic Correlation Matrix of Parameter Estimates (***The model parameter(s) -background have been estimated at a boundary point, or have been specified by the user, and do not appear in the correlation matrix) intercept slope intercept 1 -1 slope -1 1 

32 Acute Exposure Guideline Levels Parameter Estimates 95.0% Wald Confidence Interval Variable Estimate Standard Error Lower Conf. Limit Upper Conf. Limit Background 0 NA Intercept -21.8829 9.72809 -40.9496 -2.81617 slope 4.77295 2.11983 0.61815 8.92775 NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus has no standard error. Analysis of Deviance Table Model Log (likelihood) No. Parameters Deviance Test d.f. P-value Full model -5.40673 3 Fitted model -5.40679 2 0.000114402 1 0.9915 Reduced model -11.4573 1 12.101 2 0.002357 AIC: 14.8136 Goodness of Fit Dose Estimated Probability Expected Observed Size Scaled Residual 40.0000 0.0000 0.000 0.000 6 -0.008 80.0000 0.1666 1.000 1.000 6 0.000 120.0000 0.8334 5.000 5.000 6 -0.000 Chi-square = 0.00 d.f. = 1 P-value = 0.9940 Benchmark Dose Computation Specified effect = 0.05 Risk Type = Extra risk Confidence level = 0.95 BMD = 69.4182 BMDL = 39.372 Probit Model. (Version: 3.2; Date: 10/28/2009) Input Data File: C:/Users/hclynch.ESC1/Documents/BMDS 220/Data/lnp_Dax_Setting.(d) Gnuplot Plotting File: C:/Users/hclynch.ESC1/Documents/BMDS 220/Data/lnp_Dax_Setting.plt Wed Sep 11 12:39:15 2013 BMDS_Model_Run The form of the probability function is: P[response] = Background + (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), where CumNorm(.) is the cumulative normal distribution function 

Bromine Chloride 33 Dependent variable = Effect Independent variable = Dose Slope parameter is not restricted Total number of observations = 3 Total number of records with missing values = 0 Maximum number of iterations = 250 Relative Function Convergence has been set to: 1e-008 Parameter Convergence has been set to: 1e-008 User has chosen the log transformed model Default Initial (and Specified) Parameter Values background = 0 intercept = -9.28868 slope = 2.05319 Asymptotic Correlation Matrix of Parameter Estimates (***The model parameter(s) -background have been estimated at a boundary point, or have been specified by the user, and do not appear in the correlation matrix) intercept slope intercept 1 -1 slope -1 1 Parameter Estimates 95.0% Wald Confidence Interval Variable Estimate Standard Error Lower Conf. Limit Upper Conf. Limit Background 0 NA Intercept -21.8829 9.72809 -40.9496 -2.81617 slope 4.77295 2.11983 0.61815 8.92775 NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus has no standard error. Analysis of Deviance Table Model Log (likelihood) No. Parameters Deviance Test d.f. P-value Full model -5.40673 3 Fitted model -5.40679 2 0.000114402 1 0.9915 Reduced model -11.4573 1 12.101 2 0.002357 AIC: 14.8136 Goodness of Fit Dose Estimated Probability Expected Observed Size Scaled Residual 40.0000 0.0000 0.000 0.000 6 -0.008 80.0000 0.1666 1.000 1.000 6 0.000 120.0000 0.8334 5.000 5.000 6 -0.000 Chi-square = 0.00 d.f. = 1 P-value = 0.9940 

34 Acute Exposure Guideline Levels Benchmark Dose Computation Specified effect = 0.01 Risk Type = Extra risk Confidence level = 0.95 BMD = 60.1816 BMDL = 27.4878 LogProbit Model with 0.95 Confidence Level LogProbit 1 0.8 Fraction Affected 0.6 0.4 0.2 0 BMDL BMD 0 20 40 60 80 100 120 dose 12:38 09/11 2013 FIGURE C-1 LogProbit model with 0.95 confidence level. 

Bromine Chloride 35 APPENDIX D ACUTE EXPOSURE GUIDELINE LEVELS FOR BROMINE CHLORIDE Derivation Summary AEGL-1 VALUES Data on bromine chloride were insufficient to derive AEGL-1 values; therefore, AEGL-1 values are not recommended. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 1.1 ppm 1.1 ppm 0.83 ppm 0.53 ppm 0.37 ppm Data adequacy: The database on bromine chloride was inadequate for deriving AEGL-2 values. However, because bromine chloride has a steep dose-response curve (0% mortality at 40 ppm and almost 100% mortality at 120 ppm), the AEGL-2 values were derived by dividing the AEGL-3 values by 3 (NRC 2001). AEGL-3 VALUES 10 min 30 min 1h 4h 8h 3.2 ppm 3.2 ppm 2.5 ppm 1.6 ppm 1.1 ppm Key reference: Dow Chemical Co. 1977. Evaluation of Acute Inhalation Toxicity of Bromine Chloride in Rats. Dow Report No. 77 2993 EPA Document No.: 88-920002267. Test species/Strain/Number: Rat; Sprague-Dawley; 6 males/group Exposure route/Concentrations/Durations: Inhalation; 0, 40, 80, or 120 ppm for 7 h Effects: Mortality 20 ppm: 0/6 40 ppm: 0/6 80 ppm: 1/6 (death 3 days after exposure) 120 ppm: 5/6 (deaths during exposure) End point/Concentration/Rationale: Approximate threshold for death, BMCL05 of 39.4 ppm for a 7-h exposure Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3, because the mechanism of action of direct-acting irritants is not expected to differ greatly among species. Intraspecies: 3, because the mechanism of action of direct-acting irritants in not expected to differ greatly among individuals. Modifying factor: 3, to account for the sparse database and uncertainty in the exposure concentrations in the key study. Animal-to-human dosimetric adjustment: Not applied (Continued) 

36 Acute Exposure Guideline Levels AEGL-3 VALUES Continued Time scaling: Cn × t = k; default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations (NRC 2001). The 30-min value was adopted as the 10-min value. Data adequacy: The database on lethality from exposure to bromine chloride was considered adequate. The values are supported by the rich database on lethality for the related chemical chlorine.