2
Chlorine Trifluoride1
Acute Exposure Guideline Levels

SUMMARY

Chlorine trifluoride (ClF3) is a greenish-yellow liquid at temperatures <11.7°C and a colorless gas with a sweet, suffocating odor at higher temperatures. While it is not flammable, ClF3 is an extremely reactive and corrosive oxidizing agent that is used in nuclear reactor fuel processing; as a fluorinating agent; as an incendiary, igniter and propellant for rockets; and as a pyrolysis inhibitor for fluorocarbon polymers. It is unstable in air and rapidly hydrolyzes to hydrogen fluoride (HF) and a number of chlorine-containing compounds including chlorine dioxide

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This document was prepared by the AEGL Development Team composed of Sylvia Talmage (Oak Ridge National Laboratory) and the National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances members Kyle Blackman (Chemical Manager) and Robert Benson, Nancy Kim, and Mark McClanahan (Chemical Reviewers). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes 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; NRC 2001).



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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 2 Chlorine Trifluoride1 Acute Exposure Guideline Levels SUMMARY Chlorine trifluoride (ClF3) is a greenish-yellow liquid at temperatures <11.7°C and a colorless gas with a sweet, suffocating odor at higher temperatures. While it is not flammable, ClF3 is an extremely reactive and corrosive oxidizing agent that is used in nuclear reactor fuel processing; as a fluorinating agent; as an incendiary, igniter and propellant for rockets; and as a pyrolysis inhibitor for fluorocarbon polymers. It is unstable in air and rapidly hydrolyzes to hydrogen fluoride (HF) and a number of chlorine-containing compounds including chlorine dioxide 1 This document was prepared by the AEGL Development Team composed of Sylvia Talmage (Oak Ridge National Laboratory) and the National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances members Kyle Blackman (Chemical Manager) and Robert Benson, Nancy Kim, and Mark McClanahan (Chemical Reviewers). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes 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; NRC 2001).

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 (ClO2). The toxic effects of ClF3 are due, at least in part, to the actions of HF and ClO2. Chlorine trifluoride is a potent, rapidly-acting mucous membrane irritant. Skin and eye contact with ClF3 produces burns and inhalation causes acute pulmonary irritation and edema. Inhalation studies with the monkey, dog, rat, and mouse for several end points and exposure durations have been performed. Data on irritant effects were available for the dog and rat; data on sublethal and lethal concentrations were available for the monkey, rat, and mouse. One report of a very brief (1-2 min) human exposure was located, but no data on exposure concentrations were available. The data were considered adequate for derivation of the three AEGL classifications for five exposure periods. Regression analyses of the reported concentration-exposure durations for lethality for the animal species determined that the relationship between concentration and time is C1.3 × t = k. The AEGL-1 was based on slight irritation as evidenced by rhinorrhea (nasal discharge) observed in two of two dogs during the first 3 h of a 6-h exposure to an average concentration of 1.17 ppm (Horn and Weir 1956). Nasal discharge in response to an irritant gas in the sensitive nose of dogs was considered a NOAEL for the AEGL-1. No signs were observed in 20 rats exposed to this concentration for 6 h. Exposure of the dogs for longer than 3 h resulted in obvious lacrimation. Repeated, daily exposures of rats and dogs to 1.17 ppm resulted in severe signs of irritation. The rhinorrhea in dogs exposed for 3 h was considered an appropriate end point for development of the AEGL-1. Exposure to 1.17 ppm for 3 h was extrapolated using a combined interspecies and intraspecies uncertainty factor of 10 (3 for interspecies differences [the dog was more sensitive than the rat] and 3 for intraspecies differences in sensitivity [slight irritation should occur at a similar level among the general population]). Time-scaling was not applied to the AEGL-1 as adaptation to slight sensory irritation occurs. Therefore, the calculated value of 0.12 ppm was adopted for all AEGL-1 time points. The 0.12 ppm value is similar to the ClO2 AEGL-1 of 0.15 ppm and is one-eighth of the HF AEGL-1 value of 1.0 ppm. Application of an intraspecies factor of 3 is sufficient, since application of a larger factor would result in AEGL-1 values that are not consistent with those of ClO2 and HF, two of the major decomposition products of ClF3 (breakdown of one mole of ClF3 potentially forms three moles of HF and one mole of ClO2). The AEGL-2 was based on signs of irritation (salivation, lacrima-

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 tion, rhinorrhea, and blinking of the eyes) in two of two dogs exposed to a concentration of 5.15 ppm for 6 h (Horn and Weir 1955). These effects were reversible by the end of the first exposure day (i.e. dogs “did not appear markedly affected”), and therefore, were not considered an impairment to the ability to escape. Twenty rats exposed to this concentration for 6 h appeared unaffected. However, repeated daily exposures of rats and dogs to this concentration resulted in increasingly severe signs of irritation. The 6-h concentration of 5.15 ppm was divided by a combined interspecies and intraspecies uncertainty factor of 10 (3 for interspecies differences as the dog was more sensitive than the rat and 3 for intraspecies differences). The resulting value of 0.52 ppm was scaled across time using Cn × t = k, where n = 1.3; this concentration-exposure duration relationship was determined from several lethality studies (Appendix A). Because time-scaling data were available over the exposure duration of 13.5 to 222 min, the 10-min AEGL-2 was not set equal to the 30-min value as is usually done when the exposure duration of the key study is greater than 4 h. An intraspecies uncertainty factor of 3 is sufficient as these AEGL-2 values are considerably lower than those of HF (10- and 30-min and 1-, 4-, and 8-h values of 95, 34, 24, 12, and 12 ppm, respectively) and similar to the longer-term AEGL-2 values for ClO2. The 10- and 30 min AEGL-2 values for ClF3 (8.1 and 3.5 ppm) are higher than those of ClO2 (both 1.4 ppm) because information was available for time-scaling ClF3 values, whereas, in the absence of time-scaling information, the conservative value of n = 3 was used for scaling to the shorter time periods for ClO2. Lethality data (1 h LC50 values) were available for the monkey, rat, and mouse. Based on similar respiratory rates, gross respiratory tract anatomy, amount and distribution of types of respiratory epithelium, and airflow patterns, the monkey was considered the most appropriate model for deposition of ClF3 and its decomposition products in the human respiratory tract. The AEGL-3 values were based on the highest 1 h concentration that resulted in no deaths in monkeys (MacEwen and Vernot 1970). This concentration, 127 ppm, was divided by interspecies and intraspecies uncertainty factors of 2 and 3, respectively (for a total of 6), and scaled across time using the C1.3 × t = k relationship. This time-scaling relationship was determined from several lethality studies (Appendix A). The interspecies uncertainty factor of 2 was considered appropriate as LC50 values were similar in three species and the monkey is an appropriate model for humans. A smaller interspecies uncertainty fac-

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 tor would result in values that are inconsistent with the HF values. The intraspecies uncertainty factor of 3 was considered appropriate because chlorine trifluoride is a direct-acting irritant and differences among individuals should not differ greatly. In cases where animals died, death was due to massive lung hemorrhaging. Applying the same procedures to the calculated 1 h LC01 from the mouse data (135 ppm) results in similar values. The 8-h AEGL-3 value was set equal to the 4-h value because the time-scaled 8 h value of 4.3 ppm is inconsistent with the experimental data. Dogs exposed to 21 ppm for two days did not die during the following month of observation, and dogs and rats tolerated repeated 6 h exposures to 5.15 ppm for several weeks before the first death was recorded (Horn and Weir 1955). The values appear in Table 2-1. INTRODUCTION Chlorine trifluoride (ClF3) is a colorless, corrosive gas at ambient temperature and pressure. It is one of the most reactive of the halogen TABLE 2-1 Summary of AEGL Values for Chlorine Trifluoride Classification 10 min 30 min 1 h 4 h 8 h End point (Reference) AEGL–1 (Nondisabling) 0.12 ppm (0.46 mg/m3) 0.12 ppm (0.46 mg/m3) 0.12 ppm (0.46 mg/m3) 0.12 ppm (0.46 mg/m3) 0.12 ppm (0.46 mg/m3) Slight irritation - dog (Horn and Weir 1956) AEGL–2 (Disabling) 8.1 ppm (31 mg/m2) 3.5 ppm (13 mg/m3) 2.0 ppm (7.6 mg/m3) 0.70 ppm (2.7 mg/m3) 0.41 ppm (1.6 mg/m3) Threshold, impaired ability to escape -dog (Horn and Weir 1955) AEGL–3 (Lethal) 84 ppm (320 mg/m3) 36 ppm (140 mg/m3) 21 ppm (80 mg/m3) 7.3 ppm (28 mg/m3) 7.3 ppm (28 mg/m3) Threshold for lethality - monkey (MacEwen and Vernot 1970)

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 fluorides; it is a powerful oxidizing agent that reacts violently with water and may explode on contact with organic materials (Matheson 1980; O’Neil et al. 2001). Chemical and physical properties are listed in Table 2-2. In the vapor phase, ClF3 is unstable and decomposes by hydrolysis to a variety of substances including ClOF (the initial product), ClF, ClO2F, ClO3F, ClO2, Cl2, and HF; the proportion of products depends on the availability of water (Bougon et al. 1967; Cooper et al. 1972; Dost et al. 1974). Increased humidity increases the rate of decomposition (MacEwen and Vernot 1970). Chlorine trifluoride has been used in nuclear reactor fuel processing (to convert uranium to gaseous uranium hexafluoride), as a fluorinating agent, as an incendiary, igniter and propellant for rockets, and as a pyrolysis inhibitor for fluorocarbon polymers (O’Neil et al. 2001). It is TABLE 2-2 Chemical and Physical Data Parameter Value Reference Synonyms Chlorine fluoride chlorotrifluoride HSDB 2005 Molecular formula ClF3 O’Neil et al. 2001 Molecular weight 92.45 O’Neil et al. 2001 CAS Registry Number 7790-91-2 HSDB 2005 Physical description Colorless (gas) greenish-yellow (liquid) white (solid) O’Neil et al. 2001 Solubility in water Violent hydrolysis with water O’Neil et al. 2001 Vapor pressure 1064 mm Hg at 20°C Matheson 1980 Vapor density (air = 1) 3.21 at 20°C Matheson 1980 Liquid density (water = 1) 1.9 kg/L at 0°C Matheson 1980 Melting point −76.34°C O’Neil et al. 2001 Boiling point 11.75°C O’Neil et al. 2001 Flammability Not flammable, but may cause fire in contact with some materials U.S. DOT 1985 Conversion factors 1 ppm = 3.85 mg/m3 AIHA 2004   1 mg/m3 = 0.26 ppm  

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 used as a chlorine/fluorine source for plasma etching in the semiconductor industry and for in-situ cleaning of chemical vapor deposition reactors (BOC Group 1997). It is produced commercially by the continuous gas-phase reaction of chlorine and fluorine in a nickel reactor at 290°C. In 1993, U.S. production was estimated at several metric tons per year with most of the product used in nuclear fuel processing. It is shipped as a liquified compressed gas in steel cylinders in quantities of 82 kg/cylinder or less (Bailey and Woytek 1994). The BOC Group (1997) ships cylinders containing either 13 or 26 pounds. Chlorine trifluoride is a potent, rapidly-acting mucous membrane irritant. Contact with the skin and eyes produces burns and inhalation causes pulmonary irritation and edema (Teitelbaum 2001). No data on human exposures to measured concentrations were found. Inhalation studies for several exposure durations with the monkey, dog, rat, and mouse were located. Because of the reactive nature of ClF3, difficulty in generating and monitoring the compound was encountered in some of the studies (Horn and Weir 1955; Dost et al. 1974). 2. HUMAN DATA 2.1. Acute Lethality Deichmann and Gerarde (1969) concluded that exposure to 50 ppm may be fatal within 30 min to 2 h. No further details were given, and neither the source nor the basis of that conclusion was cited. 2.2. Nonlethal Toxicity Although an odor threshold was not located, Teitelbaum (2001) states that the pungent odor and irritation associated with ClF3 are detectable at such a low concentration that exposed individuals would escape before experiencing severe effects. The odor has been described as sweet and suffocating (O’Neil et al. 2001). Signs experienced by a worker exposed to an unknown concentration for 1-2 min included headache, abdominal pain, and dyspnea that lasted about 2 h (Longley et al. 1965). No systemic or local effects were found. Except for fatigue (duration not given), there were no apparent sequelae.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 2.3. Developmental/Reproductive Effects No data concerning potential developmental or reproductive toxicity of ClF3 in humans were identified. 2.4. Genotoxicity No data concerning the genotoxicity of ClF3 in humans were identified. 2.5. Carcinogenicity No data concerning the potential carcinogenicity of ClF3 in humans were identified. 2.6. Summary No studies of developmental or reproductive toxicity, genotoxicity, or carcinogenicity of ClF3 in humans were located. Exposure to sufficiently high ClF3 concentrations may cause skin and mucous membrane irritation (Teitelbaum 2001) as well as headache, abdominal pain, and dyspnea (Longley et al. 1965). Deichmann and Gerarde (1969) report that 50 ppm may be fatal within 30 min to 2 h, but neither the source nor basis of that conclusion was cited. 3. ANIMAL TOXICITY DATA 3.1. Acute Toxicity Acute toxicity data, available for the monkey, dog, rat, and mouse, are summarized in Table 2-3 and discussed below. Longer-term studies using dogs and rats described irritant effects during the first day of exposure. It should be noted that in the 2-day and longer-term studies reported by Horn and Weir (1955, 1956), groups of 2 dogs and 20 rats were exposed at the same time, presumably in the same 500-liter exposure chamber.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 TABLE 2-3 Acute Inhalation Toxicity in Laboratory Animals Species Concentration (ppm) Exposure Time Effecta Reference Monkey 230 1 h LC50 MacEwen and Vernot 1970   127 1 h No deaths; signs of sneezing, coughing, and gagging Dog 21 6 hb Extreme eye and mucous membrane irritation, singed hair; recovery by next morning except inflamed eyes irritation, salivation, sneezing, lacrimation, coughing nasal discharge within 45 min, lacrimation after 3 h Horn and Weir 1955; 1956   5.15 6 hb   1.17 6 hb Rat 800 13-14 min Approximate LC50 Dost et al. 1974     10 min No deaths; severe inflammation of mucosal surfaces, preening, skin burns, lacrimation, brittle hair, corneal ulceration, shallow respiration     400 28 min Approximately LC50     400 25 min Same signs as 10-min exposure to 800 ppm   Rat 480 70 min 100% mortality Horn and Weir 1955     40 min ET50c   Rat 299 1 h LC50 MacEwen and Vernot 1970; Vernot et al. 1977   200 1 h No deaths; signs of lacrimation, salivation, labored breathing, and rhinorrhea; bloody discharge from eyes and nares Rat 96 4.5 h 80 %mortality Horn and Weir 1955     3.7 h ET50c   Rat 21 6 hb Rhinorrhea, lacrimation, singed hair; recovery by morning Horn and Weir 1955   5.15 6 hb Little observed effect     1.17 6 hb No effects  

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 Mouse 178 1 h LC50 MacEwen and Vernot 1970; Vernot et al. 1977   125 1 h No deaths; signs of lacrimation, salivation, labored breathing, and rhinorrhea; bloody discharge from eyes and nares aLC50 values were obtained 14 days post-exposure (MacEwenand Vernot 1970). bExposures were repeated; the listed signs were observed during the first day. cET50 is defined as effective time to 50% mortality.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 3.1.1. Nonhuman Primates Groups of four Rhesus monkeys of both sexes inhaled 0, 127, 150, 200, 300, or 400 ppm for 1 h (MacEwen and Vernot 1970). Concentrations were measured based on the reaction of ClF3 or its decomposition products with dimethylamine. Measurements showed that concentrations of ClF3 were stable in the test chamber. Observations were made during exposure and continued 14 days post-exposure. Signs observed in exposed animals included sneezing, coughing, and gagging. Animals exposed to lethal concentrations (150 ppm) demonstrated general paresis, labored breathing, and cyanosis prior to coma and death. Massive alveolar and interstitial hemorrhages involving the entire lungs were present in all animals that died. Most of the deaths occurred 2 to 3 h after the cessation of exposure. Animals were cyanotic, but no methemoglobin was formed during these exposures. Mortality ratios were 0/4, 2/4, 1/4, 2/4, and 4/4 animals at the 127, 150, 200, 300, and 400 ppm concentrations, respectively. The 1-h LC50 was 230 ppm. Pulmonary congestion, edema, hemorrhage, and emphysema were observed in surviving monkeys at 14 days post-exposure. No differences in clinical chemistry parameters were found between exposed and control animals. 3.1.2. Dogs Two dogs were exposed to 21 ppm for 6 h/day for two days (Horn and Weir 1955). Shortly after exposure was initiated, lacrimation, cough, rhinorrhea, rapid respiration and salivation were observed. Rhinorrhea and lacrimation were observed approximately 10 min after the exposure was initiated. The dogs became nauseated, coughed up a small quantity of mucoid material, and had rapid respiration and salivation. The eyes were extremely irritated by the end of the exposure and the hair had a “singed feel.” The morning after the first exposure the animals appeared essentially normal with the exception of inflamed eyes. During the second day of exposure, the study was terminated due to equipment failure which resulted in a concentration considerably higher than 21 ppm. Corneal ulcers and a burn in the vicinity of the nose developed following the exposures. No deaths were reported during the following month of observation Two male dogs were exposed to 5.15 ppm for 6 h/day, 5 days/week

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 for 6 weeks (Horn and Weir 1955). Signs of exposure occurred during the first day and included salivation, lacrimation, and rhinorrhea; coughing and sneezing were also noted. However, by the end of the first day of exposure, the dogs “did not appear markedly affected.” Respiratory distress was evident at the midpoint of the study, and the dogs died on days 17 and 26. The authors experienced difficulty in maintaining constant concentrations in the exposure chambers, and during the exposures, concentrations of one-half to two times the average value were recorded. Two dogs were exposed to an average concentration of 1.17 ppm for 6 h/day, 5 days/week for 6 months (Horn and Weir 1956). During the early part of the study, signs of irritation included rhinorrhea, usually within 45 min of exposure, and obvious lacrimation after 3 hs of exposure. All animals developed a "singed feel" of the hair following the first exposure. The animals appeared normal by the following morning. By the 28th day, the dogs were coughing up bloody mucoid material and showed signs of blinking of the eyes and a change in respiratory pattern at the beginning of each exposure. After more than 60 days (42 exposures) the dogs began showing signs of pneumonia. Penicillin was administered, but one dog died on the 115th day of the study (during the 82nd exposure). The other dog was sacrificed at the termination of the experiment. Examination of the lungs revealed purulent bronchitis and pulmonary abscesses in the dog that died and alveolar hemorrhage, interstitial edema, and irritation in the surviving dog. 3.1.3. Rats Groups of 4-10 male Sprague-Dawley rats inhaled 400 ppm for 20, 25, 30, 35, or 40 min or 800 ppm for 10, 13, 15, 20, 25, or 30 min (Dost et al. 1974). Gas flow rates were measured with mass flow meters; exposure chamber ClF3 concentrations were verified by infrared spectral analysis. Rats began preening at initiation of ClF3 exposure, and exposures produced severe inflammation of all exposed mucosal surfaces. Time-respective mortalities for the 400 ppm exposure were: 0/8, 0/4, 4/6, 7/8, and 8/8. Time-respective mortalities for the 800 ppm concentration were: 0/10, 1/8, 10/10, 8/8, 6/6, and 4/4. LC50 values were not calculated by the authors. The authors found that prolonged exposures or high ClF3 concentrations caused burning of the exposed skin, and the hair became brittle

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 chlore avec l'eau. C.R. Acad. Sci. Ser. D 265:179-182. (Cited in Dost et al., 1974). Cooper, T.D., F.N. Dost and C.H. Wang. 1972. Evidence for ClOF as a primary product of the reaction of ClF3 with H2O. J. Inorg. Nucl. Chem. 34:3564-3567. Darmer, K.I., C.C. Haun, and J.D. MacEwen. 1972. The acute inhalation toxicity of chlorine pentafluoride. Am. Ind. Hygiene Assoc. J. 33:661-668. Deichmann, W.B. and H.W. Gerarde. 1969. Chlorine trifluoride. In: Toxicology of Drugs and Chemicals. New York: Academic Press. Dost, F.N., D.J. Reed. T.D. Cooper and C.H. Wang. 1970. Fluorine distribution in rats following acute intoxication with nitrogen and halogen fluorides and with sodium fluoride. Toxicol. Appl. Pharmacol. 17:573-584. Dost, F.N., D.J. Reed. V.N. Smith and C.H. Wang. 1974. Toxic properties of chlorine trifluoride. Toxicol. Appl. Pharmacol. 27:527-536. Horn, H.J. and R.J. Weir. 1955. Inhalation toxicology of chlorine trifluoride. I. Acute and subacute toxicity. A.M.A. Archives Indust. Health 12:515-521. Horn, H.J. and R.J. Weir. 1956. Inhalation toxicology of chlorine trifluoride. II. Chronic toxicity. A.M.A. Archives Indust. Health 13:340-345. HSDB (Hazardous Substances Data Bank). 2005. Chlorine trifluoride. MEDLARS Online Information Retrieval System, National Library of Medicine, National Institute of Health, Department of Health and Human Services, retrieved 4/26/05. Longley, M.Y., J.F. Pierce and E.C. Griesemer. 1965. A toxic hazard study of selected missile propellants (1965). AMRL-TR-65-99, Wright Patterson Air Force Base, OH. (Cited in NRC, 1984). Ludwig, H.R., S.G. Cairelli, and J.J. Whalen. 1994. Documentation for Immediately Dangerous to Life or Health Concentrations (IDLHS). National Institute for Occupational Safety and Health (NIOSH), Cincinnati, OH; PB94195047, National Technical Information Service, Springfield, VA. MacEwen, J.D. and E.H. Vernot. 1970. Toxic Hazards Research Unit Annual Technical Report: 1970. AMRL-TR-70-77, Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, OH; National Technical Information Service, Springfield, VA. MacEwen, J.D. and E.H. Vernot. 1971. Toxic Hazards Research Unit

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 Annual Technical Report: 1971. AD-734 543; AMRL-TR-71-83; National Technical Information Service, Springfield, VA. Matheson. 1980. Matheson Gas Data Book, 6th ed., Division Searle Medical Products USA, Inc., Lyndhurst, NJ. Ministry of Social Affairs and Employment (SDU Uitgevers). 2000. Nationale MAC (Maximum Allowable Concentration) List, 2000. The Hague, The Netherlands. NIOSH (National Institute for Occupational Safety and Health). 2004. NIOSH Pocket Guide to Chemical Hazards. Publication 94-116, U.S. Department of Health and Human Services; U.S. Government Printing Office, Washington, DC. See also http://www.cdc.gov/niosh/idlh/74873.html. NRC (National Research Council). 1984. Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 2. Committee on Toxicology, National Research Council, National Academy Press, Washington, DC. NRC (National Research Council). 1993. Guidelines for Developing Community Emergency 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: National Academy Press. NRC (National Research Council). 2004. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4. Washington, DC: National Academy Press. O'Neil, M.J., A. Smith, and P.E. Heckelman (Eds.). 2001. The Merck Index, 13th ed. Whitehouse Station, NJ: Merck & Co., Inc. Schreider, J.P. 1986. Chapter 1: Comparative anatomy and function of the nasal passages. In: C.S. Barrow, ed., Toxicology of the Nasal Passages. New York: Hemisphere Publishing Corp. Syage, J.A. 1994. Launch Safety, Toxicity, and Environmental Effects of the High Performance Oxidizer ClF5. ADA286095; Available from National Technical Information Service, Springfield, VA. Teitelbaum, D.T. 2001. The halogens. Pp. 731-825 in: Patty's Toxicology, Vol. 3, E. Bingham et al., eds. New York: John Wiley & Sons, Inc. U.S. DOT (U.S. Department of Transportation, U.S. Coast Guard). 1985. Chemical Hazard Response Information System: chlorine trifluoride.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 U.S. EPA (U.S. Environmental Protection Agency). 2005. Chlorine Dioxide: Interim Acute Exposure Guideline Levels. Washington, DC. Vernot, E.H., J.D. MacEwen, C.C. Haun and E.R. Kinkead. 1977. Acute toxicity and skin corrosion data for some organic and inorganic compounds and aqueous solutions. Toxicol. Appl. Pharmacol. 42:417-423.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 APPENDIX A TIME: CONCENTRATION RELATIONSHIP FOR LETHALITY FIGURE A-1 Chlorine trifluoride: LC50 values for three species—monkey, rat, and mouse (Horn and Weir 1955; MacEwen and Vernot 1970; Dost et al. 1974). Time Conc. Log Time Log Conc. 13.5 800 1.1303 2.9031 28 400 1.4472 2.6021 40 480 1.6021 2.6812 60 178 1.7782 2.2504 60 230 1.7782 2.3617 60 299 1.7782 2.4757 222 96 2.3464 1.9823 n = 1.3     k = 79325.99     Regression Output: Intercept 3.7684 Slope −0.7692 R Squared 0.9014 Correlation −0.9494 Degrees of Freedom 5 Observations 7

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 APPENDIX B DERIVATION OF AEGL VALUES DERIVATION OF AEGL-1 FOR CHLORINE TRIFLUORIDE Key study: Horn and Weir 1956 Toxicity end point: Mucous membrane irritation as evidenced by nasal discharge, the only sign of irritation during the first 3 h of a 6-h exposure of dogs to 1.17 ppm. Uncertainty factors: 3 for interspecies 3 for intraspecies combined uncertainty factor of 10a Scaling: No time scaling was utilized. Adaptation occurs to the slight irritation that defines the AEGL-1. Calculation: (Concentration/uncertainty factors) = AEGL-1 (1.17 ppm/10) = 0.12 ppm   Because tolerance develops to the slight irritation that defines the AEGL-1, the 0.12 ppm value was used for all AEGL-1 exposure durations. aEach uncertainty factor of 3 is actually the geometric mean of 10 which is 3.16; 3.16 × 3.16 = 10. Derivation of AEGL-2 for Chlorine Trifluoride Key study: Horn and Weir 1955 Toxicity end point: Strong irritation in dogs exposed to a concentration of 5.15 ppm for 6 h. Uncertainty Factors: 3 for interspecies 3 for intraspecies combined uncertainty of 10

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 Scaling: C1.3 × t = k (this document; based on LC50 concentration and exposure duration relationships in Horn and Weir [1955], MacEwen and Vernot [1970], and Dost et al. [1974]). Calculations:     (C1.3/uncertainty factors) × t = k ([5.15 ppm1.3] /10) × 360 min = 151.93 ppm1.3 · min   10 min AEGL-2: 151.93 ppm1.3 · min/10 min = 8.1 ppm   30 min AEGL-2: 151.93 ppm1.3 · min/30 min = 3.5 ppm   1 h AEGL-2: 151.93 ppm1.3 · min/60 min = 2.0 ppm   4 h AEGL-2: 151.93 ppm1.3 · min/240 min = 0.70 ppm   8 h AEGL-2: 151.93 ppm1.3 · min/480 min = 0.41 ppm Derivation of AEGL-3 for Chlorine Trifluoride Key study: MacEwen and Vernot 1970 Toxicity end point: Highest 1 h non-lethal value in monkeys (127 ppm) Uncertainty Factors: 2 for interspecies 3 for intraspecies combined uncertainty factor of 6 Scaling: C1.3 × t = k (this document; based on LC50 concentration and exposure duration relationships in Horn and Weir [1955], MacEwen and Vernot [1970], and Dost et al. [1974]). Calculations: (C1.3/uncertainty factors) × t = k (127 ppm1.3/6) × 60 min = 3173.2 ppm1.3 · min

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5   k = 3173.2 ppm1.3 · min 10 min AEGL-3: 3173.2 ppm1.3 · min/10 min = 84 ppm 30 min AEGL-3: 3173.2 ppm1.3 · min/30 min = 36 ppm 1 h AEGL-3: 3173.2 ppm1.3 · min/60 min = 21 ppm 4 h AEGL-3: 3173.2 ppm1.3 · min/240 min = 7.3 ppm 8 h AEGL-3: 3173.2 ppm1.3 · min/480 min = 4.3 ppmb bBecause the time-scaled 8 h AEGL-3 value of 4.3 ppm is inconsistent with the experimental data, the 8-h value was set equal to the 4-h value of 7.3 ppm.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 APPENDIX C ACUTE EXPOSURE GUIDELINE LEVELS FOR CHLORINE TRIFLUORIDE (CAS REG. NO. 7790-91-2) DERIVATION SUMMARY AEGL-1 VALUES 10 min 30 min 1 h 4 h 8 h 0.12 ppm 0.12 ppm 0.12 ppm 0.12 ppm 0.12 ppm Key Reference: Horn, H.J. and R.J. Weir. 1956. Inhalation toxicology of chlorine trifluoride. II. Chronic toxicity. A.M.A. Arch. Indust. Health 13:340-345. Test Species/Strain/Number: Two dogs and 20 rats, breed and strain not stated. Exposure Route/Concentration/Duration: Inhalation: 1.17 ppm, 6 h/day, 5 days/week for 6 months. Effects during first day: Dogs: 1.17 ppm for 6 h - nasal discharge (began within 0 to 45 min) obvious lacrimation (after 3 h). Rats: 1.17 ppm for 6 h - no observed effects. End point/Concentration/Rationale: A concentration of 1.17 ppm for 3 h resulted in no signs of irritation in dogs other than nasal discharge. Nasal discharge is considered to be within the definition of the AEGL-1 (mild sensory irritation). Lacrimation after 3 h of exposure was considered the threshold for notable discomfort. Uncertainty Factors/Rationale: Total uncertainty factor: 10 Interspecies: 3—The dog is a sensitive species for nasal irritation and provides a good model for humans. Dogs exposed to 1.17 ppm showed obvious lacrimation after 3 h yet rats showed no effects at the same concentration for 6 h. Intraspecies: 3—The concentration at which slight irritation is induced in the general population should not differ greatly. Modifying Factor: Not applicable. Animal to Human Dosimetric Adjustment: Insufficient data. Time Scaling: Not applied; adaptation occurs to the slight sensory irritation that defines the AEGL-1.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 Data Adequacy: Although only two dogs were tested in the key study, the concomitant exposure of 20 rats contributes to confidence in the data. The value was based on the dog, which appeared to be more sensitive to respiratory irritants than the rat. Although no histopathological examinations were performed until the termination of the experiment or death, exposure continued for 56 days (39 exposures) before a death occurred in the treated rats. The hydrolysis of ClF3 potentially produces three moles of hydrogen fluoride (HF). Confidence in the AEGL-1 values is boosted by the fact that the values for ClF3 are one-eighth of the AEGL-1 values for HF. The database for HF is extensive. AEGL-2 VALUES 10 min 30 min 1 h 4 h 8 h 8.1 ppm 3.5 ppm 2.0 ppm 0.70 ppm 0.41 ppm Key Reference: Horn, H.J. and R.J. Weir. 1955. Inhalation toxicology of chlorine trifluoride. I. Acute and subchronic toxicity. A.M.A. Arch. Indust. Health 12:515-521. Test Species/Strain/Sex/Number: Two dogs and 20 rats, breed and strain not stated. Exposure Route/Concentration/Duration: Inhalation: 5.15 ppm for 6 h/day, 5 days/week for 6 months. Effects (observed during the first day) for exposures to 5.15 ppm for 6 h: Dogs: strong irritation (salivation, lacrimation, rhinorrhea, coughing, sneezing) apparent recovery at end of day. Rats: no observed effects. End point/Concentration/Rationale 5.15 ppm for 6 h resulted in strong signs of irritation (salivation, lacrimation, rhinorrhea, coughing, sneezing) in the dog. These signs and symptoms are consistent with the definition of the AEGL-2 (threshold for irreversible or other serious, long-lasting effects or impaired ability to escape). Following 2 days of exposure to 21 ppm, corneal ulcers were observed. Uncertainty Factors/Rationale: Total uncertainty factor: 10 Interspecies: 3—The dog is a sensitive species for nasal irritation and provides a good model for the human. Dogs exposed to 5.15 ppm

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 showed signs of strong irritation (salivation, lacrimation, rhinorrhea, coughing, sneezing) during a 6-h exposure period yet rats showed no effects at the same concentration for 6 h. Intraspecies: 3—The concentration that induces irritation among the general population should not vary greatly. Modifying Factor: Not applicable. Animal to Human Dosimetric Adjustment: Insufficient data. Time Scaling: Cn × t = k where n = 1.3; based on the time-concentration relationship for LC50 values in monkeys, rats, and mice for exposure durations of 13.5-222 min (Horn and Weir 1955; MacEwen and Vernot 1970; Dost et al. 1974). Data Adequacy: Although only two dogs were tested in the key study, the concomitant exposure of 20 rats contributes to confidence in the data. The value was based on the dog which appeared to be more sensitive to respiratory irritants than the rat. No histopathological examinations were performed until termination of the experiment or death; exposures continued for 26 days before a death occurred in the treated dogs. AEGL-3 VALUES 10 min 30 min 1 h 4 h 8 h 84 ppm 36 ppm 21 ppm 7.3 ppm 7.3 ppm Key Reference: MacEwen, J.D. and E.H. Vernot. 1970. Toxic Hazards Research Unit Annual Technical Report: 1970, AMRL-TR-70-77, Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, OH. Test Species/Strain/Sex/Number: Male and female rhesus monkeys, 4/exposure group. Exposure Route/Concentration/Duration: Inhalation: 127, 150, 200, 300, or 400 ppm for 1 h. Effects from 1 h exposure: Concentration Mortality       127 ppm: 0/4       150 ppm: 2/4       200 ppm: 1/4       300 ppm: 2/4      

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 400 ppm: 4/4       1 h LC50 is 230 ppm (provided in reference) 1 h LC01 could not be calculated End point/Concentration/Rationale: 127 ppm for 1 h, the highest non-lethal value in the monkey, was considered the threshold for lethality, the defined end point for the AEGL-3. Uncertainty Factors/Rationale: Total uncertainty factor: 6 Interspecies: 2—Based on the similarity in respiratory parameters among primates. In addition, effects were similar among species and LC50 values varied by less than a factor of two for the monkey, rat, and mouse (indicating similar species sensitivity). Intraspecies: 3—The concentration at which extreme irritation and pulmonary damage may lead to lethality should not differ by more than a factor of 3 among the general population. Modifying Factor: Not applicable. Animal to Human Dosimetric Adjustment: Insufficient data. Time Scaling: Cn × t = k where n = 1.3; based on the time-concentration relationship for LC50 values in monkeys, rats, and mice for exposure durations of 13.5-222 min (Horn and Weir 1955; MacEwen and Vernot 1970; Dost et al. 1974). Data Adequacy: The key study was well conducted and documented. LC50 values from several additional studies were within a factor of two for all tested species. Similar values can be derived using the rat data (MacEwen and Vernot 1970; Dost et al. 1974) and a total uncertainty factor of 10.