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1 Boron Trifluoride1 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 experience notable discomfort, irritation, or certain asymptomatic, nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. 1 This document was prepared by the AEGL Development Team composed of Claudia Troxel (Oak Ridge National Laboratory), Julie Klotzbach (SRC, Inc.), Chemical Manager George Rusch (National Advisory Committee [NAC] on Acute Exposure Guideline Lev- els for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed neces- sary. Both the document and the AEGL values were then reviewed by the National Re- search Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC com- mittee has concluded 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, 2001). 13
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14 Acute Exposure Guideline Levels 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 re- sponses, could experience the effects described at concentrations below the cor- responding AEGL. SUMMARY Boron trifluoride-dimethyl ether is one of several different complexes that can be formed with boron trifluoride. The complexes are generally formed for ease of handling boron trifluoride. The ether complexes consist of a 1:1 molar ratio of boron trifluoride and the dimethyl or diethyl ether and can dissociate under the proper temperature and pressure conditions. A single study was found that addressed the toxicity of boron trifluoride-dimethyl ether, but it reported only nominal concentrations. Because the complex can dissociate to form boron trifluoride, the AEGL values are based on this one chemical species. Boron trifluoride is a colorless gas with an odor described both as pungent and suffocating and as pleasant. Although the gas is stable in dry air, it immedi- ately forms a dense white mist or cloud when exposed to moist air. Boron trifluoride reacts with moisture (even at low concentrations) to form the di- hydrate, BF3•2H2O. Boron trifluoride dihydrate is strongly corrosive to the eyes and skin of rabbits. Boron trifluoride is an excellent catalyst, and has fire retar- dant and antioxidant properties, nuclear applications, and insecticidal properties. No definitive data were available on the toxicity of inhaled boron trifluoride in humans. One study reported that a worker could detect the odor of boron trifluoride at a concentration of 4.1 mg/m3 (1.5 ppm) (Torkelson et al. 1961). Acute toxicity studies with dogs, rats, mice, and guinea pigs were avail- able, but exposure concentrations were generally expressed only in terms of nominal concentrations. Studies that measured exposure concentrations and compared them with nominal concentrations found that actual concentrations
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Boron Trifluoride 15 ranged from 2.7-56% of nominal concentrations (Torkelson et al. 1961; Rusch et al. 1986; Bowden 2005). Studies identifying end points other than mortality were few. No data were available to evaluate the potential for boron trifluoride to cause developmental or reproductive toxicity or carcinogenicity in animals. Boron trifluoride was not mutagenic in several stains of Salmonella typhi- murium. AEGL-1 values are based on a no-effect level for irritation. A group of 10 rats exposed for 4 h to measured concentrations of boron trifluoride at 25 mg/m3 had no abnormal findings, whereas rats exposed to the next higher concentration of 74 mg/m3 had histopathologic changes in the larynx and tracheal bifurcation indicative of irritation (Bowden 2005). The concentration of 25 mg/m3 was se- lected as the point of departure for calculating AEGL-1 values. The irritant ef- fects seen at 74 mg/m3 are more severe than the threshold effects for the AEGL- 1values. A total uncertainty factor of 10 was applied. An interspecies uncer- tainty factor of 3 was applied because irritation is a direct contact effect and is not expected to vary greatly among species. An intraspecies uncertainty factor of 3 was applied because the mechanism of irritation is not expected to vary greatly in subpopulations. The same AEGL value was applied to all AEGL durations because the point of departure is a no-effect level for mild irritation. Relevant data for deriving AEGL-2 values were not available. Therefore, the AEGL-3 values were divided by 3 to obtain reasonable estimates of the AEGL-2 values. Dividing AEGL-3 values by 3 is supported by the steep dose- response curve (Rusch et al. 1986). The derivation of AEGL-3 values was based on the threshold for lethality. Rusch et al. (1986) calculated a 4-h LC50 (lethal concentration 50% lethality) of 1,210 mg/m3 (exposures were to liquid aerosols of boron trifluoride dihydrate; concentrations reported are based on boron trifluoride). Using individual mortal- ity data, a 4-h BMCL05 (benchmark concentration, 95% lower confidence limit with 5% response) was calculated by a log-probit analysis using EPA Bench- mark Dose Software version 1.4.1c  (EPA 2012). The resulting 4-h BMCL05 of 554 mg/m3 was used to derive the AEGL-3 values. An interspecies uncertainty factor of 3 was applied because boron trifluoride is a corrosive irri- tant, and the mechanism of action is not expected to vary greatly among species. An intraspecies uncertainty factor of 3 was chosen, because the mechanism of irritation is not expected to vary greatly among subpopulations. An intraspecies uncertainty factor of 3 is also supported by the steep dose-response curve for lethality (3/10 rats died at 1,010 mg/m3, while 9/10 rats died at 1,540 mg/m3), which indicates little variability in the response within a population. The Rusch et al. (1986) study is supported by the Kasparov and Kiriĭ (1972) study that re- ported a 4-h LC50 of 1,180 mg/m3 in rats. Time scaling was performed using the concentration-time relationship equation Cn × t = k, where C = concentration, t = time, k is a constant, and n generally ranges from 0.8 to 3.5 (ten Berge et al. 1986). An empirical value for n could not be determined because of inadequate data, so the default value of n = 1 was used for extrapolating from shorter to longer exposure periods and a value of n = 3 was used to extrapolate from
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16 Acute Exposure Guideline Levels longer to shorter exposure periods. The 10-min value was set equal to the 30- min value because of the uncertainty associated with extrapolating data from a 4-h exposure duration to a 10-min AEGL value. The AEGL values for boron trifluoride are presented in Table 1-1. Al- though the gas is stable in dry air, boron trifluoride reacts to form the dihydrate when exposed to even low levels of moisture in the air (NIOSH 1976; Hoffman, 1981). Therefore, all AEGL values are reported only in mg/m3. 1. INTRODUCTION Boron trifluoride-dimethyl ether is one of several different complexes that can be formed with boron trifluoride. The complexes are generally formed for ease of handling of boron trifluoride (NIOSH 1976). Other complexes that can be formed include boron trifluoride with monoethylamine, water, phenol, phos- phoric acid, piperidine, dimethyl aniline, methanol, or diethyl ether (NIOSH 1976). A summary table of acute toxicity studies with some of the boron trifluoride complexes can be found in Appendix E. The ether complexes consist of a 1:1 molar ratio of boron trifluoride and either the dimethyl or diethyl ether, and can dissociate under the proper temperature and pressure conditions. A sin- gle study was found that evaluated the toxicity of boron trifluoride-dimethyl ether, but it reported only nominal concentrations. Because the complex can dissociate to form boron trifluoride, the AEGL derivations are based on this one chemical species. Boron trifluoride is a colorless gas with an odor that has been described both as pungent and suffocating (Budavari et al. 1996) and as a “rather pleasant acidic” odor (Torkelson et al. 1961). Chemical and physical data for boron trifluoride and boron trifluoride-dimethyl ether (when available) are listed in Table 1-2. Although the gas is stable in dry air, it immediately forms a dense white mist or cloud when exposed to moist air (NIOSH 1976). Hoffman (1981) reported that when exposed to moisture in the air, even at low levels, boron trifluoride reacts to form the dihydrate, BF3•2H2O. In water, boron trifluoride is believed to form the following products: fluoboric acid (HBF4), monohydroxy- fluoboric acid (HBF3OH), dihydroxyfluoboric acid (HBF2(OH)2), trihydroxyflu- roboric acid (HBF(OH)3), and boric acid (H3BO3) (NIOSH 1976). Boron trifluoride probably reacts slowly with water to form hydrogen fluoride. It has been suggested that if hydrogen fluoride is formed, it is almost immediately complexed with other species (NIOSH 1976). Dunn (1980) demonstrated that boron trifluoride dihydrate is strongly corrosive to the eyes and skin of rabbits. Topical administration of undiluted boron trifluoride dihydrate (0.1 mL) to the eye caused complete corneal opacity and necrosis of the conjunctivae, nictating membrane, and upper and lower eyelids. The corrosive action was not alleviated by irrigation of the eye with tap water. Topical application of undiluted boron trifluoride dihydrate (0.5 mL) to the skin under a semi-occlusive patch for 24 h resulted in total corrosion of the skin.
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Boron Trifluoride 17 TABLE 1-1 Summary of AEGL Values for Boron Trifluoride End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 2.5 mg/m3 2.5 mg/m3 2.5 mg/m3 2.5 mg/m3 2.5 mg/m3 No-effect level (nondisabling) for irritation at 25 mg/m3 for 4 h (Bowden 2005). AEGL-2 37 mg/m3 37 mg/m3 29 mg/m3 18 mg/m3 9.3 mg/m3 One-third (disabling) AEGL-3 values AEGL-3 110 mg/m3 110 mg/m3 88 mg/m3 55 mg/m3 28 mg/m3 4-h BMCL05 in (lethal) rats of 554 mg/m3 (Rusch et al. 1986). TABLE 1-2 Chemical and Physical Data for Boron Trifluoride Parameter Valuea Reference Synonyms Trifluoroborane; boron NIOSH 2011 trifluoride-dimethyl ether (1:1); Lewis 1996 boron trifluoride-dimethyl etherate; fluoride bority-diemthylether (1:1) CAS registry no. 7637-07-2 353-42-4 (BF3-dimethyl ether) Chemical formula BF3 C2H60•BF3 (BF3-dimethyl ether) Molecular weight 67.81 g Budavari et al. 1996 113.89 g (BF3-dimethyl ether) Lewis 1996 Physical state Gas Budavari et al. 1996 Liquid (BF3-dimethyl ether) Color Colorless Budavari et al. 1996 Melting point -128.37°C AIHA 1999 -14°C (BF3-dimethyl ether) Lewis 1996 Boiling point (760 mm Hg) -100.4°C Budavari et al. 1996 Vapor density (air =1) 3.077 g/L Budavari et al. 1996 Solubility in water 332 g/100 g at 0°C Budavari et al. 1996 Vapor pressure >1 Torr at 20°C ACGIH 1991 3 Conversion factors 1 ppm = 2.76 mg/m AIHA 1999 1 mg/m3 = 0.36 ppm (v/v) Calculated 1 ppm = 4.65 mg/m3 (BF3-dimethyl ether) a Data are for boron trifluoride unless specified otherwise. Boron trifluoride is a strong Lewis acid and is, therefore, an excellent cata- lyst that is used in polymerizations, esterifications, and alkylations (NIOSH 1976). Its fire retardant and antioxidant properties are used by the magnesium
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18 Acute Exposure Guideline Levels industry for protecting molten magnesium and its alloys from oxidation (NIOSH 1976; Budavari et al. 1996), and its nuclear applications include use in neutron detection instruments, boron-10 enrichment, and in the production of neutron- absorbing salts for molten-salt breeder reactors (NIOSH 1976). Boron trifluoride also has insecticidal properties (NIOSH 1976; Budavari et al. 1996). 2. HUMAN TOXICITY DATA 2.1. Acute Lethality No data on lethality in humans following acute inhalation exposure to bo- ron trifluoride were found. 2.2. Nonlethal Toxicity In the description of animal studies by Torkelson et al. (1961) discussed in Section 3 below, it was mentioned that a worker noted that boron trifluoride had a rather pleasant acidic odor a concentration of 4.1 mg/m3 (1.5 ppm). Stewart and Waisberg (1988) reported the only documented case of boron trifluoride poisoning found in the literature. A part-time scrap merchant knocked a valve off a gas cylinder containing boron trifluoride in his garage. A choking white gas was released, quickly overcoming him, his infant son, and his preg- nant wife. Upon admission to the hospital, hypoxemia with minimal acidosis was noted. The three patients were treated with ventilation and oxygen. The father and son recovered within 48 h, while the pregnant mother remained un- conscious for 36 h and recovered slowly. Urinary concentrations of fluoride were not increased in the 24-h urine samples collected from the subject. The authors stated that all three patients recovered uneventfully. No other details, such as the pregnancy outcome, were provided. 2.3. Developmental and Reproductive Toxicity No data on the developmental or reproductive toxicity of boron trifluoride in humans were found. 2.4. Genotoxicity No data on the genotoxicity of boron trifluoride in humans were found. 2.5. Carcinogenicity No data on the carcinogenicity of boron trifluoride in humans were found.
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Boron Trifluoride 19 2.6. Summary No definitive data on the toxicity of boron trifluoride in humans were found. One paper reported that three individuals (an adult male, an infant, and a pregnant woman) survived exposure to an unknown but debilitating concentra- tion of boron trifluoride. A worker exposed to approximately 4.1 mg/m3 (1.5 ppm) boron trifluoride reported the odor to be rather pleasant and acidic. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Rats Vernot et al. (1977) determined 1-h LC50 values for boron trifluoride in rats. Groups of five male and five female Sprague-Dawley rats were exposed at various concentrations of boron trifluoride (individual concentrations not speci- fied; not clear whether values were measured or nominal concentrations) for 1 h in either a bell jar or large desiccator (not stated which). The 1-h LC50 values, calculated by probit analysis, were 1,100 mg/m3 (95% CI [confidence interval]: 883-1,289 mg/m3) (equivalent to 387 ppm (95% CI: 320-467 ppm) for male rats, and 1,000 mg/m3 (95% CI: 809-1,294 mg/m3) (equivalent to 371 ppm; 95% CI: 293-469 ppm) for female rats. No other experimental details were provided. A series of experiments in rats investigated the acute toxicity of inhaled boron trifluoride (DuPont Company 1948); most of these tests are described below in Section 3.2.2. In one experiment, a group of six rats was exposed for 4 h to boron trifluoride at a nominal concentration of 3,900 mg/m3 (1,400 ppm). One rat died after 148 min of exposure, and another died within 24 h of expo- sure. Necropsy of the rat that died during the exposure revealed general cyano- sis, acute inflammatory reaction of the larynx and upper trachea, and slightly edematous lungs with moderate congestion of alveolar walls. The other rat had consolidation of the upper part of all the lobes of the lung, pus in the bronchi, desquamated mucosa, and areas of emphysema. The four surviving rats were observed for 4 days, and were observed to only experience weight loss. Ne- cropsy of the animals revealed areas of the lungs with thickened alveolar walls as a result of swelling of the lining cells. Groups of 10 rats, 10 mice, and 10 guinea pigs were exposed to nominal concentrations of boron trifluoride (Stokinger and Spiegl 1953). Rats were ex- posed at 2,100 mg/m3 (750 ppm) for 5.5 h or 370 mg/m3 (135 ppm) for 10.9 h. The actual exposure concentrations may have been much less since only nomi- nal concentrations were reported. Exposures were conducted in a dynamic expo- sure chamber measuring 28 ×12 × 6 inches, with plastic sides and a removable plastic top. Three screens were placed inside the chamber to separate the three
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20 Acute Exposure Guideline Levels species that were exposed simultaneously. Gaseous boron trifluoride was diluted with nitrogen, and continuously metered by a flow meter through copper lines into one end of the chamber with removal at the opposite end of the chamber using a small, motor driven compressor (approximately 1 air change/min). Ani- mals were observed for 14 days following the exposure. The chemical purity was unknown, and the age, sex, and strain of the animals were not specified. At 2,100 mg/m3 for 5.5 h, 1/10 rats died, whereas no rats died at 370 mg/m3 for 10.9 h. Animals surviving the exposure did not exhibit any weight loss during the postexposure observation period. Kasparov and Kiriĭ (1972) reported a 4-h LC50 of 1,180 mg/m3 for 50 al- bino rats exposed to boron trifluoride. It was not stated if animals were exposed to nominal or measured concentrations. Necropsy of exposed animals revealed cyanosis of mucous membranes and hemorrhage of internal organs, including the lungs. Lung weights were increased, and pulmonary examination revealed edema, alveolar duct destruction, and vascular dilation. Hyperemia and edema were observed in the kidneys, spleen, and brain. The mucous membranes of the eyes showed evidence of irritation. F344 rats were exposed by inhalation to boron trifluoride dihydrate for 4 h, 9 days, or 13 weeks (Rusch et al. 1986). The stable dihydrate of boron trifluoride was used to avoid the secondary reaction of dihydrate formation that would occur in the inhalation chamber because of the hygroscopic nature of boron trifluoride gas. A nebulizer was used to generate the aerosol, and the con- centration was controlled by regulating the airflow of the compressed, breath- ing-grade air through the nebulizer. Exposure concentrations were measured hourly by trapping a known volume of test atmosphere, dissolving the aerosol in distilled water, and analyzing the sample using an ion-selective electrode tech- nique. Particle size was measured hourly during the acute exposure, three times per week during the 9-day exposure, and twice per week during the subchronic exposure. The mean particle size ranged from 1.5-2.2 microns; more than 97% of the particles were smaller than 10 microns. For the acute study, groups of five male and five female 9-week-old F344 rats were exposed for 4 h to liquid aerosols of boron trifluoride dihydrate at mean measured concentrations of 0, 1,010, 1,220, 1,320, or 1,540 mg/m3 (ani- mals were exposed to boron trifluoride dihydrate, but the concentrations are based on boron trifluoride) (Hoffman 1981; Rusch et al. 1986). Nominal con- centrations ranged from 4,100 mg/m3 for the low-concentration group to 6,200 mg/m3 for the high-concentration group. Loss of the chemical was attributed to losses associated with high aerosol generation. Rats were observed during the exposure and daily for 14 days postexposure. Body weight was recorded prior to exposure (day 0) and on days 1, 2, 4, 7, and 14 postexposure. Gross necropsy was conducted on all animals. Mortality was observed in all exposure groups (see Table 1-3). A 4-h LC50 of 1,210 mg/m3 (95% CI: 1,080-1,350 mg/m3) was calculated using the method of Litchfield and Wilcoxon (1949). Clinical signs observed during exposure included reduced activity, closed eyes, excessive
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Boron Trifluoride 21 TABLE 1-3 Mortality in Rats Exposed to Boron Trifluoride Aerosol for 4 Hours Concentration (mg/m3) Mortality (%) [day of death] 0 0/10 (0) 1,010 3/10 (30) [0, 3, 6] 1,220 2/10 (20) [0, 3] 1,320 8/10 (80) [1, 1, 2, 3, 3, 3, 4, 5] 1,540 9/10 (90) [0, 0, 0, 1, 2, 3, 4, 5, 5] Source: Rusch et al. 1986. lacrimation, and excessive oral and nasal discharge. The high-concentration group also exhibited gasping. Clinical signs of respiratory distress (dry rales, moist rales, gasping) and/or irritation (excessive oral and nasal discharge and lacrimation) were noted 4 hours after exposure in most of the exposed animals. Two rats (one each from the 1,320- and 1,540-mg/m3 groups) had corneal opaci- ties when removed from the chamber and later died. Most clinical signs in sur- viving rats were no longer present by day 6. All rats lost weight following expo- sure, but the control rats lost less (4-11 g) than the exposed rats (19-56 g). All rats gained weight by day 14, indicating reversibility of toxicity. Necropsy of exposed animals revealed red discoloration of the lungs in all exposure groups. Discoloration of the thymus, kidney, and liver were reported in animals dying spontaneously in all groups, but it was unclear whether these changes were an effect of treatment. Slight increases in liver and lung weight were observed in exposed females (lung weight was 2-5% greater than controls; liver weight was 13-15% greater than controls). In the subacute study, groups of five male and five female F344 rats were exposed to liquid aerosols of boron trifluoride dihydrate for 6 h/day, 5 days/week for 9 days, at mean measured concentrations of 0, 24, 66, or 180 mg/m3 (animals were exposed to boron trifluoride dihydrate, but concentrations given are based on boron trifluoride) (Hoffman and Rusch 1982b; Rusch et al. 1986). Nominal concentrations were 48, 117, and 390 mg/m3, respectively. The differences between nominal and measured concentrations were attributed to absorption by the chamber wall. Animals were observed twice daily, clinical signs were recorded twice a week (exposure days 2, 5, 9, and 11), and body weight was recorded weekly. At study termination, the brains, gonads, kidneys, liver, lungs, spleen, and thymus were weighed, and the lungs, trachea, turbi- nates, liver, kidneys, stomach, duodenum, testis, and epididymis were examined microscopically. All 10 rats from the high-concentration group died before the sixth exposure. Clinical signs after two days included mucoid and/or red nasal discharge, dry or moist rales, dried red material around nose or mouth, lacrima- tion, and yellow anal-genital staining, whereas three control females exhibited mucoid nasal discharge and one control male had mucoid nasal discharge and dry rales (see Table 1-4). Clinical signs did not appear to be related to concen-
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22 Acute Exposure Guideline Levels tration at day 2. Clinical signs were increased in incidence and severity after 5 days of exposure. Mean body weight and body weight gain were statistically decreased in males of all exposure groups and in females of the mid- and high- concentration groups. Concentration-related increases in absolute and relative lung weights were observed in both sexes of the low- and mid-concentration groups (increased by 12% and 21%, respectively, compared with controls), while absolute and relative liver weights were decreased in the mid- concentration groups (approximately 79% of controls). The only treatment- related histopathologic finding was necrosis and pyknosis of the proximal tubu- lar epithelium in the kidneys from animals exposed at 180 mg/m3. TABLE 1-4 Clinical Signs in Rats Exposed to Boron Trifluoride for Nine Days Observation 0 mg/m3 24 mg/m3 66 mg/m3 180 mg/m3 Exposure day 2 Number examined 10 10 10 10 Number affected 4 7 7 7 No signs 6 3 3 3 Mucoid nasal discharge 4 5 4 5 Red nasal discharge, dried red 0 2 2 1 material around nose or mouth Dry rales 1 2 2 1 Moist rales 0 1 0 2 Lacrimation 0 0 0 1 Stained anal-genital area 0 2 1 1 Exposure day 5 Number examined 10 10 10 10 Number affected 0 6 10 10 No signs 10 4 0 0 Dead 0 0 0 3 Mucoid nasal discharge 0 0 9 2 Red nasal discharge, dried red 0 6 6 4 material around nose or mouth Dry rales 0 0 3 0 Moist rales 0 2 7 1 Lacrimation 0 0 0 7 Stained anal-genital area 0 1 5 5 Gasping, shallow or labored breathing 0 0 0 3 Poor condition 0 0 0 8 Source: Adapted from Hoffman and Rusch 1982b; Rusch et al. 1986.
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Boron Trifluoride 23 In the subchronic study, groups of 20 male and 20 female F344 rats were exposed to liquid aerosols of boron trifluoride dihydrate for 6 h/day, 5 days/week for 13 weeks, at mean measured concentrations of 0, 2.0, 6.0, or 17 mg/m3 (animals were exposed to boron trifluoride dihydrate, but the concentra- tions given are based on boron trifluoride) (Hoffman and Rusch 1982a; Rusch et al. 1986). Nominal concentrations were 6.4, 24, and 54 mg/m3, respectively. Differences between nominal and measured concentrations were again attributed to absorption by the chamber wall. Animals were observed twice daily, a de- tailed clinical assessment was performed on all animals weekly, and body weight was recorded weekly. Hematology and clinical chemistry analysis, uri- nalysis, and urinary ionic and total fluoride and serum total fluoride amounts were determined after 1 month of exposure (5 rats/sex/dose), during the final week of exposure (15 rats/sex/dose), or 2 weeks after the last exposure (retained group of 5 rats/sex/dose). In addition, urine ionic and total fluoride measure- ments were taken after 2 months of exposure, and bone fluoride analysis was conducted on all animals. All rats were subjected to gross necropsy, and the brain, lungs, heart, liver, spleen, kidneys, and gonads were weighed. Tissues from the control and high-concentration groups were examined for histopa- thologic changes, and sections of the kidneys, nasal turbinates, lungs, and liver were examined from all animals. One male rat from the high-concentration group died during week 12 (Hoffman and Rusch 1982a; Rusch et al. 1986). Clinical signs in exposed ani- mals included an increased incidence of dried red material around the nose, dried material around the mouth, excessive lacrimation, and dry rales, primarily in the high-concentration group. In the low-concentration groups, irritation in the form of excessive lacrimation was observed in 5 rats of the 2 mg/m3 group (1-2 times starting at week 10), and in 16 rats of the 6-mg/m3 group (1-2 times starting at week 2). No differences in body weight, ophthalmologic findings, hematology analysis, organ weight, or gross necropsy findings were observed in exposed animals compared with controls. Urinalysis revealed a concentration- related decrease in urinary calcium and concentration-related increase in urinary fluoride. Clinical chemistry analysis revealed concentration-related decreases in serum protein and globulin concentrations, and one male rat with elevated blood urea nitrogen (BUN) concentration. A concentration-related increase in fluoride concentration in the femurs of exposed animals was observed. The concentra- tions persisted during the recovery period, suggesting either slow release from the bone or irreversible binding. Histopathologic examination of the male rat in the high-concentration group that died had findings consistent with toxic renal tubular necrosis, and the rat with elevated BUN concentrations exhibited mild renal lesions that probably would not have affected its survival. 3.1.2. Mice Groups of 10 mice, 10 rats, and 10 guinea pigs were exposed to nominal concentrations of boron trifluoride (Stokinger and Spiegl 1953). Mice were ex-
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48 Acute Exposure Guideline Levels APPENDIX A DERIVATION OF AEGL VALUES FOR BORON TRIFLUORIDE Derivation of AEGL-1 Values Key study: Bowden, A.M. 2005. Boron Trifluoride Dihydrate Acute (Four-H) Inhalation Irritation Threshold Study in Rats. Conducted by Huntingdon Life Sciences Ltd.: Cambridgeshire, England; Sponsored by Honeywell International, Inc., Morristown, NJ. Toxicity end points: No-effect level for irritation of 25 mg/m3 for 4 h. Time scaling Values were set equal across all AEGL durations because the point of departure is a no-effect level for irritation. Uncertainty factors: 3 for interspecies variability 3 for intraspecies variability Combined uncertainty factor of 10 Modifying factor: Not applicable 10-min AEGL-1: Set equal to 4-h AEGL-1 value of 2.5 mg/m3 30-min AEGL-1: Set equal to 4-h AEGL-1 value of 2.5 mg/m3 1-h AEGL-1: Set equal to 4-h AEGL-1 value of 2.5 mg/m3 4-h AEGL-1: 25 mg/m3 ÷ 10 = 2.5 mg/m3 8-h AEGL-1: Set equal to 4-h AEGL-1 value of 2.5 mg/m3 Derivation of AEGL-2 Values Calculations: Because there were no relevant data for deriving AEGL-2 values, AEGL-3 values were divided by 3 to estimate AEGL-2 values
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Boron Trifluoride 49 10-min AEGL-2: 110 mg/m3 ÷ 3 = 37 mg/m3 30-min AEGL-2: 110 mg/m3 ÷ 3 = 37 mg/m3 1-h AEGL-2: 88 mg/m3 ÷ 3 = 29 mg/m3 4-h AEGL-2: 55 mg/m3 ÷ 3 = 18 mg/m3 8-h AEGL-2: 28 mg/m3 ÷ 3 = 9.3 mg/m3 Derivation of AEGL-3 Values Key study: Rusch, G.M., G.M. Hoffman, R.F. McConnell, and W.E. Rinehart, W.E. 1986. Inhalation toxicity studies with boron trifluoride. Toxicol. Appl. Pharmacol. 83(1):69-78. Toxicity end point: 4-h BMCL05 in rats of 554 mg/m3 Time scaling: Cn × t = k (default of n = 3 for extrapolation from longer to shorter durations; default of n = 1 for extrapolation from shorter to longer durations) [(554 mg/m3 ÷ 10)]1 × 4 h = 221.6 mg/m3-h [(554 mg/m3) ÷ 10]3 × 4 h = 680,125.9 mg/m3-h Uncertainty factors: 3 for interspecies variability 3 for intraspecies variability Combined uncertainty factor of 10 Modifying factor: Not applicable 10-min AEGL-3: Set equal to the 30-min value of 110 mg/m3 because of uncertainty with extrapolating from a 4-h exposure to 10 min. 30-min AEGL-3: C3 × 0.5 h = 680,125.9 mg/m3-h C3 = 1,360,251.8 mg/m3 C = 110 mg/m3 1-h AEGL-3: C3 × 1 h = 680,125.9 mg/m3 -h C3 = 680,125.9 mg/m3 C = 88 mg/m3
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50 Acute Exposure Guideline Levels 4-h AEGL-3: C1 × 4 h = 221.6 mg/m3-h C1 = 55.4 mg/m3 C = 55 mg/m3 8-h AEGL-3: C1 × 8 h = 221.6 mg/m3-h C1 = 27.7 mg/m3 C = 28 mg/m3
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Boron Trifluoride 51 APPENDIX B BENCHMARK DOSE CALCULATIONS FOR BORON TRIFLUORIDE Probit Model. (Version: 3.1; Date: 05/16/2008) Input Data File: C:\USEPA\BMDS2\Data\LogBF3Set.(d) Gnuplot Plotting File: C:\USEPA\BMDS2\Data\LogBF3Set.plt Thu Aug 27 09:29:46 2009 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 = No._affected Independent variable = DOSE Slope parameter is restricted as slope > = 1 Total number of observations = 5 Total number of records with missing values = 0 Maximum number of iterations = 250 Relative Function Convergence has been set = 1E-008 Parameter Convergence has been set = 1E-008 User has chosen the log transformed model Default Initial (and Specified) Parameter Values Background = 0 Intercept = -33.8553 Slope = 4.76995 Asymptotic Correlation Matrix of Parameter Estimates Intercept Slope Intercept 1 -1 Slope -1 1 (***The model parameter(s) background has been estimated at a boundary point, or has been specified by the user, and do not appear in the correlation matrix).
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52 Acute Exposure Guideline Levels Parameter Estimates 95.0% Wald Confidence Interval Variable Estimate Standard Error Lower Limit Upper Limit Background 0 NA Intercept -32.9607 10.9082 -54.3404 -11.581 Slope 4.64094 1.53091 1.64041 7.64146 NA: indicates that this parameter has hit a bound implied by some inequality constraint and thus has no standard error. Analysis of Deviance Table Log No. Deviance Model (likelihood) Parameters Test DF P-value Full model -19.3675 5 Fitted model -22.3 2 5.86491 3 0.1184 Reduced model -34.2965 1 29.8579 4 <0.0001 AIC: 48.6 Goodness of Fit Scaled Estimated Dose Probability Expected Observed Size Residual 0 0 0 0 10 0 1,010 0.196 1.96 3 10 0.829 1,220 0.5082 5.082 2 10 -1.95 1,320 0.6503 6.503 8 10 0.992 1,540 0.8647 8.647 9 10 0.326 Chi-square = 5.58; DF = 3 P-value = 0.1340 Benchmark Dose Computation Specified effect = 0.01 Risk type = Extra risk Confidence level = 0.95 BMD = 735.755 BMDL = 408.953 Benchmark Dose Computation Specified effect = 0.05 Risk type = Extra risk Confidence level = 0.95 BMD = 852.132 BMDL = 554.475
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Probit 1 0. 8 F r a ct i o n A f f e c t e d 0. 6 0. 4 0. 2 0 BMDL B MD 0 200 400 600 800 1000 1200 1400 1600 dose 09:41 08/27 2009 FIGURE B-1 Probit model with 0.95 confidence level. Note: A log transformed model was used to generate the graph; the fact the x-axis does not indicate log dose is an artifact of the program. 53
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54 APPENDIX C RAW DATA FOR BORON TRIFLUORIDE CATEGORY PLOT TABLE C-1 Raw Data for Boron Trifluoride Category Plot Source Species Sex No. Exposures mg/m3 Min Categorya NAC/AEGL-1 2.5 10 AEGL NAC/AEGL-1 2.5 30 AEGL NAC/AEGL-1 2.5 60 AEGL NAC/AEGL-1 2.5 240 AEGL NAC/AEGL-1 2.5 480 AEGL NAC/AEGL-2 37 10 AEGL NAC/AEGL-2 37 30 AEGL NAC/AEGL-2 29 60 AEGL NAC/AEGL-2 18 240 AEGL NAC/AEGL-2 9.3 480 AEGL NAC/AEGL-3 110 10 AEGL NAC/AEGL-3 110 30 AEGL NAC/AEGL-3 88 60 AEGL NAC/AEGL-3 55 240 AEGL NAC/AEGL-3 28 480 AEGL Vernot et al. 1977 Rat Male 1,100 60 PL Vernot et al. 1977 Rat Female 1,000 60 PL DuPont Company 1948 Rat 3,900 240 PL
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Stokinger and Spiegl 1953 Rat 2,100 330 PL Stokinger and Spiegl 1953 Rat 370 654 0 Kasparov and Kiriĭ 1972 Rat 1,180 240 PL Rusch et al. 1986 Rat 1,010 240 PL Rat 1,220 240 PL Rat 1,320 240 PL Rat 1,540 240 PL Stokinger and Spiegl 1953 Mice 2,100 330 PL Mice 370 654 0 Kasparov and Kiriĭ 1972 Mice 3,460 120 PL DuPont Company 1948 Guinea pig 2,760 5 3 DuPont Company 1948 Guinea pig 720 180 PL Stokinger and Spiegl 1953 Guinea pig 2,100 330 3 Stokinger and Spiegl 1953 Guinea pig 970 84 PL Stokinger and Spiegl 1953 Guinea pig 370 654 PL Kasparov and Kiriĭ 1972 Guinea pig 109 240 PL DuPont Company 1948 Dog 1,380 30 1 DuPont Company 1948 Dog 1,380 180 2 DuPont Company 1948 Rat 2,760 60 2 DuPont Company 1948 Rat 720 180 0 Bowden 2005 Rat 9 240 0 Bowden 2005 Rat 25 240 0 Bowden 2005 Rat 74 240 1 a 0 = no effect; 1 = discomfort; 2 = disabling; PL = partially lethal; 3 = lethal. 55
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56 Acute Exposure Guideline Levels APPENDIX D ACUTE EXPOSURE GUIDELINE LEVELS FOR BORON TRIFLUORIDE Derivation Summary AEGL-1 10 min 30 min 1h 4h 8h 2.5 mg/m3 2.5 mg/m3 2.5 mg/m3 2.5 mg/m3 2.5 mg/m3 Key reference: Bowden, A.M. 2005. Boron Trifluoride Dihydrate Acute (Four-H) Inhalation Irritation Threshold Study in Rats. Conducted by Huntingdon Life Sciences Ltd., Cambridgeshire, England; Sponsored by Honeywell International, Inc., Morristown, NJ. Test species/Strain/Number: Rat, Sprague-Dawley, 10 male and 10 female per group Exposure route/Concentrations/Durations: Inhalation; 0, 9, 25, or 74 mg/m3 for 4 h Effects: 9 mg/m3: No effects 25 mg/m3: No effects 74 mg/m3: Histopathologic changes in the larynx and tracheal bifurcation indicative of irritation. End point/Concentration/Rationale: 25 mg/m3 is a no-effect level for irritation Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3, because the irritation is a direct contact effect, so mechanism of action is not expected to vary greatly among species (NRC 2001; Section 220.127.116.11.3.). Intraspecies: 3, because the mechanism of action is not expected to vary greatly in subpopulations (NRC 2001; Section 18.104.22.168.4.). Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Not applicable Time scaling: The 4-h AEGL value was applied to all AEGL durations because the point of departure is a no-effect level for mild irritation. Data adequacy: The Bowden (2005) study is the only acute study addressing nonlethal end points after exposure to a quantified concentration of boron trifluoride. Data inadequacies include data addressing acute, nonlethal exposures. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 3 3 3 3 37 mg/m 37 mg/m 29 mg/m 18 mg/m 9.3 mg/m3 Data adequacy: No acute toxicity data relevant to deriving AEGL-2 values were available. Therefore, the AEGL-3 values wre divided by 3.
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Boron Trifluoride 57 AEGL-3 VALUES 10 min 30 min 1h 4h 8h 3 3 3 3 110 mg/m 110 mg/m 88 mg/m 55 mg/m 28 mg/m3 Key reference: Rusch, G.M., G.M. Hoffman, R.F. McConnell, and W.E. Rinehart. 1986. Inhalation toxicity studies with boron trifluoride. Toxicol. Appl. Pharmacol. 83(1):69-78. Test species/Strain/Number: Rat, F344, 5 male and 5 female per group Exposure route/Concentrations/Durations: Inhalation; 0, 1,010, 1,220, 1,320, or 1,540 mg/m3 for 4 h Effects: Concentration (mg/m3) Mortality 0 0/10 1,010 3/10 1,220 2/10 1,320 8/10 1,540 9/10 LC50: 1,210 mg/m3 LC01: 736 mg/m3 BMCL05 = 554 mg/m3 End point/Concentration/Rationale: 4-h BMCL05 was chosen as point of departure for AEGL-3 to represent the threshold for lethality. Uncertainty factors/Rationale: Total uncertainty factor: 10 Intraspecies: 3, because boron trifluoride is a corrosive irritant and the mechanism of action is not expected to vary greatly among species. Intraspecies: 3, because the mechanism of irritation is not expected to vary greatly among subpopulations; an uncertainty factor of 3 is also supported by the steep dose- response curve for lethality (3/10 rats died at 1,010 mg/m3, while 9/10 rats died at 1,540 mg/m3), which indicates there is not much variability in the response within a population. Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Not applicable Time scaling: Extrapolation to different exposure durations was performed using the equation Cn × t = k (ten Berge et al. 1986), where n = 3 for extrapolation to durations of 30-min and 1 h, and n = 1 for extrapolation to 8 h. The 30-min value was adopted as the 10-min value because of the uncertainty with extrapolating from a 4-h exposure to 10 min. Data adequacy: AEGL-3 values based on a calculated BMCL05 from a study with measured concentrations of boron trifluoride. A limitation of the study was that mortality was observed at all exposure concentrations. Another limiting factor is that other studies addressing mortality after acute exposure did not provide analytic exposure concentrations; therefore, there are no other studies using the same or other species to support the values. Nonetheless, a study by Kasparov and Kiriĭ (1972) provide some supporting evidence with a 4-h LC50 of 1,180 mg/m3 in rats.
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58 Acute Exposure Guideline Levels APPENDIX E SUMMARY OF ACUTE TOXICITY STUDIES WITH BORON TRIFLUORIDE COMPLEXES TABLE E-1 Acute Toxicity Studies of Boron Trifluoride Complexes Test Substance Study Design Results References Boron trifluoride Dermal irritation 6 rabbits, 0.5 mL, 24 h, Dunn 1980 dihydrate total corrosion Eye irritation 6 rabbits, 0.1 mL, corrosive Oral LD50 Male rats, LD50 = 464 mg/kg; Derelanko and Female rats, LD50 = 282-363 Gad 1982 mg/kg Boron trifluoride Primary dermal 6 rabbits, PDI = 5.5, corrosive Braun and dinbutyl ether irritation (PDI) Killeen 1975a Acute dermal Rabbits (2 males, 2 Braun and toxicity females/group); only 2 groups Killeen 1975b tested; LD50 = 1-2 g/kg Eye irritation 6 rabbits, 0.1 mL, corrosive Braun and Killeen 1975c,d Oral LD50 Rabbits (1 male and 1 female/dose), LD50 = 0.25 g/kg Oral LD50 Rats (5 males, 5 females/group), Braun and LD50 = 0.71 g/kg Killeen 1975e Boron trifluoride Primary dermal 6 rabbits, 0.5 mL, corrosive Eibert 1969 diethyl ether irritation Dermal LD50 Rabbits (6 males, 6 females/group, 2 groups), LD50 = 1-2 g/kg Eye irritation 6 rabbits, 1.1 mL, corrosive Oral, minimal Rabbits (1 male, lethal dose 1 female/group), 0.32-1.0 g/kg, lethality at 0.32 g/kg Oral LD50 Rats, 6/group, LD50 = 375 mg/kg Inhalation screen, Rats (5 males, 5 females/group), 1 h exposure 2.54 mg/L, 3 males and 1 female died, 1-h LC50 ≥2.54 mg/L Boron trifluoride Oral Rats (5 males, 5 females/group); Bonnette 2001 diethyl etherate male: LD50 >0.28 but <0.56 g/kg; females: 0.30 g/kg