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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 Appendix

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 This page in the original is blank.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 1 Phosgene1 Acute Exposure Guideline Levels SUMMARY Phosgene is a colorless gas at ambient temperature and pressure. Its odor has been described as similar to new-mown hay. Phosgene is manufactured from a reaction of carbon monoxide and chlorine gas in the presence of activated charcoal. The production of dyestuffs, isocyanates, carbonic acid esters (polycarbonates), acid chlorides, insecticides, and pharmaceutical chemicals requires phosgene. Manufacture of phosgene is approximately 1 million tons per year (y) in the United States, and more than 10,000 workers are involved in its manufacture and use. Manufacture of phosgene in the United States is 1   This document was prepared by AEGL Development Team member Cheryl Bast of Oak Ridge National Laboratory and Bill Bress (Chemical Manager) of the National Advisory Committee on Acute Exposure Guideline Levels for Hazardous Substances (NAC). The NAC reviewed and revised the document, which was 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 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 2 almost entirely captive—it is used in the manufacture of other chemicals within a plant boundary. Only one company sells phosgene on the U.S. merchant market. Inhalation is the most important route of exposure for phosgene. Because of phosgene’s mild upper respiratory, eye, and skin irritancy and mildly pleasant odor, an exposed victim may not actively seek an avenue of escape before lower respiratory damage has occurred (Currie et al. 1987a; Lipsett et al. 1994). Pulmonary edema is the cause of death after a clinical latency period of ≤24 hours (h) (Franch and Hatch 1986). Appropriate data were not available for deriving AEGL-1 values for phosgene. Odor cannot be used as a warning for potential exposure. The odor threshold is reported to be between 0.5 and 1.5 parts per million (ppm), a value above or approaching AEGL-2 and AEGL-3 values, and tolerance to the pleasant odor of phosgene occurs rapidly. Furthermore, following odor detection and minor irritation, serious effects may occur after a clinical latency period of ≤24 h. AEGL-2 values were based on chemical pneumonia in rats (exposure at 2 ppm for 90 min) (Gross et al. 1965). An uncertainty factor (UF) of 3 was applied for interspecies extrapolation because little species variability is observed for lethal and nonlethal end points after exposure to phosgene. A UF of 3 was applied to account for sensitive human subpopulations due to the steep concentration-response curve and because the mechanism of phosgene toxicity (binding to macromolecules and causing irritation) is not expected to vary greatly among individuals. Therefore, the total UF is 10. The 1.5-h value was then scaled to the 30-min and 1-, 4-, and 8-h AEGL exposure periods using Cn×t=k, where n=1 (Haber’s law), because Haber’s law has been shown to be valid for phosgene within certain limits. Haber’s law was originally derived from phosgene data (Haber 1924). The 30-min value is also adopted as the 10-min value, because extrapolation would yield a 10-min AEGL-2 value approaching concentrations that produce alveolar edema in rats; Diller et al. (1985) observed alveolar pulmonary edema in rats exposed to phosgene at 5 ppm for 10 min. Applying a total UF of 10 to this data point yields a supporting 10-min AEGL-2 value of 0.5 ppm. The 30-min and 1-, 4-, and 8-h AEGL-3 values were based on the highest concentration causing no mortality in the rat after a 30-min exposure (15 ppm) (Zwart et al. 1990). A UF of 3 was applied for interspecies extrapolation because little species variability is observed for lethal and nonlethal end points after exposure to phosgene. A UF of 3 was applied to account for sensitive human subpopulations due to the steep concentration-response curve and

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 because the mechanism of phosgene toxicity (binding to macromolecules and causing irritation) is not expected to vary greatly between individuals. Therefore, the total UF is 10. The value was then scaled to the 1-, 4-, and 8-h AEGL periods using Cn×t=k, where n=1 (Haber’s Law), because Haber’s Law has been shown to be valid for phosgene within certain limits. Haber’s Law was originally derived from phosgene data (Haber 1924). The 10-min AEGL-3 value was based on the highest concentration causing no mortality in the rat or mouse (36 ppm) after a 10-min exposure (Zwart et al. 1990). A UF of 3 was applied for interspecies extrapolation because little species variability is observed for lethal and nonlethal end points after exposure to phosgene. A UF of 3 was applied to account for sensitive human subpopulations due to the steep concentration-response curve and because the mechanism of phosgene toxicity (binding to macromolecules and causing irritation) is not expected to vary greatly between individuals (total UF, 10). The calculated values are listed in Table 1–1. 1. INTRODUCTION Phosgene is a colorless gas at ambient temperature and pressure. Its odor has been described as similar to new-mown hay (Leonardos et al. 1968). This mild odor and the weak acute irritant properties, however, provide little warning of its presence (Lipsett et al. 1994). The odor threshold has been established between 0.5 and 1.5 ppm (2.06 and 6.18 mg/m3) (Lipsett et al. 1994). Phosgene is manufactured from a reaction of carbon monoxide and chlorine gas in the presence of activated charcoal. Manufacture of phosgene is approximately 1 million tons per year (y) in the United States, and more than 10,000 workers are involved in its manufacture and use (Currie et al. 1987a). Manufacture of phosgene in the United States is almost entirely captive (more than 99% is used in the manufacture of other chemicals within a plant boundary). Only one company sells phosgene on the U.S. merchant market. Over 80% of the phosgene used in the United States is involved in the manufacture of polyisocyanates in the polyurethane industry. The polycarbonate industry accounts for approximately 10% of phosgene used, and the remaining 10% is used in the production of aliphatic diisocyanates, monoisocyanates, chloroformates, agrochemicals, and intermediates for dyestuffs and pharmaceuticals. Phosgene can also be used in metal recovery operations (platinum, uranium, plutonium, and niobium) and has been used for manufacturing aluminum chloride, beryllium chloride, and boron trichloride. It has been pat-

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 TABLE 1–1 Summary of Proposed AEGL Values for Phosgene (ppm [mg/m3]) Classification 10 min 30 min 1 h 4 h 8 h End Point (Reference) AEGL-1 NA NA NA NA NA NA (Nondisabling)   AEGL-2 0.60 0.60 0.30 0.08 0.04 Chemical pneumonia rats (Gross et al. 1965) (Disabling) (2.5) (2.5) (1.2) (0.33) (0.16) AEGL-3 3.6 1.5 0.75 0.20 0.09 Highest concentration causing no mortality in the rat after a 30-min or 10-min exposure (Zwart et al. 1990) (Lethal) (15) (6.2) (3.1) (0.82) (0.34) ented as a stabilizer for liquid SO2. In addition, many pesticides have been produced by reaction of a thiol or dithiol with phosgene to produce thiol chloroformates (Kirk-Othmer 1991). Inhalation is the most important route of exposure for phosgene. Because of phosgene’s mild upper respiratory, eye, and skin irritancy and mildly pleasant odor, an exposed victim may not actively seek an avenue of escape before lower respiratory damage has occurred (Currie et al. 1987a; Lipsett et al. 1994). Pulmonary edema is the cause of death after a clinical latency period of ≤24 h (Franch and Hatch 1986). The chemical structure is depicted below, and the physicochemical properties of phosgene are presented in Table 1–2. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality Diller and Zante (1982) performed an extensive literature review concerning human phosgene exposure, and found that a great majority of data were

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 TABLE 1–2 Physical and Chemical Data Parameter Data Reference Synonyms Carbonyl chloride, carbon oxychloride, carbonic dichloride, chloroformyl chloride Lipsett et al. 1994; EPA 1986 Chemical formula COCL2 Lipsett et al. 1994 Molecular weight 98.92 Lipsett et al. 1994 CAS registry no. 75–44–5 Lipsett et al. 1994 Physical state Gas Lipsett et al. 1994 Vapor pressure 1215 mm Hg at 20°C EPA 1986 Vapor density 3.4 (air=1) Lipsett et al. 1994 Specific gravity 1.381 g/l at 20°C ACGIH 2000 Melting/boiling/ flash point −128°C/8.2°C/not applicable Lipsett et al. 1994; NIOSH 1994 Solubility Decomposes in water and alcohol; soluble in organic solvents EPA 1986 Conversion factors in air 1 ppm=4.11 mg/m3 1 mg/m3=0.24 ppm Lipsett et al. 1994 Incompatibility Alkalis, ammonia, alcohols, copper NIOSH 1997 anecdotal or rough estimates and, thus, did not contain reliable exposure concentrations and/or durations. Information synthesized from this review is presented in Table 1–3. Based on observations during World War I, the 2 min LC50 value for humans was estimated to be 790 ppm (Chasis 1944). Many case reports describe symptomology and postmortem results from human phosgene poisonings; however, exposure concentrations were not reported. Six men were occupationally exposed to phosgene when a pipe ruptured (Stavrakis 1971). A 24-y-old who had received the heaviest exposure arrived at the emergency room minutes after the accident. Upon admission, the patient was symptom-free; however, he was treated with methenamine intravenously and admitted for a 24-h observation. During this time, he remained symptom free and was discharged with no evidence of phosgene injury. The other five patients arrived at the emergency room between 6 and

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 TABLE 1–3 Effect of Phosgene Exposure in Healthy Humans Effecta Cumulative Phosgene Exposure LCT1 ~300 ppm·min LCT50 ~500 ppm·min LCT100 ~1,300 ppm·min aLethal concentration × time product. Source: Diller and Zante 1982. 12 h after the accident, presenting with various degrees of phosgene intoxication. One 31-y-old who had been exposed “in almost the same degree as the previous patient” rapidly developed pulmonary edema. He also exhibited extreme hemoconcentration and leukocytosis. He did not respond to methenamine treatment and died 3.5 h after admission. The other four exposed workers were hospitalized for various periods of time and recovered satisfactorily. A 23-y-old man (healthy nonsmoker) was exposed to phosgene at an estimated concentration of at least 5–10 ppm for 5 to 10 seconds (s) (Bradley and Unger 1982). He began coughing upon exposure to phosgene and experienced dyspnea and chest tightness within 30 min. Four hours after exposure, he was hospitalized with hypotension, tachycardia, tachypnea, cyanosis, and pulmonary edema. The patient was intubated and administered dopamine and methylprednisolone. From the second to the sixth day of hospitalization, he developed mediastinal and subcutaneous emphysema, bilateral pneumohydrothoraces, elevated white blood cell counts, fever, and hemiparesis on the right side. Death occurred after the patient developed ventricular fibrillation. Misra et al. (1985) described another accidental occupational phosgene poisoning case. A 30-y-old male was exposed to phosgene at an undetermined concentration and immediately began coughing and experienced a sense of suffocation and burning eyes. After removal to fresh air and administration of oxygen, he felt better. However, approximately 7.5 h after the exposure, he was rushed to the emergency room with difficulty breathing. Despite oxygen administration and antibiotic therapy, his condition deteriorated. He died approximately 18 h after exposure. An autopsy showed pulmonary edema and bronchiolar necrosis, both of which were more severe in the lower lobes of the lungs than in the upper lobes. Hegler (1928) reported the effects of a phosgene accident that occurred in Hamburg, Germany, on May 20,1928. Eleven metric tons of “pure phosgene”

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 were released from a storage tank on a warm, dry, slightly windy day. Within a few hours, people as far as six miles from the release site began reporting to hospitals. Three hundred people reported to hospitals within a few days of the accident. Effects ranged from mild or moderate illness to death; ten people were reported to have died. In general, exposed persons exhibited symptoms consistent with other reported phosgene poisonings (headache, dizziness, nausea and vomiting, irritant cough, and sickening-sweet taste, followed by a latency period and then pulmonary symptoms). Autopsies on six of the fatalities showed pulmonary effects in all cases. Fatty degeneration of the kidneys, liver, and heart were observed in a few cases and were thought to be secondary to the pulmonary damage. In an atypical case, damage in the gray matter of the brain and spinal cord, hyperemia, and signs of bleeding in the white matter were observed at autopsy. That patient died 11.5 days (d) postexposure from a blood clot lodged in the lung. It was uncertain if the extrapulmonary effects were due to phosgene exposure. 2.2. Nonlethal Toxicity NIOSH (1976) performed two studies to determine the odor threshold of phosgene. In the first, 56 military personnel were exposed to phosgene at increasing concentrations until all subjects could detect odor. The lowest detectable concentration was 0.4 ppm. Thirty-nine percent of subjects could detect odor at 1.2 ppm, and 50% of subjects detected odor at 1.5 ppm. In the other study, four subjects identified 1.0 ppm as the lowest concentration at which the distinctive “new-mown hay” odor of phosgene could be detected. In their literature review, Diller and Zante (1982) also identified nonlethal effects from phosgene exposure (lethal effects are described in Section 2.1). Nonlethal information synthesized from this review is presented in Table 1–4. From the above data and from animal data for “initial lung damage,” Diller and Zante (1982) synthesized information for nonlethal effects of phosgene in humans (Table 1–5). 2.2.1. Case Reports A 30-y-old male was occupationally exposed to phosgene at an unknown concentration (Stavrakis 1971). After a short episode of coughing, he returned to work and completed the final 3 h of his shift. Approximately 4 h post-

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 TABLE 1–4 Acute Irritative Effects of Phosgene Exposure in Humans Effect Phosgene Concentration Throat irritation 3.1 ppm Ocular irritation 4.0 ppm Cough 4.8 ppm Severe eye and airway irritation 10 ppm   Source: Diller and Zante 1982 exposure, he presented at the emergency room with severe dyspnea, restlessness, chest pain, and persistent, productive cough. Chest x-rays confirmed acute pulmonary edema. He was treated and discharged free of symptoms 5 d after the phosgene exposure. An investigator was exposed to phosgene at an undetermined concentration during an experiment (Delephine 1922). He entered the phosgene chamber “at frequent intervals” over a period of 45 min to take instrument readings. At first, he experienced only laryngeal and conjunctival irritation, but as the phosgene concentration increased, he was forced to hold his breath and not stay in the room for more than 1 min. Toward the end of the experiment, some phosgene escaped from the chamber. At this time, the investigator and a colleague experienced a violent cough and began to run away. During their escape, both men had to stop frequently due to the violent nature of their coughs. After exiting the contaminated area, both individuals continued to cough for approximately 20 min. They then improved for 3 or 4 h, after which they experienced a choking sensation that lasted approximately 24 h. Marked lassitude lasted for an additional few days, after which recovery appeared to be complete. Everett and Overholt (1968) discussed a 40-y-old male who received a “massive” phosgene exposure. His initial symptoms included coughing and burning of the eyes, which subsided within 5 min. He was asymptomatic for the next 2 h, after which a hacking cough began. Three hours after exposure, mild dyspnea was present, and 6 h postexposure, severe dyspnea and moist rales were observed. He was admitted to an intensive care unit 8 h postexposure and presented with anxiety, agitation, cyanosis, thirst, constant cough, and severe pulmonary edema. By the fifth day in the hospital, he was asymptomatic, and by the seventh day, pulmonary function and chest x-ray were normal. A 2-y follow-up was unremarkable.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 TABLE 1–5 Effect of Phosgene Exposure in Humans Effect Phosgene Exposure Odor perception >0.4 ppm Odor recognition >1.5 ppm Ocular, nasal, throat, and bronchiolar irritation >3 ppm Initial lung damage >30 ppm·min Clinical pulmonary edema >150 ppm·min   Source: Diller and Zante 1982. Regan (1985) described a phosgene release from a toluene diisocyanate plant. Fifteen employees were exposed to phosgene at an undetermined concentration, resulting in the hospitalization of four workers. Two of the four were released after an overnight observation. The other two were in more serious condition. One of them, a 31-y-old male, had pulmonary edema, rales in both lungs, and left chest pain 8 h postexposure. He was treated with oxygen, bronchodilators, steroids, and antibiotics and returned to work 6 d after the accident. His follow-up was unremarkable. The second man, a 47-y-old smoker, presented with dyspnea, bilateral rales, and pulmonary edema 11 h postexposure. He was also treated with oxygen, bronchodialators, steroids, and antibiotics but continued to deteriorate. He remained critical for 3 d with low right-side heart pressure, low arterial pressure, hemoconcentration, and leukocytosis. He was asymptomatic by 12 d postexposure. He had mild pulmonary obstruction four weeks after the accident; however, it is unclear if that was a result of phosgene exposure or of his smoking. Longer-term effects from acute phosgene exposure have also been described. Galdston et al. (1947a) described the late effects of phosgene poisoning in six workers (two male, four female; ages 31–50). After an acute, accidental, occupational exposure to phosgene all of these workers experienced the typical effects of acute phosgene exposure. Chronic clinical findings present from 1 to 24 months (mo) postexposure included rapid, shallow breathing and changes in pulmonary function. However, no correlation was observed between the magnitude of phosgene exposure or the severity of acute effects and the severity of chronic symptoms. Galdston et al. (1947a) attributed the severity of chronic symptoms to the subjects’ psychological state. Smoking habits were not reported, and long-term follow-up was not performed.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 1923]. Berlin, Germany: Verlag von Julius Springer; pp. 76–92. (Cited in EPA 1986) Halpern, B.N., Cruchaud, S., Vermeil, G., and Roux, J.L. 1950. Experimental study on the pathogenesis and treatment of acute pulmonary edema. Arch. Int. Pharmacodyn. Ther. 82:425–476. (Cited in EPA 1986) Hatch, G.E., Slade, R., Stead, A.G., and Graham, J.A. 1986. Species comparison of acute inhalation toxicity of ozone and phosgene. J. Toxicol. Environmental Health 19:43–53. Hedlund, L.W., and Putman, C.E. 1985. Methods for detecting pulmonary edema. Toxicol. Ind. Health. 1:59–67. Hegler, C. 1928. On the mass poisoning by phosgene in Hamburg. I. Clinical observations. 54:1551–1553. Henschler, D. 1971. German MAK Criteria. (From Ehrlicher, H. 1971. Personal Communication, Department of Medicine, Bayer AG, Leverkusen). Henschler, D. and Laux, W. 1960. On the specificity of a tolerance increase by repeated inhalation of pulmonary edema-producing gases. Naunyn-Schmiedbergs Arch. Exp. Pathol. Pharmakol. 239:433–441. (Cited in EPA 1986) Herzog, H. And Pletscher, A. 1955. Die wirkung von industriellen reizgasen auf die bronchialschleimhaut des menschen. Schweizerische Medizinische Wochenschrift. 85:477–481. Illing, J.W., Mole, M.L., Graham, J.A, et al. 1988. Influence of phosgene inhalation on extrapulmonary effects in mice . Inhalation Toxicol. 1:13–20. Jaskot, R.H., Grose, E.C., and Stead, A.G. 1989. Increase in angiotensin-converting enzyme in rat lungs following inhalation of phosgene. Inhalation Toxicol. 1:71– 78. Jaskot, R.H., Grose, E.C., Richards, J.H., and Doerfler, D.L. 1991. Effects of inhaled phosgene on rat lung antioxidant systems. Fund. Appl. Toxicol. 17:666–674. Kaerkes, B. 1992. Experiences with a phosgene indicator badge during an elevenyear period. M.D. Dissertation, Heinrich-Heine University. Duesseldorf, Germany. Karel, L. and Weston, R.E. 1947. The biological assay of inhaled substance by the dosimetric method: The retained median lethal dose and the respiratory response in unanesthetized, normal goats exposed to different concentrations of phosgene. J. Ind. Hyg. Toxicol. 29:23–28. Kawai, M. 1973. [Inhalation toxicity of phosgene and trichloronitromethane (chloropicrin)]. J. Sangyo Igaku 15:406–407. Keeler, J.R., Hurt, H.H., Nold, J.B., Corcoran, K.D., and Tezak-Reid, T.M. 1990a. Phosgene-induced lung injury in sheep. Inhalation Toxicol. 2:391–406. Keeler, J.R., Hurt, H.H., Nold, J.B., and Lennox, W.J. 1990b. Estimation of the LCt50 of phosgene in sheep. Drug Chem Toxicol. 13:229–239.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 Kimmerle, G. and Diller, W. 1977. Unveroffentilichte Untersuchungen. (Cited in EPA 1986) Kirk-Othmer.. 1991. Encyclopedia of Chemical Technology. Fourth Edition. Volume 18. John Wiley & Sons. New York. Phosgene, pp. 645–655. Laquer, E. and Magnus, R. 1921. Combat gas poisoning. III. Experimental pathology of phosgene poisoning. Z. Gesamte Exp. Med. 13:31–107. Leonardos, G., Kendall, D.A., and Barnard, N.J. 1968. Odor threshold determinations of 53 odorant chemicals. Presented at the 61th Annual Meeting of the Air Pollution Control Association, St. Paul, Minn., June 23–27. [Requested. NIOSH, 1976, page 29] Lipsett, M.J., Shusterman, D.J., and Beard, R.R. 1994. Phosgene. In: Industrial hygiene and toxicology, 4th ed. Vol. II, part F. Clayton, G.D. and Clayton, F.E. editors, J.Wiley & Sons, Inc. pp. 4557–4563. MAC (Maximaal Aanvaaarde Concentratie [Maximal Accepted Concentration]). 2000. SDU Uitgevers (under the auspices of the Ministry of Social Affairs and Employment), The Hague, The Netherlands. MAK (Maximale Argeitsplatzkonzentration [Maximum Workplace Concentration]) 2000. Deutsche Forschungsgemeinschaft (German Research Association). Mansuy, D., Beaune, P., Crestell, T., Lange, M., and Leroux, M. 1977. Evidence for phosgene formation during liver microsomal oxidation of chloroform. Biochem. Biophys. Res. Comm. 79:513–517. Meek, W.J. and Eyster, J.A.E. 1920. Experiments on the pathological physiology of acute phosgene poisoning. Am. J. Physiol. 51:303–320. Misra, N.P., Manoria, P.C., and Saxena, K. 1985. Fatal pulmonary oedema with phosgene poisining. J. Assoc. Physicians India. 33:430–431. Moor, S. and Gates, M. 1946. Technical report of division G/NDRC. (Cited in EPA 1986) NIOSH (National Institute of Occupational Safety and Health). 1976. Criteria for a recommended standard: occupational exposure to phosgene. NIOSH-76–137. NIOSH (National Institute of Occupational Safety and Health). 1997. Phosgene. NIOSH Pocket Guide to Chemical Hazards, pp. 252–253. NRC (National Research Council). 1985. Emergency and Continuous Exposure Limits for Selected Airborne Contaminants. Phosgene, pp. 69–86. National Academy Press. Washington, D.C. Ong, S.G. 1972. Treatment of phosgene poisoning with antiserum: anaphylactic shock by phosgene. Arch. Toxicol. 29:267–278. (Cited in EPA 1986) OSHA (Occupational Safety and Health Administration). 1994. Limits for Air Contaminants. U.S. Department of Labor. 29 CFR 1910.1000. Patt, H.M., Tobias, J.M., Swift, M.N., Postel, S., and Gerard, R.W. 1946. Hemodynamics in pulmonary irritant poisoning. Am. J. Physiol. 147:329–339.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 Pawlowski, R. and Frosolono, M.F. 1977. Effect of phosgene on rat lungs after single high-level exposure. II. Ultrastructural alternations. Arch. Environ. Health 32:278–283. Pohl, L.R., Bhooshan, B., Whittaker, N.F., and Krishna, G. 1977. Phosgene: a metabolite of chloroform. Biochem. Biophys. Res. Comm. 79:684–691. Pohl, L.R., Martin, J.L., and George, J.W. 1980a. Mechanism of metabolic activation of chloroform by rat liver microsomes. Biochem. Pharmacol. 29:3271–3276. Pohl, L.R., Martin, J.L., Taburet, A.M. and George, J.W. 1980b. Oxidative bioactivation of haloforms into hepatotoxins. In: Microsomes, Drug Oxidations, and Chemical Carcinogenesis, Vol. II. Coon, M.J., et al., Eds. Academic Press, New York. Pp. 881–884. Pohl, L.R., Branchflower, R.V., Highet, R.J., et al. 1981. The formation of diglutathionyl dithiocarbonate as a metabolite of chloroform, bromotrichloromethane, and carbon tetrachloride. Drug. Metab. Dispos. 9:334–338. Polednak, A.P. and Hollis, D.R. 1985. Mortality and causes of death among workers exposed to phosgene in 1943–1945. Toxicol. Ind. Health. 1:137–148. Polednak, A.P. 1980. Mortality among men occupationally exposed to phosgene in 1943–1945. Environ. Res. 22:357–367. Postel, S. and Swift, M. 1945. Evaluation of the bleeding-transfusion treatment of phosgene poisoning. In: Fasciculus on chemical warfare medicine: v. II, respiratory tract. Washington, DC: National Research Council, Committee on Treatment of Gas Casualties; pp. 664–690. (Cited in EPA 1986) Regan, R.A. 1985. Review of clinical experience in handling phosgene exposure cases. Toxicol. Ind. Health. 1:69–71. Reynolds, E.S. 1967. Liver parenchymal cell injury. IV. Pattern of incorporation of carbon and chlorine from carbon tetrachloride into chemical constituents of liver in vivo. J. Pharmacol. Exp. Ther. 155:126–127. Rinehart, W.E. 1962. A study of the concentration × time (CT) relationship in sublethal exposures to phosgene (dissertation). Pittsburgh, PA. University of Pittsburgh. Publication No. 62–6675. University Microfilms, Inc. Ann Arbor, MI. Rinehart, W.E. and Hatch, T. 1964. Concentration-time product (CT) as an expression of dose in sublethal exposures to phosgene. AIHA Journal. 25:545–553. Rothlin, E. 1941. Pathogenesis and treatment for phosgene intoxication. Schweiz. Med. Wochenschr. 71:1526–1535. (Cited in EPA 1986) Sandall, T.E. 1922. The later effects of gas poisoning. Lancet. 203:857–859. (Cited in EPA 1986) Schultz, J. 1945. The prophylactic action of hexamethylenetetramine in phosgene poisoning. In: Fasciculus on chemical warfare medicine: v. II, Respiratory tract. Washington, DC: National Research Council, Committee on Treatment of Gas Casualties; pp. 691–712.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 Selgrade, M.K., Starnes, D.M., Illing, J.W., Daniels, M.J., and Graham, J.A. 1989. Effects of phosgene exposure on bacterial, viral, and neoplastic lung disease susceptability in mice. Inhalation Toxicol. 1:243–259. Shah, H., Hartman, S.P., and Weinhouse, S. 1979. Formation of carbonyl chloride in carbon tetrachloride metabolism by rat liver in vitro. Cancer Res. 39:3942– 3947. Shils, S.E. 1943. The therapeutic and prophylactic value of hexamethylenetetramine in phosgene poisoning. MD (EA) Memorandum report Nr. 81 V. 19. (Cited in EPA 1986) Sipes, I.G., Krishna, G., and Gillette, J.R. 1977. Bioactivation of carbon tetrachloride, chloroform, and bromotrichloromethane: role of cytochrome P-450. Life Sciences. 20:1541–1548. Slade, R., Highfill, J.W., and Hatch, G.E. 1989. Effects of depletion of ascorbic acid or nonprotein sulfhydryls on the acute inhalation toxicity of nitrogen dioxide, ozone, and phosgene. Inhalation Toxicol. 1:261–271. Stavrakis, P. 1971. The use of hexamethylenetetramine (HMT) in treatment of acute phosgene poisoning. Ind. Med. 40:30–31. TEMIS (Trauma Emergency Medical Information System). 1997. Phosgene. ten Berge, W.F., Zwart, A. and Appleman, L.M. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Hazardous Materials 13:301–309. Tobias, J.M. 1945. The pathological physiology of the lung after phosgene. In: Fasciculus on chemical warfare medicine: v. II, respiratory tract. Washington, DC: National Research Council, Committee on Treatment of Gas Casualties; pp. 331–391. (Cited in EPA 1986) Underhill, F.P. 1920. The lethal war gases. Physiology and experimental treatment. New Haven Yale University Press. Weston, R.E. and Karel, L. 1946. An application of the dosimetric method for biologically assaying inhaled substances: The determination of the retained median lethal dose, percentage retention, and respiratory response in dogs exposed to different concentrations of phosgene. J. Pharmacol. Exptl. Ther. 88:195. Weston, R.E. and Karel, L. 1947. An adaptation of the dosimeteric method for use in smaller animals. The retained median lethal dose and the respiratory response in normal, unanesthetized, Rhesus monkeys (Macaca mulatta) exposed to phosgene. J. Ind. Hyg. Toxicol. 29:29–33. Winternitz, M.C, Lambert, R.A., and Jackson, L. 1920. The pathology of phosgene poisoning. In: Collected studies on the pathology of was gas poisoning. New Haven, CT: Yale Univ. Press; pp. 35–66. Wirth, W. 1936. Uber die wirkung kleinster phosgenmengen. Arch. Exp. Pathol. Pharmacol. 181:198–206. Zwart, A., Arts, J.H.E., Klokman-Houweling, J.M., and Schoen, E.D. 1990. Determination of concentration-time-mortality relationships to replace LC50 values. Inhalation Toxicol. 2:105–117.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 Appendixes

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 APPENDIX A DERIVATION OF AEGL VALUES Derivation of AEGL-1 Data were insufficient for derivation of AEGL-1 values for phosgene. Derivation of AEGL-2 Key study: Gross et al. (1965) Toxicity end point: Chemical pneumonia in rats Scaling: C×t=k (2 ppm)×1.5 h=3 ppm·h Uncertainty factors: 3 for interspecies variability 3 for intraspecies variability 10-min AEGL-2: 0.6 ppm (30-min value adopted as the 10-min value) 30-min AEGL-2: C×0.5 hr=3 ppm·h C=6 ppm 30-min AEGL-2=6 ppm/10=0.6 ppm 1-h AEGL-2: C×1 h=3 ppm·h C=3 ppm 1-h AEGL-2=3 ppm/10=0.3 ppm 4-h AEGL-2: C×4 h=3 ppm·h C=0.75 ppm 4-h AEGL-2=0.75 ppm/10=0.075 ppm 8-h AEGL-2: C×8 h=3 ppm·h C=0.375 ppm

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2   8-h AEGL-2=0.375 ppm/10=0.038 ppm Derivation of AEGL-3 Key study: Zwart et al. (1990) Toxicity end point: The highest concentration causing no mortality in the rat or mouse after a 10-min exposure (10-min). The highest concentration causing no mortality in the rat after a 30-min exposure (30-min, 1-, 4-, and 8-h). Scaling (30-min, 1-, 4-, and 8-h): C×t=k (15 ppm)×0.5 h=7.5 ppm·h Uncertainty factors: 3 for interspecies variability 3 for intraspecies variability 10-min AEGL-3: 10-min AEGL-3=36 ppm/10=3.6 ppm 30-min AEGL-3: C×0.5 h=7.5 ppm·h C=15 ppm 30-min AEGL-3=15 ppm/10=1.5 ppm 1-h AEGL-3: C×1 h=7.5 ppm·h C=7.5 ppm 1-h AEGL-3=7.5 ppm/10=0.75 ppm 4-hr AEGL-3: C×4 h=7.5 ppm·h C=1.875 ppm 4-h AEGL-3=1.875 ppm/10=0.19 ppm 8-h AEGL-3: C×8 h=7.5 ppm·h C=0.94 ppm 8-h AEGL-3=0.94 ppm/10=0.094 ppm

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 APPENDIX B DERIVATION SUMMARY FOR ACUTE EXPOSURE GUIDELINE LEVELS FOR PHOSGENE (CAS No. 75–44–5) AEGL-1 10 min 30 min 1 h 4 h 8 h NA NA NA NA NA Key reference: NA Test species/Strain/Number: NA Exposure route/Concentrations/Durations: NA Effects: NA End point/Concentration/Rationale: NA Uncertainty factors/Rationale: NA Modifying factor: NA Animal to human dosimetric adjustment: NA Time scaling: NA Confidence and Support for AEGL values: Data were insufficient for derivation of AEGL-1 values for phosgene. Odor cannot be used as a warning for potential exposure. The odor threshold is reported to be between 0.5 and 1.5 ppm, a value above or approaching AEGL-2 and AEGL-3 values, and tolerance to the pleasant odor of phosgene occurs rapidly. Furthermore, following odor detection and minor irritation, serious effects may occur after a clinical latency period of ≤24 h.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 AEGL-2 10 min 30 min 1 h 4 h 8 h 0.60 ppm 0.60 ppm 0.30 ppm 0.08 ppm 0.04 ppm Key reference: Gross, P., Rinehart, W.E., and Hatch, T. 1965. Chronic pneumonitis caused by phosgene. Arch. Environ. Health. 10:768–775. Test species/Strain/Number: Wistar rats/118 males Exposure route/Concentrations/Durations: Rats/Inhalation: 0.5 to 4.0 ppm for 5 min to 8 h to give C×T products between 12 and 360 ppm·min (2 ppm for 1.5 h was determinant for AEGL-2) Effects: 2 ppm for 1.5 h: chemical pneumonia; 0.9 ppm for 1 h: “chronic pneumonitis” End point/Concentration/Rationale: Rats/2 ppm for 1.5 h/chemical pneumonia Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3—little species variability is observed with both lethal and nonlethal end points in many studies after exposure to phosgene Intraspecies: 3—due to the steep concentration-response curve and effects appear to be due to irritation and binding to macromolecules are not expected to differ greatly among individuals. Modifying factor: Not applicable Animal to human dosimetric adjustment: Insufficient data Time scaling: Cn×t=k where n=1. Haber’s Law (C×t=k) has been shown to be valid for phosgene within certain limits (EPA 1986). Haber’s Law was originally derived from phosgene data (Haber 1924). Reported 1.5 h data point used for AEGL-2 derivation. AEGL values for the 30-min and 1-, 4-, and 8-h exposure periods were based on extrapolation from the 1.5 h value. The 30-min value is also adopted as the 10-min value because Diller et al. (1985) observed alveolar pulmonary edema in rats exposed to 5 ppm phosgene for 10 min. Applying a total UF of 10 to this data point yields a supporting 10-min value of 0.5 ppm. Data adequacy: The database is rich. The calculated AEGL-2 values are supported by rat studies where exposure of rats to 1 ppm phosgene for 4 h resulted in severe pulmonary edema and body weight loss. (Franch and Hatch 1986; Erlich et al. 1989). Use of these data (and application of a total UF of 10) results in supporting AEGL-2 values of 0.8, 0.4, 0.1, and 0.05 ppm for the 30 min, 1 h, 4 h, and 8 h time points, respectively. The 10-min value is supported by Diller et al. (1985) as described above in the time scaling section.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 AEGL-3 10 min 30 min 1 h 4 h 8 h 3.6 ppm 1.5 ppm 0.75 ppm 0.20 ppm 0.09 ppm Reference: Zwart, A. et al. 1990. Determination of concentration-time-mortality relationships to replace LC50 values. Inhalation Toxicol. 2:105–117. Test species/Strain/Sex/Number: Wistar rats/5 males and 5 females Exposure route/Concentrations/Durations: Rats/Inhalation: 12, 15, 16, 17, or 24 ppm for 30 min (the highest concentration causing no mortality in the rat after a 30-min exposure of 15 ppm was determinant for AEGL-3) Effects: Concentration Mortality   12 ppm 0/10   15 ppm 0/10   16 ppm 1/10   17 ppm 5/10   24 ppm 9/10 End point/Concentration/Rationale: The highest concentration causing no mortality in the rat after a 30-min exposure 30-min experimental no-effect-level for death (15 ppm) was used as a threshold for death in rats for the 30-min, 1-, 4-, and 8-h values. The highest concentration causing no mortality in the rat after a 10-min exposure (36 ppm) was utilized for the 10-min value. Uncertainty Factors/Rationale: Total uncertainty factor: 10 Interspecies: 3—little species variability is observed with both lethal and nonlethal end points in many studies after exposure to phosgene Intraspecies: 3—due to the steep concentration-response curve and effects appear to be due to irritation and binding to macromolecules are not expected to differ greatly among individuals . Modifying factor: Not applicable Animal to human dosimetric adjustment: Insufficient data Time scaling: Cn×t=k where n=1. Haber’s Law (C×t=k) has been shown to be valid for phosgene within certain limits (EPA 1986). Haber’s Law was originally derived from phosgene data (Haber 1924). Reported 30-min data point used to determine the 30-min AEGL value. AEGL-3 values for 1-, 4-, and 8-h were based on extrapolation from the 30 min value. The 10-min value was based on a reported 10-min data point. Data adequacy: The AEGL-3 values are based on a well-conducted study in rats and the database is rich.