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

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2 Carbonyl Fluoride1 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 Jennifer Rayner (Oak Ridge National Laboratory), Julie Klotzbach (SRC, Inc.), Chemical Manag- er Iris Camacho (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 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). 37 

38 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 respons- es, could experience the effects described at concentrations below the corre- sponding AEGL. SUMMARY Carbonyl fluoride is a colorless and irritating gas, with a pungent odor. It is hygroscopic, and is hydrolyzed into carbon dioxide and hydrogen fluoride by water. It is used as an intermediate in the synthesis of organic compounds. The thermal decomposition of fluoropolymers, such as polytetrafluoroethylene and polyfluoroethylenepropylene, is a major source of exposure because carbonyl fluoride is the major reaction product from the rapid destruction of plastic mate- rials at temperatures above 500°C. Pyrolysis products are composed of a large number of compounds, can be of variable composition, and pose significant ana- lytic challenges. Pyrolysis products of polytetrafluoroethylene include a number of highly toxic compounds in addition to carbonyl fluoride, including perfluoroisobu- tylene, which is approximately 10-fold more toxic than phosgene (Patocka and Bajgar 1998; IPCS 2004). Carbonyl fluoride is a strong irritant of the eyes and respiratory tract. Its irritancy is hypothesized to be due to hydrogen fluoride, a known sensory irri- tant. However, the toxicity of carbonyl fluoride is greater than that of hydrogen fluoride, and may be the result of the chemical’s deep penetration into the lungs as well as the production of hydrogen fluoride. No data on exposure of humans to carbonyl fluoride were found. No AEGL-1 values for carbonyl fluoride were derived because of insuffi- cient data. Data were also inadequate to derive AEGL-2 values. According to the standing operating procedures for deriving AEGL values (NRC 2001), AEGL-3 values may be divided by 3 to estimate AEGL-2 values. That approach is justified because carbonyl fluoride appears to have a steep concentration- 

Carbonyl Fluoride 39 response curve. Rats exposed to carbonyl fluoride at 5 or 10 ppm for 4 h experi- enced dyspnea and rapid, shallow respiration (DuPont 1956, 1959). At concen- trations of 26.7 ppm or higher for 4 h death occurred (DuPont 1976). The AEGL-3 values for carbonyl fluoride were derived by using the BMCL05 (benchmark concentration, 95% lower confidence limit with 5% re- sponse) of 5.2 ppm from a study in rats (DuPont 1976) as the point-of-departure. Rapid to convulsive respiration and pulmonary edema were observed in rats exposed to carbonyl fluoride for 4 h. Death occurred at all concentrations tested. An interspecies uncertainty factor of 3 was applied, because the toxicity of a direct-acting irritant in not expected to differ greatly among species. A study by Scheel et al. (1968a) provides some support for a factor of 3. However, carbonyl fluoride was generated via polytetrafluoroethylene pyrolysis in that study; there- fore, exposure included other pyrolysis products. Exposure of rats to carbonyl fluoride at 310 ppm resulted in focal hemorrhage of the lungs and pulmonary edema, observed 24 h after exposure. The investigators stated that those effects were produced at the same concentration in other species, including the dog, rabbit, guinea pig, and mouse, although individual data and photomicrographs of the lungs were not provided for those species. As noted earlier, carbonyl fluoride also has a steep concentration-response curve. An intraspecies uncertainty factor of 3 was applied because effects from a direct-acting irritant of the lungs and respiratory tract are not expected to differ greatly among individuals. Time scal- ing was performed using the equation Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). Data on carbonyl fluoride were inade- quate to derive an empirical value for n, so default values of n = 3 for extrapolat- ing to shorter durations and n = 1 when extrapolating to longer durations were used (NRC 2001). The 30-min AEGL-3 value was adopted for the 10-min value in accordance with the standing operating procedures for developing AEGL values (NRC 2001). The AEGL values for carbonyl fluoride are presented in Table 2-1. TABLE 2-1 AEGL Values for Carbonyl Fluoride End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 NRa NRa NRa NRa NRa Insufficient (nondisabling) data. AEGL-2 0.35 ppm 0.35 ppm 0.28 ppm 0.17 ppm 0.087 ppm One-third of the (disabling) (0.95 (0.95 (0.76 (0.46 (0.23 AEGL-3 values mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (NRC 2001) AEGL-3 1.0 ppm 1.0 ppm 0.83 ppm 0.52 ppm 0.26 ppm 4-h rat BMCL05 (lethal) (2.7 (2.7 (2.2 (1.4 (0.70 (DuPont 1976) mg/m3) mg/m3) mg/m3) mg/m3) 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. 

40 Acute Exposure Guideline Levels 1. INTRODUCTION Carbonyl fluoride is a colorless, pungent, and irritating gas. It is hygro- scopic, and is hydrolyzed by water (HSDB 2009). Chemical and physical prop- erties of carbonyl fluoride are presented in Table 2-2. Carbonyl fluoride can be prepared from fluorine or bromine trifluoride and carbon monoxide. Alternately, it can be prepared by the action of silver fluoride on carbon monoxide or through the reaction of phosgene with sodium fluoride and hydrogen cyanide. It is a thermal decomposition product of fluoropolymers, such as polytetrafluoro- ethylene and polyfluoroethylenepropylene, heated at temperatures above 500°C. Pyrolysis products are composed of a large number of compounds, can be of vari- able composition, and pose significant analytic challenges. For polytetrafluoroeth- ylene, pyrolysis products include a number of highly toxic compounds in addition to carbonyl fluoride, including perfluoroisobutylene, which is approximately 10- fold more toxic than phosgene (Patocka and Bajgar 1998; IPCS 2004). Carbonyl fluoride is used as a chemical intermediate in the synthesis of organic com- pounds, such as fluorinated alkyl isocyanates (HSDB 2009). Recent production data were not found. Carbonyl fluoride is shipped as a liquefied compressed gas (NIOSH 2011a). TABLE 2-2 Chemical and Physical Properties of Carbonyl Fluoride Parameter Value References Synonyms Carbon difluoride oxide; carbon fluoride oxide; HSDB 2009 carbonic difluoride; carbon oxyfluoride; carbonyl fluoride, difluoroformaldehyde; fluophosgene; fluoroformyl fluoride; fluorophosgene CAS registry no. 353-50-4 HSDB 2009 Chemical formula COF2 NIOSH 2011a Molecular weight 66.007 HSDB 2009 Physical state Colorless gas HSDB 2009 Melting point -111.26°C HSDB 2009 Boiling point -84.57°C HSDB 2009 Solubility in water Unstable in presence of water, very hygroscopic HSDB 2009 Vapor density (air = 1) 2.29 NIOSH 2011a Vapor pressure 4.45 × 104 mm Hg at 25°C HSDB 2009 Flammability limits Nonflammable NIOSH 2011a 3 Conversion factors 1 ppm = 2.7 mg/m NIOSH 2011a 1 mg/m3 = 0.37 ppm 

Carbonyl Fluoride 41 2. HUMAN TOXICITY DATA 2.1. Acute Lethality No reports of human lethality following exposure to carbonyl fluoride were found. 2.2. Nonlethal Toxicity The odor of carbonyl fluoride is described as pungent and irritating (NIOSH 2011a), but no information on the odor threshold was available. No case reports or epidemiologic studies of exposure to carbonyl fluoride were found. 2.3. Developmental and Reproductive Toxicity No data regarding the developmental or reproductive toxicity of carbonyl fluoride in humans were found. 2.4. Genotoxicity No data regarding the genotoxicity of carbonyl fluoride in humans were found. 2.5. Carcinogenicity No data regarding the carcinogenicity of carbonyl fluoride in humans were found. 2.6. Summary No information on human exposure to carbonyl fluoride was available. Carbonyl fluoride is a strong irritant to the skin, eyes, mucous membranes, and respiratory tract; direct contact with the skin may cause frostbite (HSDB 2009). 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Rats Groups of two male ChR-CD rats were exposed to carbonyl fluoride by inhalation at nominal concentrations of 5 or 10 ppm and a group of six rats was exposed at 100 ppm for 4 h. Three rats exposed at 100 ppm died, and pathologic examination showed they had acute tracheobronchitis and pulmonary conges- tion. The surviving rats exhibited no pathologic changes. The 4-h LC50 (lethal 

42 Acute Exposure Guideline Levels concentration, 50% lethality) was approximately 100 ppm. No deaths occurred in the groups exposed at lower concentrations. The data were presented in a ta- ble of a one-page preliminary report (DuPont 1959). Scheel et al. (1968a) evaluated the acute inhalation toxicity of carbonyl fluoride in groups of five male and five female Greenacres Controlled Flora rats (8 and 24 weeks old). Carbonyl fluoride was generated by polytetrafluoroeth- ylene pyrolysis at 550ºC. The authors referenced work by Coleman et al. (1968), which identified carbonyl fluoride as a principal toxic component of the pyroly- sis gases, as their rationale for using polytetrafluoroethylene pyrolysis to pro- duce carbonyl fluoride. Atmospheres were generated with a metered air stream into the exposure chamber, and concentrations were measured by the hydrolysa- ble fluoride method. Rats were exposed at various concentrations with the low- est being 310 ppm for 1 h, followed by a 14-day observation period. (With the exception of the 310-ppm value, actual concentrations were not provided). Deaths usually occurred within 24 h with few latent deaths. The LC50 values for the 8- and 24-week-old rats were 360 and 460 ppm, respectively. Although an age difference in mortality was apparent, no difference between the sexes was found. Exposure at 310 ppm resulted in focal hemorrhage of the lungs and pul- monary edema, observed 24 h after exposure. The authors stated that those ef- fects were produced at the same concentration in other species, including the dog, rabbit, guinea pig, and mouse, although individual data and photomicro- graphs of the lungs were not provided for those species. The lungs showed rapid cellular reorganization and clearing of edema 48 h after exposure, but alveolar damage was still present. Extravasation of red cells from damaged capillaries continued for up to 7 days; the effect was accompanied by mild interstitial fibro- sis. Although data were not provided, Scheel et al. (1968a) reported that a 4-h exposure at 90 ppm also resulted in approximately 50% mortality. DuPont (1976) exposed male ChR-CD rats (10/group) to carbonyl fluoride (>97% pure) at 26.7, 30.8, 32.7, 41.3, 44.7, 47.2 (48.8 by infra-red analysis), or 47.6 ppm for 4 h. Test atmospheres were analyzed with a fluoride-specific elec- trode and confirmed by infra-red analysis. Deaths occurred at every concentra- tion. Mortalities in the respective groups were 5/10, 3/10, 3/10, 6/10, 8/10, 9/10, and 6/10. The calculated LC50 was 34.3 ppm. The calculated BMC01 was 10.4 ppm and the BMCL05 was 5.2 ppm. Respiration in the rats varied directly with exposure concentration and ranged from rapid shallow breathing to convulsive respiration. Pathologic examination revealed white plaques, red focal spots, and consolidation and edema of the lungs. Liver congestion and bright red spleens were also found. 3.2. Nonlethal Toxicity 3.2.1. Rats Groups of four male albino rats were exposed to carbonyl fluoride at nom- inal concentrations of 2.5 or 5 ppm for 2 and 2.5 h in a preliminary investigation 

Carbonyl Fluoride 43 of toxicity (DuPont 1956). The rats were then observed for 24 h or 8 days. The low concentration of 2.5 ppm was not lethal to the rats and no clinical signs de- veloped. At 5 ppm, the rats developed slight dyspnea and cyanosis. No other information was reported. In other studies conducted by DuPont (1959), groups of two male ChR-CD rats were exposed to carbonyl fluoride at nominal concentrations of 5 or 10 ppm and a group of six rats was exposed at 100 ppm for 4 h. Clinical signs included rapid, shallow respiration and loss of weight in the 5- and 10-ppm groups, but no pathologic changes were found. The data were presented in a table of a one-page preliminary report. TABLE 2-3 Summary of Acute Inhalation Data in Laboratory Animals Species (age) Concentration (ppm) Exposure Duration Effect Reference Rat 2.5a 2, 2.5 h None0 DuPont 1956 5.0a 2, 2.5 h Slight dyspnea and cyanosis Rat 5a 4h Rapid, shallow DuPont 1959 respiration 10a 4h Rapid, shallow respiration 100a 4h LC50, pulmonary congestion Rat (8 wk) 360 1h LC50 Scheel et al. 1968ab Rat (24 wk) 460 1h LC50 Rat (8 wk) 90 4h LC50 Rat 26.7 4h 50% mortality DuPont 1976 30.8 4h 30% mortality 32.7 4h 30% mortality 34.3 4h LC50 (calculated) 41.3 4h 60% mortality 44.7 4h 80% mortality 47.2 (48.8 IRc) 4h 90% mortality 47.6 4h 60% mortality a Nominal concentrations. b Exposed rats to polytetrafluoroethylene pyrolysis products (550ºC) and reported concen- trations of measured fluoride. c Measurement by infrared analysis. 

44 Acute Exposure Guideline Levels 3.3. Repeated Dose Toxicity Scheel et al. (1968b) examined whether the toxic action of carbonyl fluo- ride is due to the toxicity of hydrogen fluoride. Twenty male and 20 female rats (Greenacres Controlled Flora) were exposed to polytetrafluoroethylene pyrolysis products (temperature not reported) for 1 h per day for 5 days. Although the authors state that the exposures were to carbonyl fluoride at 50 ppm, the total exposure reported of 158 ppm-h and graphic data presented in the report indicate that successive daily exposures were at concentrations of 52, 43, 29, 25, and 9 ppm. Urine was collected and analyzed for fluoride, tissues were collected and analyzed for inhibition of succinic dehydrogenase, and urine was analyzed for protein, glucose, ketones, and occult blood. After 5 days of exposure (158 ppm- h plus 18 g of particulates), mortality was 22%; rats died during or shortly after exposure, and rats that died exhibited extreme malaise and weakness. No deaths occurred until the third day. Urinary fluoride increased from 3 to 42 mg/L in 5 days. Eighteen days after the last exposure, the urinary fluoride concentration was four times that of controls. Protein, glucose, ketones, and occult blood were detected in the urine. A 30% weight loss occurred subsequent to exposure. The succinic dehydrogenase activity in the kidneys was inhibited to less than 5% of its normal value. Increased levels of succinic dehydrogenase activity were pro- duced in the lungs. The liver showed enlarged nuclei and fatty infiltration. The metabolic inhibition was reversible, as were the pathologic changes in the lungs (with the exception of a small amount of emphysematous change), liver, and kidneys (examined 18 days after exposure). The authors concluded that the toxic syndrome described in this study is compatible with the descriptions of hydro- gen fluoride toxicity. 3.4. Developmental and Reproductive Toxicity No data on the developmental or reproductive toxicity of carbonyl fluoride were found. 3.5. Genotoxicity No data on the genotoxicity of carbonyl fluoride were found. 3.6. Chronic Toxicity and Carcinogenicity No data on the chronic toxicity or carcinogenicity of carbonyl fluoride were found. 3.7. Summary Acute inhalation of carbonyl fluoride causes rapid or labored respiration and respiratory irritation, pulmonary congestion and edema, increases in urinary 

Carbonyl Fluoride 45 fluoride excretion, proteinuria, and can cause death in rats. Varying LC50 values for rats have been reported: 4-h LC50 of 34.3 ppm (DuPont 1976), 90 ppm (Scheel et al. 1968a), and 100 ppm (DuPont 1959), and 1-h LC50s of 360 ppm and 460 ppm for 8-week-old and 24-week-old rats, respectively. The 1-h LC50 for hydrogen fluoride in rats is 1,278 ppm (MacEwen and Vernot 1970). Con- verting the carbonyl fluoride concentration of 460 ppm to an equivalent concen- tration of hydrogen fluoride yields a concentration of 867 ppm, which suggests that carbonyl fluoride produces toxicity greater than that caused by hydrogen fluoride released by hydrolysis. Converting the LC50 for hydrogen fluoride to an equivalent concentration of carbonyl fluoride gives a predicted value of 680 ppm, nearly 50% greater than that observed. No data on the developmental tox- icity, reproductive toxicity, genotoxicity, chronic toxicity, or carcinogenicity of carbonyl fluoride were found. 4. SPECIAL CONSIDERATIONS 4.1. Metabolism and Disposition Carbonyl fluoride is hygroscopic and hydrolyzed in the moist respiratory tract to carbon dioxide and two moles of hydrogen fluoride (Arito and Soda 1977). Hydrogen fluoride is soluble in water and is absorbed by the respiratory tract (HSDB 2012). It has a relatively low dissociation constant (3.5 × 10-4), which allows the non-ionized compound to penetrate the skin, respiratory sys- tem, or gastrointestinal tract. The fluoride ion is readily absorbed into the blood- stream and is distributed to all organs. Equilibrium is rapidly reached (Perry et al. 1994). Elimination is primarily through the kidneys. 4.2. Mechanism of Toxicity Carbonyl fluoride is a contact irritant that hydrolyzes in the presence of water to hydrogen fluoride. Hydrogen fluoride is irritating to the skin, eyes, and respiratory tract. Exposure via inhalation produces pulmonary hemorrhage, con- gestion, and death in laboratory animals (HSDB 2012). Carbon dioxide is also produced when carbonyl fluoride is hydrolyzed. However, carbon dioxide tox- icity occurs at very high concentrations, and the 10-h time-weighted average is currently set at 5,000 ppm (NIOSH 2011b). 4.3. Structure-Activity Relationships Carbonyl fluoride is the fluorine analogue of phosgene (carbonyl chlo- ride). However, only a small amount of phosgene hydrolyzes when it comes into contact with moisture (NRC 2002), whereas carbonyl fluoride is “instantly hy- drolyzed by water” (HSDB 2009). The primary mechanism of action of phos- gene is acylation resulting in lipid and protein denaturation, irreversible mem- brane changes, and disruption of enzymatic function. Death is caused by 

46 Acute Exposure Guideline Levels pulmonary edema following a latency period of 24 h or longer (NRC 2002). The mechanism of action for carbonyl fluoride is unknown. A latency period was not reported by DuPont (1976), but Scheel et al. (1968a) reported that deaths usually occurred within 24 h of exposure with few latent deaths. In the DuPont (1976) study, a 4-h exposure to carbonyl fluoride in rats led to pulmonary consolidation and edema. Scheel et al. (1968a) reported deep lung focal hemorrhage and ede- ma in rats exposed for 1 h to carbonyl fluoride produced from polytetrafluoro- ethylene pyrolysis. 4.4. Other Relevant Information No additional relevant information on carbonyl fluoride was found. 4.4.1. Species Variability According to Scheel et al. (1968a), pathologic changes in the respiratory tract and liver following exposure to carbonyl fluoride at 310 ppm for 1 h were similar in the dog, rat, mouse, rabbit, and guinea pig. 4.4.2. Susceptible Populations No information was available on populations especially sensitive to car- bonyl fluoride toxicity. 4.4.3. Concentration-Exposure Duration Relationship The concentration-exposure duration relationship for many irritant and systemically acting vapors and gases may be described by the equation Cn × t = k, where the exponent ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the ab- sence of chemical-specific data from which to derive an empirical value for the exponent n, default values of n = 3 when extrapolating to shorter durations and n = 1 when extrapolating to longer durations were used (NRC 2001). 4.4.4. Concurrent Exposure Issues No concurrent exposure issues for carbonyl fluoride were identified. 5. DATA ANALYSIS FOR AEGL-1 5.1. Human Data Relevant to AEGL-1 No human data relevant to developing AEGL-1 values for carbonyl fluo- ride were found. 

Carbonyl Fluoride 47 5.2. Animal Data Relevant to AEGL-1 Male albino rats were exposed to carbonyl fluoride at nominal concentra- tions of 2.5 or 5 ppm for 2 and 2.5 h (DuPont 1956). The low concentration of 2.5 ppm was not lethal to the rats and no clinical signs developed. 5.3. Derivation of AEGL-1 Values Details of the animal study of carbonyl fluoride (DuPont 1956) were in- sufficient to consider using it as a basis to derive AEGL-1 values. Therefore, AEGL-1 values are not recommended. 6. DATA ANALYSIS FOR AEGL-2 6.1. Human Data Relevant to AEGL-2 No human data relevant to developing AEGL-2 values for carbonyl fluo- ride were found. 6.2. Animal Data Relevant to AEGL-2 In a study of rats exposed to carbonyl fluoride at nominal concentrations of 2.5 or 5 ppm for 2 or 2.5 h, the no-effect level was 2.5 ppm for both dura- tions. Rats exposed at 5 ppm exhibited dyspnea and cyanosis (DuPont 1956). Rats exposed to carbonyl fluoride at nominal concentrations of 5 or 10 ppm for 4 h (DuPont 1956, 1959) also experienced dyspnea and rapid shallow respira- tion; a no-effect level was not identified in the study. However, almost no in- formation on the experimental details or assessments of the animals was report- ed. Thus, the DuPont (1956, 1959) studies do not provide adequate information to accurately define a no-effect level for AEGL-2 effects. 6.3. Derivation of AEGL-2 Values The available studies on carbonyl fluoride are inadequate for deriving AEGL-2 values. Results of the DuPont (1956, 1959, 1976) studies indicate a steep exposure-response curve. The highest no-effect level for lethality was 10 ppm for 4 h (DuPont 1959) and the lowest lethal concentration was 26.7 ppm for 4 h, with 50% lethality (DuPont 1976). Thus, AEGL-2 values for carbonyl fluoride were set at one-third of the AEGL-3 values, in accordance with the standing operating pro- cedures for developing AEGL values (NRC 2001). TABLE 2-4 AEGL-2 Values for Carbonyl Fluoride 10 min 30 min 1h 4h 8h 0.35 ppm 0.35 ppm 0.28 ppm 0.17 ppm 0.087 ppm (0.95 mg/m3) (0.95 mg/m3) (0.76 mg/m3) (0.46 mg/m3) (0.23 mg/m3) 

48 Acute Exposure Guideline Levels 7. DATA ANALYSIS FOR AEGL-3 7.1. Human Data Relevant to AEGL-3 No human data relevant to developing AEGL-3 values for carbonyl fluo- ride were found. 7.2. Animal Data Relevant to AEGL-3 DuPont (1976) exposed male ChR-CD rats to carbonyl fluoride at 26.7, 30.8, 32.7, 41.3, 44.7, 47.2, or 47.6 ppm for 4 h. Deaths occurred at every concen- tration. The calculated LC50 was 34.3 ppm. The calculated BMC01 was 10.4 ppm and the BMCL05 was 5.2 ppm (DuPont 1976). The study by Scheel et al. (1968a) was not considered relevant because animals were exposed to a mixture of pyroly- sis products of polytetrafluoroethylene, including carbonyl fluoride (Arito and Soda 1977). 7.3. Derivation of AEGL-3 Values The AEGL-3 values for carbonyl fluoride were determined by using the BMCL05 of 5.2 ppm derived from the study by DuPont (1976) as the point-of- departure. The BMCL05 was more conservative than the BMC01 calculated from the same study. Rapid to convulsive respiration and pulmonary edema were ob- served in rats exposed for 4 h. Death occurred at all concentrations. An interspe- cies uncertainty factor of 3 was applied because the toxicity of a direct-acting irritant is not expected to differ substantially among species. The Scheel et al. (1968a) study provides some support for the interspecies uncertainty factor of 3. However exposure to carbonyl fluoride was generated via polytetrafluoroeth- ylene pyrolysis; therefore, exposure included other pyrolysis products. Exposure of rats to carbonyl fluoride at 310 ppm resulted in focal hemorrhage of the lungs and pulmonary edema, observed 24 h after exposure. The investigators stated that the same effects were produced at the same concentration in other species, including the dog, rabbit, guinea pig, and mouse, but individual data and photo- micrographs of the lungs were not provided for those species. An intraspecies uncertainty factor of 3 was applied because carbonyl fluoride is a direct-acting irritant of the lungs and its effects are not expected to differ greatly among indi- viduals. The concentration-exposure duration relationship for many irritant and sys- temically-acting vapors and gases can be described by the equation Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the absence of chemical-specific data from which to derive an empirical value for the exponent n, default values of n = 3 for extrapolating to shorter durations and n = 1 for ex- trapolating to longer durations were used (NRC 2001). The AEGL-3 values for carbonyl fluoride are presented in Table 2-5. 

Carbonyl Fluoride 49 8. SUMMARY OF AEGLS 8.1. AEGLS Values and Toxicity End Points AEGL-1 values for carbonyl fluoride are not recommended because of in- sufficient data. AEGL-2 values are based on a three-fold reduction of the AEGL-3 values because experimental data were not available to empirically derive AEGL-2 values. AEGL-3 values for carbonyl fluoride are based on a BMCL05 derived from lethality data in rats. AEGL values for carbonyl fluoride are presented in Table 2-6. For comparison, Table 2-7 provides the AEGL val- ues for phosgene and hydrogen fluoride, because those chemicals are also pyro- lysis products of polytetrafluorethylene (see Sections 3.7, 4.1, and 4.2). 8.2. Other Standards and Guidelines Standards and guidelines for carbonyl fluoride are presented in Table 2-8. No other emergency standards such as emergency response planning guidelines or immediately dangerous to life and health values are available for carbonyl fluoride. The threshold limit value–time-weighted average for carbonyl fluoride was established by the American Conference of Governmental Industrial Hy- gienists (ACGIH) on the basis of data from Scheel et al. (1968a). The 8-h AEGL values are much lower than the industrial standards and guidelines for carbonyl fluoride. The values of ACGIH and the National Institute for Occupational Safe- ty and Health were determined by analogy with fluorides and hydrogen fluoride and are intended to minimize the potential for pulmonary irritation and disabling bone changes. TABLE 2-5 AEGL-3 Values for Carbonyl Fluoride 10 min 30 min 1h 4h 8h 1.0 ppm 1.0 ppm 0.83 ppm 0.52 ppm 0.26 ppm (2.7 mg/m3) (2.7 mg/m3) (2.2 mg/m3) (1.4 mg/m3) (0.70 mg/m3) TABLE 2-6 AEGL Values for Carbonyl Fluoride Classification 10 min 30 min 1h 4h 8h AEGL-1 NR a NR a NR a NR a NR a (nondisabling) AEGL-2 0.35 ppm 0.35 ppm 0.28 ppm 0.17 ppm 0.087 ppm (disabling) (0.95 mg/m3) (0.95 mg/m3) (0.76 mg/m3) (0.46 mg/m3) (0.23 mg/m3) AEGL-3 1.0 ppm 1.0 ppm 0.83 ppm 0.52 ppm 0.26 ppm (lethal) (2.7 mg/m3) (2.7 mg/m3) (2.2 mg/m3) (1.4 mg/m3) (0.70 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. 

50 Acute Exposure Guideline Levels TABLE 2-7 AEGL Values for Phosgene and Hydrogen Fluoride Classification 10 min 30 min 1h 4h 8h Phosgene (NRC 2002) AEGL-1 NRa NRa NRa NRa NRa (nondisabling) AEGL-2 0.60 ppm 0.60 ppm 0.30 ppm 0.08 ppm 0.04 ppm (disabling) AEGL-3 3.6 ppm 1.5 ppm 0.75 ppm 0.20 ppm 0.09 ppm (lethal) Hydrogen fluoride (NRC 2004) AEGL-1 1.0 ppm 1.0 ppm 1.0 ppm 1.0 ppm 1.0 ppm (nondisabling) AEGL-2 95 ppm 34 ppm 24 ppm 12 ppm 12 ppm (disabling) AEGL-3 170 ppm 62 ppm 44 ppm 22 ppm 22 ppm (lethal) a Not recommended. Absence of an AEGL-1 value does not imply that exposures below the AEGL-2 value are without adverse effects. TABLE 2-8 Standards and Guidelines for Carbonyl Fluoride Exposure Duration Guideline 10 min 15 min 30 min 1h 4h 8h AEGL-1 NR – NR NR NR NR AEGL-2 0.35 ppm – 0.35 ppm 0.28 ppm 0.17 ppm 0.087 ppm (0.95 (0.95 (0.76 (0.46 (0.23 mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 1.0 ppm – 1.0 ppm 0.83 ppm 0.52 ppm 0.26 ppm (2.7 (2.7 (2.2 (1.4 (0.70 mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) TLV-TWA – – – – – 2 ppm (ACGIH)a (5.4 mg/m3) REL-TWA – – – – – 2 ppm (NIOSH)b (5.4 mg/m3) TLV-STEL – 5 ppm – – – – (ACGIH)c (13 mg/m3) REL-STEL – 5 ppm – – – – (NIOSH)d (15 mg/m3) MAC (The – 0.38 ppm – – – – Netherlands)e (1 mg/m3) a TLV-TWA (threshold limit value – time-weighted average, American Conference of Governmental Industrial Hygienists) (ACGIH 2012) is the time-weighted average con- centration for a normal 8-h workday and a 40-h workweek to which nearly all workers may be repeatedly exposed, day after day, without adverse effect. 

Carbonyl Fluoride 51 b REL-TWA (recommended exposure limit – time-weighted average, National Institute for Occupational Safety and Health) (NIOSH 2011a) is defined as the time-weighted average concentration for up to a 10-h workday during a 40-h workweek. c TLV-STEL (threshold limit value – short-term exposure limit, American Conference of Governmental Industrial Hygienists) (ACGIH 2012) is defined as a 15-min time- weighted average exposure which should not be exceeded at any time during the workday even if the 8-h time-weighted average is within the TLV-TWA. Exposures above the TLV-TWA up to the STEL should not be longer than 15 min and should not occur more than four times per day. There should be at least 60 min between successive exposures in that range. d REL-STEL (recommended exposure limit – short-term exposure limit, National Institute for Occupational Safety and Health) (NIOSH 2011a) is defined as a 15-min time- weighted average exposure that should not be exceeded at any time during the workday. e MAC (maximaal aanvaarde concentratie [maximal accepted concentration], Dutch Ex- pert Committee for Occupational Standards, The Netherlands (MSZW 2004) is defined analogous to the ACGIH TLV-TWA. 8.3. Data Adequacy and Research Needs There are no human data available on carbonyl fluoride. DuPont (1956, 1959, and 1976) conducted studies of rats exposed to carbonyl fluoride for 2-4 h, but two of the studies reported only nominal concentrations, used relatively few animals, and reported few study details. Scheel et al. (1968a, 1968b) ex- posed rats to carbonyl fluoride produced by burning polytetrafluoroethylene. While carbonyl fluoride is a major pyrolysis product, it is not the only pyrolysis product produced (Arito and Soda 1977) and the rats were probably exposed to other compounds that contain fluoride. The animals were also exposed to the particulate matter produced from polytetrafluoroethylene pyrolysis, which may have increased observed effects. Additional acute animal studies in other species and with a greater range of concentrations would be helpful in deriving AEGL values. No studies on genotoxicity or reproductive and developmental toxicity were found; additional studies evaluating those outcomes would also help to strengthen the basis of the AEGL values for carbonyl fluoride. 9. REFERENCES ACGIH (American Conference of Government and Industrial Hygienists). 2012. Carbon- yl Fluoride (CAS Reg. No. 353-50-4). Documentation of the Threshold Limit Val- ues and Biological Exposure Indices. American Conference of Government and Industrial Hygienists, Cincinnati, OH. Arito, H., and R. Soda. 1977. Pyrolysis products of polytetrafluoroethylene and polyfluo- roethylenepropylene with reference to inhalation toxicity. Ann. Occup. Hyg. 20(3): 247-255. Coleman, E., L.D. Scheel, R.E. Kupel, and R.L. Larkin. 1968. The identification of toxic compounds in the pyrolysis products of polytetrafluoroethylene. Am. Ind. Hyg. Assoc. J. 29(1):33-40. 

52 Acute Exposure Guideline Levels DuPont (E.I. DuPont de Nemours and Company, Inc.). 1956. Toxicity Studies of Pyroly- sis Products of Fluorinated Polymers (Teflon Polytetrafluoroethylene). Haskell Laboratory Report No. 18-56. Submitted to EPA by DuPont , Haskell Laboratory, Newark, DE, with Cover Letter Dated 10/15/92. EPA Document No. 8EHQ-1092- 11415. Microfiche No. OTS0571353. DuPont (E.I. DuPont de Nemours and Company, Inc.). 1959. Toxicity Studies of Car- bonyl Fluoride. Haskell Laboratory Report No. 32-59. DuPont , Haskell Laborato- ry, Newark, DE. DuPont (E.I. DuPont de Nemours and Company, Inc.). 1976. Acute Inhalation Toxicity Studies of Hydrogen Fluoride and Carbonyl Fluoride. Haskell Laboratory Report No. 485-76. DuPont, Haskell Laboratory, Newark, DE. HSDB (Hazardous Substances Data Bank). 2009. Carbonyl Fluoride (CAS Reg. No. 353- 50-4). TOXNET, Specialized Information Services, U.S. National Library of Med- icine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/html gen?HSDB [accessed August 2013]. HSDB (Hazardous Substances Data Bank). 2012. Hydrogen fluoride (CAS Reg. No. 7664-39-3). TOXNET, Specialized Information Services, U.S. National Library of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/ htmlgen?HSDB [accessed August 2013]. IPCS (International Programme on Chemical Safety). 2004. Perfluoroisobutylene. IPCS Card No. 1216. International Programme on Chemical Safety and the Commission of the European Communities [online]. Available: http://www.inchem.org/documents/ic sc/icsc/eics1216.htm [accessed May 2013]. MacEwen, J.D., and E.H. Vernot. 1970. Toxic Hazards Research Unit Annual Technical Report: 1970. AMRL-TR-70-77. AD 714694. Aerospace Medical Research La- boratory, Wright-Patterson Air Force Base, OH [online]. Available: http://www. dtic.mil/dtic/tr/fulltext/u2/714694.pdf [accessed june 23, 2014]. MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst 2004: Carbonyfluoride en PTFE-pyrolyseproducten. Den Haag: SDU Uitgevers [online]. Available: http://www.lasrook.net/lasrookNL/maclijst2004.htm [accessed June 24, 2014]. NIOSH (National Institute for Occupational Safety and Health). 2011a. NIOSH Pocket Guide to Chemical Hazards: Carbonyl Fluoride [online]. Available: http://www. cdc.gov/niosh/npg/npgd0108.html [accessed August 2013]. NIOSH (National Institute for Occupational Safety and Health). 2011b. NIOSH Pocket Guide to Chemical Hazards: Carbon Dioxide [online]. Available: http://www. cdc.gov/niosh/npg/npgd0103.html [accessed August 2013]. 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). 2002. Phosgene. Pp. 15-70 in Acute Exposure Guide- line Levels for Selected Airborne Chemicals. Washington, DC: The National Academies Press. NRC (National Research Council). 2004. Hydrogen fluoride. Pp 123-197 in Acute Expo- sure Guideline Levels for Selected Airborne Chemicals, Vol. 4. Washington, DC: The National Academies Press. 

Carbonyl Fluoride 53 Patocka, J., and J. Bajgar. 1998. Toxicology of Perfluoroisobutene. ASA Newsletter [on- line]. Available: http://www.asanltr.com/ASANews-98/pfib.html [accessed August 2013]. Perry, W.G., F.A. Smith, and M.B. Kent. 1994. The halogens. Pp. 4449-4522 in Patty’s Industrial Hygiene and Toxicology, 4th Ed., Vol. II, Part F, G.F. Clayton, and F.E. Clayton, eds. New York: John Wiley & Sons. Scheel, L.D., W.C. Lane, and W.E. Coleman. 1968a. The toxicity of polytetrafluoroeth- ylene pyrolysis products – including carbonyl fluoride and a reaction product, sili- con tetrafluoride. Am. Ind. Hyg. Assoc. J. 29(1):41-48. Scheel L.D., L. McMillan, and F.C. Phipps. 1968b. Biochemical changes associated with toxic exposures to polytetrafluoroethylene pyrolysis products. Am. Ind. Hyg. As- soc. J. 29(1):49-53. ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Haz- ard. Mater. 13(3):301-309. 

54 Acute Exposure Guideline Levels APPENDIX A DERIVATION OF AEGL VALUES FOR CARBONYL FLUORIDE Derivation of AEGL-1 Values AEGL-1 values are not recommended because of insufficient data on carbonyl fluoride. Absence of AEGL-1 values does not imply that exposures below the AEGL-2 values are without adverse effects. Derivation of AEGL-2 Values In the absence of empirical data on carbonyl fluoride, the AEGL-2 values for carbonyl fluoride were set at one-third of the AEGL-3 values. That approach is in in accordance with the standing operating procedures for developing AEGL values for chemicals with steep concentration-response curves (NRC 2001). Rats exposed to carbonyl fluoride at 5 or 10 ppm for 4 h experienced dyspnea and rapid shallow res- piration (DuPont 1956, 1959). At higher concentrations (26.7 ppm or higher for 4 h), death occurred, indicating a steep exposure-response curve (DuPont 1976). Calculations: 10-min AEGL-2: 1.04 ppm ÷ 3 = 0.35 ppm 30-min AEGL-2: 1.04 ppm ÷ 3 = 0.35 ppm 1-h AEGL-2: 0.83 ppm ÷ 3 = 0.28 ppm 4-h AEGL-2: 0.52 ppm ÷ 3 = 0.17 ppm 8-h AEGL-2: 0.26 ppm ÷ 3 = 0.087 ppm Derivation of AEGL-3 Values Key study: DuPont (E.I. DuPont de Nemours and Company, Inc.). 1976. Acute Inhalation Toxicity Studies of Hydrogen Fluoride and Carbonyl Fluoride. Haskell Laboratory Report No. 485-76. DuPont, Haskell Laboratory, Newark, DE Toxicity end point: Threshold for lethality; BMCL05 of 5.2 ppm Time scaling: The concentration-exposure duration relationship for many irritant and systemically- acting vapors and gases may be described by 

Carbonyl Fluoride 55 the relationship Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the absence of chemical-specific data to derive an empirical value for n, default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations were used (NRC 2001). The 30-min AEGL-3 value was adopted for the 10-min value in accordance with the standing operating procedures for developing AEGL values (NRC 2001). 5.2 ppm ÷ 10 = 0.52 ppm (0.52 ppm)3 × 240 min = 33.74592 ppm-min (0.52 ppm)1 × 240 min = 124.8 ppm-min Uncertainty factors: Interspecies: 3, effects of a direct-acting irritant of the lungs and respiratory tract are not expected to differ greatly among species. The study by Scheel et al. (1968a) provides some support for a factor of 3. However, exposure to carbonyl fluoride was generated via polytetrafluoroethylene pyrolysis; therefore, exposure included other pyrolysis products. Exposure of rats to carbonyl fluoride at 310 ppm resulted in focal hemorrhage of the lungs and pulmonary edema, observed 24 h after exposure. The investigators stated that those effects were produced at the same concentration in other species, including the dog, rabbit, guinea pig, and mouse. However, individual data and photomicrographs of the lungs were not provided for those species. Intraspecies: 3, effects of a direct-acting irritant of the lungs and respiratory tract are not expected to differ greatly among individuals. Modifying factor: None applied Calculations: 10-min AEGL-3: C3 × 30 min = 33.74592 ppm-min C = 1.0 ppm 30-min AEGL-3: C3 × 30 min = 33.74592 ppm-min C = 1.0 ppm 

56 Acute Exposure Guideline Levels 1-h AEGL-3: C3 × 60 min = 33.74592 ppm-min C = 0.83 ppm 4-h AEGL-3: C × 240 min = 124.8 ppm-min C = 0.52 ppm 8-h AEGL-3: C × 480 min = 124.8 ppm-min C = 0.26 ppm 

Carbonyl Fluoride 57 APPENDIX C ACUTE EXPOSURE GUIDELINE LEVELS FOR CARBONYL FLUORIDE Derivation Summary AEGL-1 VALUES No AEGL-1 values were derived for carbonyl fluoride because of insuffi- cient data. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 0.35 ppm 0.35 ppm 0.28 ppm 0.17 ppm 0.087 ppm Data adequacy: Data on carbonyl fluoride were inadequate for deriving AEGL-2 values, so values were estimated by dividing the AEGL-3 values by 3. That procedure, based on guidance in NRC (2001), is applicable for chemicals with steep concentration- response curves. Rats exposed to carbonyl fluoride at 5 or 10 ppm for 4 h experienced dyspnea and rapid shallow respiration (DuPont 1956, 1959). At higher concentrations (26.7 ppm and higher for 4 h), death occurred indicating a steep exposure-response curve (DuPont 1976). AEGL-3 VALUES 10 min 30 min 1h 4h 8h 1.0 ppm 1.0 ppm 0.83 ppm 0.52 ppm 0.26 ppm Key reference: DuPont (E.I. DuPont de Nemours and Company, Inc.) 1976. Acute Inhalation Toxicity Studies of Hydrogen Fluoride and Carbonyl Fluoride. Haskell Laboratory Report No. 485-76. DuPont, Haskell Laboratory, Newark, DE. Test species/Strain/Number: Rat; ChR-CD; 10/group Exposure route/Concentrations/Durations: Inhalation; 26.7, 30.8, 32.7, 41.3, 44.7, 47.2, 47.6 ppm for 4 h Effects: Rapid shallow respiration and pulmonary edema. 26.7 ppm: 50% mortality 30.8 ppm: 30% mortality 32.7 ppm: 30% mortality 41.3 ppm: 60% mortality 44.7 ppm: 80% mortality 47.2 ppm: 90% mortality 47.6 ppm: 60% mortality End point/Concentration/Rationale: Threshold for lethality (BMCL05 of 5.2 ppm) Uncertainty factors/Rationale: Interspecies: 3, effects of a direct-acting irritant of the lungs and respiratory tract are not expected to differ greatly among species. The study by Scheel et al. (1968a) provides some support for a factor of 3. However exposure to carbonyl fluoride was generated (Continued) 

58 Acute Exposure Guideline Levels AEGL-3 VALUES Continued via polytetrafluoroethylene pyrolysis; therefore, exposure included other pyrolysis products. Exposure of rats to carbonyl fluoride at 310 ppm resulted in focal hemorrhage of the lungs and pulmonary edema, observed 24 h after exposure. The investigators stated that this effect was produced at the same concentration in other species, including the dog, rabbit, guinea pig, and mouse. However, individual data and photomicrographs of the lungs were not provided for those species. Intraspecies: 3, effects of a direct-acting irritant of the lungs and respiratory tract are not expected to differ greatly among individuals. Modifying factor: None Animal-to-human dosimetric adjustment: Not applied Time scaling: The concentration-exposure duration relationship for many irritant and systemically-acting vapors and gases has been described by the relationship Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the absence of chemical-specific to derive an empirical value for n, default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations were used (NRC 2001). The 30-min AEGL-3 value was adopted for the 10-min value in accordance with the standing operating procedures for developing AEGL values (NRC 2001). Data adequacy: The study was well done with an appropriate number of animals. Analytic concentrations were measured and an end point consistent with the AEGL-3 definition was observed. 

Carbonyl Fluoride 59 APPENDIX D BENCHMARK DOSE CALCULATIONS BMDS MODEL RUN BMCL05 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 = COLUMN3 Independent variable = COLUMN1 Slope parameter is restricted as slope >= 1 Total number of observations = 8 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 = -7.52665 Slope = 2.13336 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 -6.88857 2.62927 -12.0418 -1.7353 Slope 1.94933 0.724479 0.529374 3.36928 NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus has no standard error. 

60 Acute Exposure Guideline Levels Analysis of Deviance Table Model Log (likelihood) # Param’s Deviance Test d.f. P-value Full model -40.8638 8 Fitted model -44.0906 2 6.45349 6 0.3744 Reduced model -55.4518 1 29.1759 7 0.0001344 AIC: 92.1812 Goodness of Fit Dose Estimated Probability Expected Observed Size Scaled Residual 0.0000 0.0000 0.000 0 10 0.000 26.7000 0.3136 3.136 5 10 1.271 30.8000 0.4179 4.179 3 10 -0.756 32.7000 0.4639 4.639 3 10 -1.039 41.3000 0.6423 6.423 6 10 -0.279 44.7000 0.6981 6.981 8 10 0.702 47.2000 0.7340 7.340 9 10 1.188 47.6000 0.7394 7.394 6 10 -1.004 Chi-square = 6.26 d.f. = 6 P-value = 0.3951 Benchmark Dose Computation Specified effect = 0.05 Risk Type = Extra risk Confidence level = 0.95 BMD = 14.7319 BMDL = 5.21965 Probit Model with 0.95 Confidence Level Probit 1 BMD Lower Bound 0.8 Fraction Affected 0.6 0.4 0.2 0 BMDL BMD 0 10 20 30 40 50 dose 07:45 01/08 2008 

Carbonyl Fluoride 61 BMDS MODEL RUN BMC01 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 = COLUMN3 Independent variable = COLUMN1 Slope parameter is restricted as slope >= 1 Total number of observations = 8 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 = -7.52665 Slope = 2.13336 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 -6.88857 2.62918 -12.0417 -1.73548 Slope 1.94933 0.724454 0.529424 3.36923 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 -40.8638 8 Fitted model -44.0906 2 6.45349 6 0.3744 Reduced model -55.4518 1 29.1759 7 0.0001344 AIC: 92.1812 

62 Acute Exposure Guideline Levels Goodness of Fit Dose Estimated Probability Expected Observed Size Scaled Residual 26.7000 0.3136 3.136 5 10 1.271 30.8000 0.4179 4.179 3 10 -0.756 32.7000 0.4639 4.639 3 10 -1.039 41.3000 0.6423 6.423 6 10 -0.279 44.7000 0.6981 6.981 8 10 0.702 47.2000 0.7340 7.340 9 10 1.188 47.6000 0.7394 7.394 6 10 -1.004 0.0000 0.0000 0.000 0 10 0.000 Chi-square = 6.2 d.f. = 6 P-value = 0.3951 Benchmark Dose Computation Specified effect = 0.01 Risk Type = Extra risk Confidence level = 0.95 BMD = 10.3855 BMDL = 2.64042 Probit Model with 0.95 Confidence Level Probit 1 BMD Lower Bound 0.8 Fraction Affected 0.6 0.4 0.2 0 BMDL BMD 0 10 20 30 40 50 dose 11:24 11/15 2007 

Carbonyl Fluoride 63 APPENDIX E CATEGORY PLOT FOR CARBONYL FLUORIDE Chemical Toxicity Carbonyl Fluoride 1000.0 Human - No Effect Human - Discomfort 100.0 Human - Disabling Animal - No Effect 10.0 ppm Animal - Discomfort 1.0 AEGL-3 Animal - Disabling Animal - Some Lethality AEGL-2 0.1 Animal - Lethal AEGL 0.0 0 60 120 180 240 300 360 420 480 Minutes FIGURE E-1 Category plot of toxicity data and AEGL values for carbonyl fluoride. 

64 TABLE E-1 Data Used in the Category Plot for Carbonyl Fluoride Source Species Sex No. of Exposures ppm Time (min) Category Comments AEGL-2 0.35 10 AEGL AEGL-2 0.35 30 AEGL AEGL-2 0.28 60 AEGL AEGL-2 0.17 240 AEGL AEGL-2 0.087 480 AEGL AEGL-3 1 10 AEGL AEGL-3 1 30 AEGL AEGL-3 0.83 60 AEGL AEGL-3 0.52 240 AEGL AEGL-3 0.26 480 AEGL DuPont 1956 Rat M 1 2.5 120 0 No effect DuPont 1956 Rat M 1 2.5 150 0 No effect DuPont 1956 Rat M 1 5 120 1 Slight dyspnea; cyanosis DuPont 1956 Rat M 1 5 150 1 Slight dyspnea; cyanosis DuPont 1959 Rat M 1 5 240 1 Rapid, shallow respiration DuPont 1959 Rat M 1 10 240 1 Rapid, shallow respiration DuPont 1959 Rat M 1 100 240 SL Pulmonary congestion Scheel et al. 1968a Rat B 1 360 60 SL 50% mortality Scheel et al. 1968a Rat B 1 460 60 SL 50% mortality 

Scheel et al. 1968a Rat B 1 90 240 SL 50% mortality DuPont 1976 Rat M 1 26.7 240 SL 50% mortality DuPont 1976 Rat M 1 30.8 240 SL 30% mortality DuPont 1976 Rat M 1 32.7 240 SL 30% mortality DuPont 1976 Rat M 1 41.3 240 SL 60% mortality DuPont 1976 Rat M 1 44.7 240 SL 80% mortality DuPont 1976 Rat M 1 47.2 240 SL 90% mortality DuPont 1976 Rat M 1 47.6 240 SL 60% mortality For category: 0 = no effect, 1 = discomfort, 2 = disabling, SL = some lethality, 3 = lethality. 65