1 

2 

3 

4 

5 

6 

7 

8 

9 PHOSGENE 

10 

11 CAS No. 75-44-5 

12 

13 

14 

15 

16 

17 

18 

19 

20 ACUTE EXPOSURE GUIDELINE LEVELS 

21 

22 Draft-Revised 

23 

24 

25 

26 

27 

28 

29 

30 

31 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 2 of 73 

1 PREFACE

2 

3 Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of 

4 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous 

5 Substances (NAC/AEGL Committee) has been established to identify, review and interpret 

6 relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic 

7 chemicals. 

8 

9 AEGLs represent threshold exposure limits for the general public and are applicable to 

10 emergency exposure periods ranging from 10 minutes to 8 hours. Three levels C AEGL-1, 

11 AEGL-2 and AEGL-3 C are developed for each of five exposure periods (10 and 30 minutes, 1 

12 hour, 4 hours, and 8 hours) and are distinguished by varying degrees of severity of toxic effects. 

13 The three AEGLs are defined as follows: 

14 

15 AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per 

16 cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general 

17 population, including susceptible individuals, could experience notable discomfort, 

18 irritation, or certain asymptomatic, non-sensory effects. However, the effects are not 

19 disabling and are transient and reversible upon cessation of exposure. 

20 

21 AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance 

22 above which it is predicted that the general population, including susceptible 

23 individuals, could experience irreversible or other serious, long-lasting adverse health 

24 effects or an impaired ability to escape. 

25 

26 AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance 

27 above which it is predicted that the general population, including susceptible 

28 individuals, could experience life-threatening health effects or death. 

29 

30 Airborne concentrations below the AEGL-1 represent exposure levels that could 

31 produce mild and progressively increasing but transient and nondisabling odor, taste, and 

32 sensory irritation or certain asymptomatic, non-sensory effects. With increasing airborne 

33 concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence 

34 and the severity of effects described for each corresponding AEGL. Although the AEGL values 

35 represent threshold levels for the general public, including susceptible subpopulations, such as 

36 infants, children, the elderly, persons with asthma, and those with other illnesses, it is 

37 recognized that individuals, subject to unique or idiosyncratic responses, could experience the 

38 effects described at concentrations below the corresponding AEGL. 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 3 of 73 

1 EXECUTIVE SUMMARY

2 

3 Phosgene is a colorless gas at ambient temperature and pressure. Its odor has been 

4 described as similar to new-mown hay. Phosgene is manufactured from a reaction of carbon 

5 monoxide and chlorine gas in the presence of activated charcoal. The production of dyestuffs, 

6 isocyanates, carbonic acid esters (polycarbonates), acid chlorides, insecticides, and 

7 pharmaceutical chemicals requires phosgene. Manufacture of phosgene is approximately 1 

8 million tons per year in the United States with more than 10,000 workers involved in its 

9 manufacture and use. Manufacture of phosgene in the United States is almost entirely captive, 

10 in that it is used in the manufacture of other chemicals within a plant boundary. 

11 

12 Inhalation is the most important route of exposure for phosgene. Because of its mild 

13 upper respiratory, eye and skin irritancy, and a mildly pleasant odor, an exposed victim may not 

14 actively seek an avenue of escape before lower respiratory damage has occurred (Currie et al., 

15 1987a; Lipsett et al., 1994). Pulmonary edema is the cause of death after a clinical latent period 

16 of 24 hours (Franch and Hatch, 1986). 

17 

18 Appropriate data were not available for deriving AEGL-1 values for phosgene. Odor 

19 cannot be used as a warning for potential exposure. The odor threshold is reported to be 

20 between 0.5 to 1.5 ppm, a value above or approaching AEGL-2 and AEGL-3 values, and 

21 tolerance to the pleasant odor of phosgene occurs rapidly. Furthermore, following odor 

22 detection and minor irritation, serious effects may occur after a clinical latency period of 24 

23 hours. 

24 

25 The NOAEL for increased PMNs in BAL fluid observed in dogs (2.3 ppm for 30 

26 minutes) (Pauluhn, 2006c) was used as the basis for deriving AEGL-2 values. The dog was 

27 chosen over rodents because, with regard physiology of the respiratory tract and acinar structure 

28 of the lung, dogs are more similar to humans than rodents. This endpoint was chosen because 

29 BAL fluid changes are a sensitive marker of phosgene-induced noncardiogenic pulmonary high30 permeability edema following acute inhalation exposure (Pauluhn et al., 2007). 

31 

32 An uncertainty factor of 1 was applied for interspecies extrapolation. In rats, c x t 

33 products of between 48 ppm·min and 60 ppm·min induced increased protein in BAL fluid , and 

34 no increase was noted from 24-30 ppm·min. In mice and hamsters, a c x t product of 48 

35 ppm·min induced an increase of protein in BAL fluid, and no increase was noted at 24 ppm·min. 

36 However, in dogs, a c x t product of 129 ppm·min was necessary to cause an increase in protein 

37 in BAL fluid, and no increase was observed at 63 ppm·min. Thus, the CT product required to 

38 induce an increase in protein in BAL fluid in dogs is approximately two-fold greater than in 

39 rodents, and the NOAEL for increased BAL protein in dogs (63 ppm·min) is higher than the 

40 LOAEL values in rodents (48-60 ppm·min). Additionally, with regard to physiology of the 

41 respiratory tract and acinar structure of the lung, dogs are more similar to humans than rodents 

42 (Pauluhn, 2006a, 2006b, 2006c; Pauluhn et al., 2007). Collectively, these data suggest that an 

43 interspecies uncertainty factor of no more than 1 is justified when extrapolating from laboratory 

44 animals to humans. 

45 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 4 of 73 

1 An uncertainty factor of 3 was applied to account for sensitive human subpopulations. 

2 The intraspecies UF of 3 is considered sufficient due to the steep concentration-response curve 

3 (death in 2/10 rats exposed to 52.3 ppm and 6/10 exposed to 61.9 ppm for 10 min; 4/10 exposed 

4 to 13.4 ppm and 10/10 exposed to 16.7 ppm for 30-min; 4/10 exposed to 7.4 ppm and 10/10 

5 exposed to 11.8 ppm for 1-hr; Pauluhn, 2006a) which implies limited intra-individual 

6 variability. Also, the mechanism of phosgene toxicity (binding to macromolecules and 

7 irritation) is not expected to vary greatly between individuals. The concentration-time 

relationship for many irritant and systemically-acting vapors and gases may be described by cn 8 

9 x t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et al., 1986). Haber=s Law c x 

10 t = k; n=1 has been shown to be valid for phosgene within certain limits and will be used for 

11 scaling of the AEGL values for phosgene. 

12 

13 The AEGL-3 values were based on an estimated 1-hour lethality threshold of 3.9 ppm 

14 (BMCL05) in rats (Pauluhn, 2006a). Uncertainty factor application and time scaling are as 

15 described above for derivation of AEGL-2 values. 

16 

17 The calculated values are listed in the table below. 

18 

TABLE S 1. Summary of Proposed AEGL Values for Phosgene 

Classification 10-min 30-min 1-hr 4-hr 8-hr Endpoint (Reference)

AEGL-1 

(Nondisabling) 

NR NR NR NR NR Not Recommended

AEGL-2 

(Disabling) 

2.3 ppm 

(9.5 mg/m3

)

0.77 ppm 

(3.2 mg/m3) 

0.38 ppm 

(1.6 mg/m3) 

0.096 ppm 

(0.39 mg/m3)

0.048 ppm 

(0.19 mg/m3) 

Increased PMNs in 

BAL fluid in dogs 

(Pauluhn, 2006c) 

AEGL-3 

(Lethal) 

7.8 ppm 

(32 mg/m3

) 

2.6 ppm 

(11 mg/m3) 

1.3 ppm 

(5.3 mg/m3) 

0.33 ppm 

(1.4 mg/m3) 

0.16 ppm 

(0.66 mg/m3) 

Estimated 1-hr lethality 

threshold (BMCL05) in 

rats (Pauluhn, 2006a) 

NR: Not Recommended. Absence of AEGL-1 values does not imply that exposure to concentrations below AEGL-2 

are without effect. 

19 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 5 of 73 

1 TABLE OF CONTENTS

2 PREFACE................................................................................................................................................... 2 

3 EXECUTIVE SUMMARY......................................................................................................................... 3 

4 LIST OF TABLES...................................................................................................................................... 8 

5 1. INTRODUCTION.............................................................................................................................. 9 

6 2. HUMAN TOXICITY DATA........................................................................................................... 10 

7 2.1. Acute Lethality ........................................................................................................................ 10 

8 2.2. Nonlethal Toxicity................................................................................................................... 11 

9 2.2.1. Case Reports........................................................................................................................ 12 

10 2.2.2. Epidemiologic Studies ........................................................................................................ 14 

11 2.3. Developmental/Reproductive Toxicity.................................................................................... 15 

12 2.4. Genotoxicity ............................................................................................................................ 15 

13 2.5. Carcinogenicity........................................................................................................................ 15 

14 2.6. Summary.................................................................................................................................. 15 

15 3. ANIMAL TOXICITY DATA.......................................................................................................... 16 

16 3.1. Acute Lethality ........................................................................................................................ 16 

17 3.1.1. Mouse.................................................................................................................................. 16 

18 3.1.2. Rats...................................................................................................................................... 16 

19 3.1.3. Guinea Pigs ......................................................................................................................... 19 

20 3.1.4. Rabbits................................................................................................................................. 20 

21 3.1.5. Cats...................................................................................................................................... 20 

22 3.1.6. Dogs .................................................................................................................................... 20 

23 3.1.7. Goats ................................................................................................................................... 21 

24 3.1.8. Sheep................................................................................................................................... 21 

25 3.1.9. Non-human Primates.......................................................................................................... 21 

26 3.2. Nonlethal Toxicity................................................................................................................... 22 

27 3.2.1. Mice..................................................................................................................................... 22 

28 3.2.2. Rats...................................................................................................................................... 23 

29 3.2.3. Guinea Pigs ......................................................................................................................... 30 

30 3.2.4. Hamsters.............................................................................................................................. 30 

31 3.2.5. Rabbits................................................................................................................................. 31 

32 3.2.6. Dogs .................................................................................................................................... 31 

33 3.2.7. Sheep................................................................................................................................... 32 

34 3.2.8. Goats ................................................................................................................................... 33 

35 3.2.9. Cats...................................................................................................................................... 33 

36 3.2.10. Monkeys ........................................................................................................................ 33 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 6 of 73 

1 3.3. Repeated Exposure Studies ..................................................................................................... 33 

2 3.4. Developmental/Reproductive Toxicity.................................................................................... 35 

3 3.5. Genotoxicity ............................................................................................................................ 35 

4 3.6. Carcinogenicity........................................................................................................................ 35 

5 3.7. Summary.................................................................................................................................. 35 

6 4. SPECIAL CONSIDERATIONS ...................................................................................................... 39 

7 4.1. Metabolism and Disposition.................................................................................................... 39 

8 4.2. Mechanism of Toxicity............................................................................................................ 39 

9 4.3. Structure-Activity Relationships ............................................................................................. 39 

10 4.4. Other Relevant Information..................................................................................................... 40 

11 4.4.1. Haber=s Law and Time-Scaling.......................................................................................... 40 

12 4.4.2. Species Variability .............................................................................................................. 41 

13 5. RATIONALE AND PROPOSED AEGL-1 ..................................................................................... 42 

14 5.1. Human Data Relevant to AEGL-1........................................................................................... 42

15 5.2. Animal Data Relevant to AEGL-1 .......................................................................................... 42

16 5.3. Derivation of AEGL-1............................................................................................................. 42 

17 6. RATIONALE AND PROPOSED AEGL-2 ..................................................................................... 43 

18 6.1. Human Data Relevant to AEGL-2........................................................................................... 43

19 6.2. Animal Data Relevant to AEGL-2 .......................................................................................... 43

20 6.3. Derivation of AEGL-2............................................................................................................. 43 

21 7. RATIONALE AND PROPOSED AEGL-3 ..................................................................................... 44 

22 7.1. Human Data Relevant to AEGL-3........................................................................................... 44

23 7.2. Animal Data Relevant to AEGL-3 .......................................................................................... 44

24 7.3. Derivation of AEGL-3............................................................................................................. 44 

25 8. SUMMARY OF PROPOSED AEGLS............................................................................................ 46 

26 8.1. AEGL Values and Toxicity Endpoints.................................................................................... 46 

27 8.2. Comparison with Other Standards and Guidelines.................................................................. 46 

28 8.3 Data Adequacy and Research Needs ...................................................................................... 47 

29 9. REFERENCES................................................................................................................................. 47 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 7 of 73 

1 APPENDIX A: DERIVATION OF AEGL VALUES.............................................................................. 56 

2 APPENDIX B: DERIVATION SUMMARY FOR PHOSGENE AEGLS............................................... 59 

3 APPENDIX C: CATEGORY PLOT FOR PHOSGENE.......................................................................... 63 

4 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 8 of 73 

1 LIST OF TABLES 

2 

3 TABLE S 1. Summary of Proposed AEGL Values for Phosgene ...................................................................4

4 TABLE 1. Physical and Chemical Data..................................................................................10 

5 TABLE 2. Acute Irritative Effects of Phosgene Exposure in Humans.................................11 

6 TABLE 3. Effect of Phosgene Exposure in Humans ..............................................................12 

7 TABLE 4. Acute Lethality of Phosgene in Mice .....................................................................16 

8 TABLE 5. Acute Lethality Data in Rats Exposed to Phosgene .............................................18 

9 TABLE 6. Acute Lethality of Phosgene in Rats.....................................................................19 

10 TABLE 7. Acute Lethality of Phosgene in Guinea Pigs.........................................................20 

11 TABLE 8. Acute Lethality of Phosgene in Rabbits ................................................................20 

12 TABLE 9. Acute Lethality of Phosgene in Dogs ....................................................................21 

13 TABLE 10. Group Means (±SD) of Findings in Rats Exposed for 4 Hours to Phosgene ...24 

14 TABLE 11. Group Means (±Sd) of Findings In Rats Exposed for 30 Minutes to Phosgene

15 ......................................................................................................................................................25 

16 TABLE 12. Summary of Non-Lethal Animal Inhalation Studies With Phosgene..............37 

17 TABLE 13. Mean BAL Protein Values for Various Species..................................................42 

18 TABLE 14. AEGL-1 Values for Phosgene...............................................................................43 

19 TABLE 15. AEGL-2 Values for Phosgene...............................................................................44 

20 TABLE 16. AEGL-3 Values for Phosgene...............................................................................45 

21 TABLE 17. Summary of AEGL Values for Phosgene............................................................46 

22 TABLE 18. Extant Standards and Guidelines for Phosgene .................................................46 

23 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 9 of 73 

1 1. INTRODUCTION

2 

3 Phosgene is a colorless gas at ambient temperature and pressure. Its odor has been 

4 described as similar to new-mown hay (Leonardos et al., 1968). This mild odor and the weak 

5 acute irritant properties, however, provide little warning of its presence (Lipsett et al., 1994). 

The odor threshold has been established between 0.5 to 1.5 ppm (2.06 to 6.18 mg/m3 6 ) (Lipsett 

7 et al., 1994). 

8 

9 Phosgene is manufactured from a reaction of carbon monoxide and chlorine gas in the 

10 presence of activated charcoal. Manufacture of phosgene is approximately 1 million tons per 

11 year in the United States with more than 10,000 workers involved in its manufacture and use 

12 (Currie et al., 1987a). Manufacture of phosgene in the United States is almost entirely captive, 

13 in that >99% is used in the manufacture of other chemicals within a plant boundary. Only one 

14 company sells phosgene on the U.S. merchant market. Over 80% of the phosgene used in the 

15 United States is involved in the manufacture of polyisocyanates in the polyurethane industry. 

16 The polycarbonate industry accounts for approximately 10% of phosgene used, and the 

17 remaining 10% is utilized in the production of aliphatic diisocyanates, monoisocyanates, 

18 chloroformates, agrochemicals, and intermediates for dyestuffs and pharmaceuticals. Phosgene 

19 can also be used in metal recovery operations (platinum, uranium, plutonium, and niobium), and 

20 has been used for manufacturing aluminum chloride, beryllium chloride, and boron trichloride. 

21 It has been patented as a stabilizer for liquid SO2. Additionally, many pesticides have been 

22 produced by reaction of a thiol or dithiol with phosgene to produce thiol chloroformates. (Kirk23 Othmer, 1991). 

24 

25 Inhalation is the most important route of exposure for phosgene. Because of its mild 

26 upper respiratory, eye and skin irritancy, and a mildly pleasant odor, an exposed victim may not 

27 actively seek an avenue of escape before lower respiratory damage has occurred (Currie et al., 

28 1987a; Lipsett et al., 1994). Pulmonary edema is the cause of death after a clinical latent period 

29 of 24 hours (Franch and Hatch, 1986). 

30 

31 The chemical structure is depicted below, and the physicochemical properties of 

32 phosgene are presented in Table 1. 

33 

34 

35 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 10 of 73 

TABLE 1. Physical and Chemical Data 

Parameter Data Reference 

Synonyms Carbonyl chloride, Carbon oxychloride, 

Carbonic dichloride, Chloroformyl chloride 

Lipsett et al., 1994; U.S. 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 U.S. 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, 2005 

Solubility Decomposes in water and alcohol; soluble 

in organic solvents 

U.S. 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, 2005 

1 

2 

3 2. HUMAN TOXICITY DATA 

4 2.1. Acute Lethality 

5 

6 Based on observations during World War I, the two minute LC50 value for humans was 

7 estimated to be 790 ppm (Chasis, 1944). 

8 

9 Many case reports describe symptomology and post-mortem results from human 

10 phosgene poisonings; however, exposure concentrations were not reported. Six men were 

11 occupationally exposed to phosgene when a pipe ruptured (Stavrakis, 1971). A 24-year-old 

12 who had received the heaviest exposure arrived at the emergency room minutes after the 

13 accident. Upon admission, the patient was symptom-free; however, he was treated with 

14 methenamine intravenously and admitted for a 24-hour observation. During this time, he 

15 remained symptom free and was discharged with no evidence of phosgene injury. The other 

16 five patients arrived at the emergency room between 6 and 12 hours after the accident, present17 ing with various degrees of phosgene intoxication. One 31-year-old who had been exposed Ain 

18 almost the same degree as the previous patient@ rapidly developed pulmonary edema. He also 

19 exhibited extreme hemoconcentration and leukocytosis. He did not respond to methenamine 

20 treatment and died 3.5 hours after admission. The other four exposed workers were 

21 hospitalized for various periods of time and recovered satisfactorily. 

22 

23 A 23-year-old man (healthy nonsmoker) was exposed to at least 5-10 ppm phosgene 

24 (estimated concentration) for five to ten seconds (Bradley and Unger, 1982). He began 

25 coughing upon exposure to phosgene and experienced dyspnea and chest tightness within thirty 

26 minutes. Four hours after exposure, he was hospitalized with hypotension, tachycardia, 

27 tachypnea, cyanosis, and pulmonary edema. The patient was intubated and administered 

28 dopamine and methylprednisolone. From the second to the sixth day of hospitalization, he 

29 developed mediastinal and subcutaneous emphysema, bilateral pneumohydrothoraces, elevated 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 11 of 73 

1 white blood cell counts, fever, and hemiparesis on the right side. Death occurred after 

2 developing ventricular fibrillation. 

3 

4 Misra et al. (1985) described another accidental occupational phosgene poisoning case. 

5 A 30 year-old male was exposed to an undetermined concentration of phosgene and 

6 immediately began coughing and experienced a sense of suffocation and burning eyes. After 

7 removal to fresh air and oxygen administration, he felt better. However, approximately 7.5 

8 hours after the exposure, he was rushed to the emergency room with difficulty breathing. 

9 Despite oxygen administration and antibiotic therapy, his condition deteriorated. He died 

10 approximately 18 hours after exposure. An autopsy showed pulmonary edema and bronchiolar 

11 necrosis, both of which were more severe in the lower lobes than the upper lobes of the lungs. 

12 

13 Hegler (1928) reported the effects of a phosgene accident that occurred in Hamburg, 

14 Germany on May 20, 1928. Eleven metric tons of Apure phosgene@ were released from a 

15 storage tank on a warm, dry, slightly windy day. Within a few hours, people as far as 6 miles 

16 from the release site began reporting to hospitals. Three hundred people reported to hospitals 

17 within a few days of the accident. Effects ranged from mild or moderate illness to death; ten 

18 people were reported to have died. In general, exposed persons exhibited symptoms consistent 

19 with other reported phosgene poisonings (headache, dizziness, nausea and vomiting, irritant 

20 cough, and sickening-sweet taste followed by a latency period and then pulmonary symptoms). 

21 Autopsies on six of the fatalities showed pulmonary effects in all cases. Fatty degeneration of 

22 the kidneys, liver, and heart were observed in a few cases and were thought to be secondary to 

23 the pulmonary damage. In an atypical case damage in the gray matter of the brain and spinal 

24 cord, and hyperemia and signs of bleeding in the white matter were observed at autopsy. This 

25 patient died 11.5 days post-exposure from a blood clot lodged in the lung. It was uncertain if 

26 the extrapulmonary effects were due to phosgene exposure. 

27 

28 2.2. Nonlethal Toxicity

29 

30 NIOSH (1976) performed two studies to determine the odor threshold of phosgene. In 

31 the first, 56 military personnel were exposed to increasing phosgene concentrations until all 

32 subjects could detect odor. The lowest detectable concentration was 0.4 ppm. Thirty-nine 

33 percent of subjects could detect odor at 1.2 ppm, and 50% of subjects detected odor at 1.5 ppm. 

34 In the other study, four subjects identified 1.0 ppm as the lowest concentration at which the 

35 distinctive Anew mown hay@ odor of phosgene could be detected.

36 

37 In their literature review, Diller and Zante (1982) identified nonlethal effects from 

38 phosgene exposure. Nonlethal information synthesized from this review is presented in Table 

39 2. 

40 

TABLE 2. 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 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 12 of 73 

Diller and Zante, 1982 

1 

2 

3 From the above data and from animal data for Ainitial lung damage,@ Diller and Zante 

4 (1982) synthesized information for nonlethal effects of phosgene in humans (Table 3). 

5 

TABLE 3. 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 

Diller and Zante, 1982 

6 

7 

8 2.2.1. Case Reports

9 

10 A 30-year-old male was occupationally exposed to an unknown concentration of 

11 phosgene (Stavrakis, 1971). After a short episode of coughing, he returned to work and 

12 completed the final three hours of his shift. Approximately four hours post-exposure, he 

13 presented at the emergency room with severe dyspnea, restlessness, chest pain, and persistent, 

14 productive cough. Chest X-rays confirmed acute pulmonary edema. He was treated and 

15 discharged free of symptoms five days after the phosgene exposure. 

16 

17 An investigator was exposed to an undetermined concentration of phosgene during an 

18 experiment (Delephine, 1922). He entered the phosgene chamber Aat frequent intervals@ over a 

19 period of 45 minutes to take instrument readings. At first, he experienced only laryngeal and 

20 conjunctival irritation, but as the phosgene concentration increased, he was forced to hold his 

21 breath and not stay in the room for more than one minute. Toward the end of the experiment, 

22 some phosgene escaped from the chamber. At this time, the investigator and a colleague 

23 experienced a violent cough and began to run away. During their escape, both men had to stop 

24 frequently due to the violent nature of their coughs. After exiting the contaminated area, both 

25 individuals continued to cough for approximately 20 minutes. They then improved for three or 

26 four hours after which they experienced a choking sensation that lasted approximately 24 hours. 

27 Marked lassitude lasted for an additional few days, after which recovery appeared to be 

28 complete. 

29 

30 Everett and Overholt (1968) discussed a 40 year-old man who received a Amassive@

31 phosgene exposure. His initial symptoms included coughing and burning of the eyes, which 

32 subsided within 5 minutes. He was asymptomatic for the next two hours after which a hacking 

33 cough began. Three hours after exposure, mild dyspnea was present, and 6 hours post-exposure 

34 severe dyspnea and moist rales were observed. He was admitted to an intensive care unit 

35 8 hours post-exposure and presented with anxiety, agitation, cyanosis, thirst, constant cough, 

36 and severe pulmonary edema. By the fifth day in the hospital, he was asymptomatic, and by the 

37 seventh day, pulmonary function and chest x-ray were normal. A two-year follow-up was 

38 unremarkable. 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 13 of 73 

1 

2 Regan (1985) described a phosgene release from a toluene diisocyanate plant. Fifteen 

3 employees were exposed to an undetermined concentration of phosgene, resulting in the 

4 hospitalization of four workers. Two of the four were released after an overnight observation. 

5 The other two were in more serious condition. One of them, a 31-year-old male, had pulmonary 

6 edema, rales in both lungs, and left chest pain 8 hours post-exposure. He was treated with 

7 oxygen, bronchodilators, steroids, and antibiotics and returned to work 6 days after the accident. 

8 His follow up was unremarkable. The second man, a 47 year-old smoker, presented with 

9 dyspnea, bilateral rales, and pulmonary edema 11 hours post-exposure. He was also treated 

10 with oxygen, bronchodialators, steroids, and antibiotics, but continued to deteriorate. He 

11 remained critical for three days with low right-side heart pressure, low arterial pressure, hemo12 concentration, and leukocytosis. He was asymptomatic by 12 days post-exposure. He had mild 

13 pulmonary obstruction four weeks after the accident; however, it is unclear if this was a result 

14 of phosgene exposure or because of his smoking. 

15 

16 Longer-term effects from acute phosgene exposure have also been described. Galdston 

17 et al. (1947a) described the late effects of phosgene poisoning in six workers (2 male, 4 female; 

18 ages 31-50). These workers all experienced acute, accidental, occupational exposure to 

19 phosgene, and experienced the typical effects of acute exposure to phosgene. Chronic clinical 

20 findings present from 1 to 24 months post-exposure included rapid shallow breathing, and 

21 changes in pulmonary function. However, no correlation was observed between the magnitude 

22 of phosgene exposure or severity of acute effects and severity of chronic symptoms. Galdston et 

23 al. (1947a) attributed the severity of chronic symptoms to the subjects= psychological state. 

24 Smoking habits were not reported and long-term follow up was not performed. 

25 

26 Galdston et al. (1947b) also examined five males (ages 24-50) who had repeated 

27 occupational exposure to Asmall amounts@ of phosgene during the course of 1.5 to 3.5 years. 

28 The subjects were examined with regard to pulmonary function and cardiac status. The subjects 

29 exhibited transitory effects such as cough, shortness of breath on exertion, and pain or tightness 

30 of the chest. These symptoms abated upon removal from phosgene exposure for several weeks. 

31 Results suggested that although symptoms of chronic exposure to low concentrations of 

32 phosgene are generally not as disabling as those from acute exposure, emphysema may develop 

33 after chronic exposure. Also, pulmonary function effects are more severe after chronic low 

34 level exposure than after recovery from a serious acute exposure. 

35 

36 Diller et al. (1979) examined 12 originally healthy workers three to nine years after 

37 intoxication with phosgene (10 workers), nitric oxide (1 worker), or teflon smoke (1 worker). 

38 Six of the 12 individuals complained of pulmonary symptoms for three years post-exposure, and 

39 3 of the twelve showed slight to severe lung function effects. The severity of lung function 

40 decrement correlated more closely with smoking habits than with the severity of chemical 

41 intoxication. Diller et al. (1979) concluded that originally healthy survivors of phosgene 

42 intoxication recover fairly well over a period of years. However, individuals with preexisting 

43 chronic bronchitis may suffer significant chronic deterioration of lung function after acute 

44 phosgene intoxication, as an additional observation over 25 years showed. The individual, a 

45 light smoker who had mild chronic bronchitis since childhood, was exposed to phosgene and 

46 smoke at age 35. He developed severe pulmonary edema and was hospitalized for 7 weeks 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 14 of 73 

1 following the exposure. During the months following the exposure, his general condition 

2 worsened and the bronchitis became more severe. After two years, pulmonary function (FEV 

3 and VC) was decreased to 70% of normal. Ten years post-exposure, he developed pulmonary 

4 emphysema, and VC and FEV were decreased to 50% of normal. 

5 

6 Herzog and Pletscher (1955) observed squamous metaplasia of the cilitaed bronchial 

7 epithelium in two patients exposed to undetermined concentrations of phosgene. The 

8 metaplasia was observed 3 months or three years post-exposure, respectively. 

9 

10 In a phosgene processing factory, phosgene concentrations were measured over an 8-

11 month period with a device capable of detecting of 0-0.5 ppm phosgene (Henschler, 1971). 

12 Positive values, of relatively short duration, were recorded only on 32 of 240 days: on 22 days, 

13 0.05 ppm; on 6 days, between 0.06 and 0.1 ppm; on 3 days, between 0.1 and 0.5 ppm; on 1 day, 

14 0.5 ppm (of short duration). For longer time periods, elevated concentrations were measured 

15 on three occasions: twice for 3 hours, between 0.015 and 0.035 ppm and once for 1.5 hours, 

16 0.35 ppm. The above described conditions produced no intoxication or effects on lung 

17 function. 

18 

19 In another factory, use of a phosgene indicator badge revealed an average of 34 

20 phosgene exposures per year during the period from 1978 to 1988 (Kaerkes, 1992). The 

21 workforce contained approximately 200 individuals ranging in age from <20 to 60 years. 

22 Exposure concentrations ranged from <50 to 300 ppm. min. Below 50 ppm.min, no signs or 

23 symptoms of phosgene toxicity were observed in 75/88 individuals; however, three cases of 

24 temporary pulmonary edema were observed. 

25 

26 In another report, Sandall (1922) examined 83 British soldiers three years after 

27 phosgene exposure. Shortness of breath upon exertion (70%), cough with expectoration (54%), 

28 tight feeling in chest (25%), sporadic giddiness (14%), and nausea (12%) were the most 

29 frequently reported complaints. No physical lung abnormalities were noted in 53% of the men. 

30 

31 2.2.2. Epidemiologic Studies

32 

33 Polednak (1980) studied a uranium processing plant where phosgene was produced as a 

34 by-product of a chemical process in which UO3 was combined with CCl4 to produce UCl4. 

35 Leaks and system failures resulted in the accidental release of phosgene into work areas. 

36 Although extensive monitoring data were not available, it was determined that the average 

37 exposure was below the detection limit of monitoring instruments used at that time. However, 

38 there were 3 to 5 episodes daily when concentrations exceeded the 1 ppm exposure limit 

39 recognized as the occupational standard of the time. 

40 

41 Approximately 30 years after exposure, there were no statistically significant increases 

42 in mortality from overall cancer or cancers at specific anatomical sites, from diseases of the 

43 respiratory system, or overall mortality noted in this cohort. However, the exposure period 

44 covered by the study was short, the exposed groups were small, and exposure levels were not 

45 well documented. Consequently, evidence presented in this study is inadequate to assess the 

46 carcinogenicity of phosgene. 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 15 of 73 

1 

2 Polednak and Hollis (1985) reported a follow-up of the study discussed above. The 

3 study update reported the mortality experience of individuals through the end of 1978 and 

4 included 694 routinely exposed white male chemical workers, 97 acutely exposed chemical 

5 workers, and 9280 controls. Vital status ascertainment for the routinely exposed group and the 

6 controls was approximately 90% complete using Social Security Administration (SSA) records. 

7 For the acutely exposed group SSA records as well as state death indexes were used to 

8 ascertain vital status, which was approximately 92% complete. Five individuals in the routinely 

9 exposed group, 9 in the acutely exposed group, and 72 controls were lost to follow-up. 

10 

11 Approximately 35 years after exposure to phosgene no increase in overall mortality or 

12 mortality from cancer or respiratory disease was noted in this cohort. 

13 

14 NIOSH (1976) compared the medical records of 326 workers exposed to phosgene with 

15 those of 6288 unexposed workers from the same plant. Personal air sample measurements at 

16 this plant (20 min samples) showed phosgene concentrations ranging from undetectable to 

17 0.02 ppm, with a 15 sample average of 0.003 ppm. Fixed-position air samples (20 min or 2 hr 

18 collection) ranged from undectable to 0.13 ppm in 51/56 samples, and >0.14 ppm in 5/56 

19 samples. There were no differences in pulmonary function or deaths attributable to respiratory 

20 disease between the exposed and control populations. 

21 

22 2.3. Developmental/Reproductive Toxicity 

23 

24 Developmental/reproductive studies regarding acute human exposure to phosgene were 

25 not available. 

26 

27 2.4. Genotoxicity 

28 

29 Genotoxic studies regarding acute human exposure to phosgene were not available. 

30 

31 2.5. Carcinogenicity 

32 

33 Polednak (1980) and Polednak and Hollis (1985) examined a cohort of chemical 

34 workers exposed to chronic low levels of phosgene as well as daily exposures above 1 ppm. 

35 Approximately 35 years after exposure to phosgene, no increase in overall mortality or 

36 mortality from cancer or respiratory disease was noted. These studies are described in detail in 

37 Section 2.2.2 (Epidemiologic Studies). 

38 

39 2.6. Summary 

40 

41 Although there is a paucity of acute human data containing known exposure 

42 concentrations and times, reports of human phosgene poisonings present a relatively consistent 

43 set of clinical effects and sequale. After acute phosgene exposure, brief (20 min.) ocular and 

44 throat irritation, cough, nausea and vomiting, and dizziness are experienced, followed by a 

45 period (24 hr) of apparent well being. After this clinical latent phase, cough accompanied by 

46 expectoration, a sensation of pain or tightness of the chest, shortness of breath, and a choking 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 16 of 73 

1 sensation are experienced. Clinical findings may include hemoconcentration, leukocytosis, 

2 rales, and pulmonary edema. After recovery, rapid, shallow breathing, shortness of breath on 

3 exertion, and a sense of decreased physical fitness may persist for months. Pulmonary 

4 emphysema may occur with repeated exposure to phosgene. Epidemiology studies have shown 

5 no increase in cancer in workers exposed to phosgene compared to controls. No information 

6 concerning reproductive/developmental toxicity or genotoxicity was available. 

7 

8 3. ANIMAL TOXICITY DATA

9 3.1. Acute Lethality 

10 3.1.1. Mouse

11 

12 Zwart et al. (1990) exposed groups of five male and five female Swiss mice to varying 

13 concentrations of phosgene for 5, 10, 30, or 60 minutes. The test atmosphere was monitored at 

14 both the inlet and outlet of the glass exposure chambers by gas chromatography and infrared 

15 analysis. Ten minute LC50 values were 77 and 61 ppm for males and females, respectively. 

16 Thirty minute LC50 values were 18 and 11 ppm for males and females, respectively, and 

17 60 minute LC50 values were determined to be 9 and 5 ppm for males and females, respectively. 

18 

19 Cameron et al. (1942) exposed 20 mice to an average phosgene concentration of 0.86 

20 ppm for five hours. Twelve mice were dead the next morning. Several other acute lethality 

21 studies of phosgene in mice have been reported. However, these studies do not contain 

22 experimental details such as strain or sex of mouse, number of animals exposed, or analytical 

23 methodology. These values, in addition to those of Zwart et al. (1990), are presented in Table 

24 4. 

25 

TABLE 4. Acute Lethality of Phosgene in Mice 

Time (Minutes) LC50 (ppm) Reference 

1 850 Chasis, 1944 

1 3300 Moor and Gates, 1946 

5 33 Kawai, 1973 

10 77 (male); 61 (female) Zwart et al., 1990 

15 15 Cameron and Foss, 1941 

30 18 (male); 11 (female) Zwart et al., 1990 

30 5.1 Kawai, 1973 

60 9 (male); 5 (female) Zwart et al., 1990 

26 

27 3.1.2. Rats

28 

29 Five male and five female young adult Wistar rats/group were exposed nose-only to 

30 phosgene gas in a GLP acute lethality study (Pauluhn, 2006a). Rats were exposed for 10, 30, 60 

31 and 240 minutes, and animals were examined for up to 2 weeks post-exposure. Subgroups of 

32 eight male rats/group were exposed for 30 minutes to 0, 0.11, 0.29, 3.3, 6.1, or 11.8 ppm 

33 phosgene and one additional group was exposed for 10 min. to 52 ppm to measure respiratory 

34 function. The following parameters were measured in nose-only animal restrainers with 

35 pneumotachographs and differential pressure transducers fitted onto a plethysmograph: 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 17 of 73 

1 respiratory rate (RR), tidal volume (TV), respiratory minute volume (MV), peak inspiratory and 

2 expiratory time (ET) and average duration of the apnea period (AP). 

3 

4 Once the LC50s were established and physiological data were generated, an LC01 was 

5 calculated. Then, thirty male rats were exposed once to 1.0 ppm phosgene for 240 minutes 

6 (concentration in the range of the estimated LCt01) and were sacrificed on post-exposure days 1, 

7 7, 14 or 28. Bronchoalveolar lavage fluid was examined in six rats/sacrifice, and an additional 

8 six rats were examined for histopathology on day 28 post-exposure. 

9 

10 For all exposures, an aluminum nose-only chamber was used that consisted of two 

11 segments with a total of 40 exposure ports at the perimeter. Each segment had dimensions as 

12 follows: inner diameter- 14 cm.; outer diameter- 35 cm; height- 25 cm and an internal volume 

13 about 3.8L. All airflows were monitored and adjusted continuously with calibrated flow 

14 controllers. Target concentration was achieved by dilution cascades prior to entering the 

15 directed-flow nose-only chamber. The supply airflow was 30 L/min and maintained an airflow 

16 rate of 0.75 L/min per exposure port. Scrubbing devices were used for the exhausted air. The 

17 concentration of phosgene gas was calculated nominally and measured analytically by gas 

18 chromatography from test atmosphere samples taken from the vicinity of the breathing zone. 

19 

20 Combined male and female LC50 values were 62.5, 13.5, 7.7, and 2.1 ppm for 10, 30, 

21 60 and 240 min, respectively. Most mortality occurred within 24 hours. Clinical signs 

22 observed included labored breathing, rales, lacrimation, cyanosis and decreased body weight. 

23 Necropsy results showed grayish, distended lungs, edema, a foamy exudate in the trachea and a 

24 few pulmonary hemorrhages. An increase in apnea time (AT) and transiently decreased 

25 respiratory minute volumes were observed at 0.29 ppm and above; these effects leveled off after 

26 an exposure duration longer than 10-15 minutes. In the thirty rats exposed to 1.0 ppm for 240 

27 minutes, no mortality occurred. Lung weight and bronchoalveolar lavage (BAL) protein, PMNs 

28 and total cell counts were all significantly (p<0.01 or 0.05) increased compared to controls on 

29 post-exposure day 1, with most values similar to those of controls by post-exposure day 14. 

30 Histopathological examination at 28 days post-exposure showed minimal to slight 

31 hypercellularity in the terminal bronchioles, focal septal thickening, and no edema or fibrin. 

32 Sirius red staining of the lungs showed no increased deposition of collagen. Table 5 below 

33 summarizes mortality data from the study. 

34 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 18 of 73 

TABLE 5. Acute Lethality Data in Rats Exposed to Phosgene

Concentration Mortality LC50 BMCL05 BMC01

(ppm) 

Exposure 

duration 

(min) 

M F 

41.1 10 2/5 1/5 

44.8 10 0/5 0/5 

52.3 10 1/5 1/5 

61.9 10 3/5 3/5 

62.5 ppm 24.3 ppm 32.6 ppm 

 

12.6 30 3/5 1/5 

13.4 30 3/5 1/5 

16.7 30 5/5 5/5 

21.4 30 5/5 4/5 

13.5 ppm 5.0 ppm 7.4 ppm 

 

0 60 0/5 0/5 

7.4 60 2/5 2/5 

9.7 60 5/5 4/5 

11.8 60 5/5 5/5 

7.7 ppm 3.9 ppm 5.3 ppm 

 

2.2 240 5/5 1/5 

2.7 240 5/5 4/5 

2.1 ppm - - 

Pauluhn, 2006a 

1 

2 

3 Zwart et al. (1990) exposed groups of five male and five female Wistar rats to varying 

4 concentrations of phosgene for 5, 10, 30, or 60 minutes. The test atmosphere was monitored at 

5 both the inlet and outlet of the glass exposure chambers by gas chromatography and infrared 

6 analysis. The ten minute LC50 value was 80 ppm, while the thirty and 60 minute LC50 values 

7 were 20 and 12 ppm, respectively. 

8 

9 A total of 118 male Wistar rats were exposed to 0.5 to 4.0 ppm phosgene for 5 minutes 

10 to 8 hours (Rinehart, 1962; Rinehart and Hatch, 1964). The exposures were varied to give CT 

11 products between 12 and 360 ppm-min and were carried out in 1700 L wooden exposure 

12 chambers, operating at a constant ventilation rate of 1000 L/min. The chamber surfaces were 

13 lacquered, and thus, potential loss of phosgene by reaction with the wooden surface was 

14 minimized. This system provided for air Aturn-over@ every 2 minutes and a 99% equilibrium 

15 time of 8 minutes. Air samples were taken frequently during exposures, and adjustments were 

16 made when necessary to maintain constant phosgene concentrations. An L(CT)0 of 180 ppm17 min, a 75 min LC50 of 4 ppm, and a 125 min LC100 of 4 ppm were determined. The authors 

18 concluded that different combinations of concentration and time exposure giving equal products 

19 of C x T constitute equally effective doses. 

20 

21 Several other acute lethality studies of phosgene in rats have been reported. However, 

22 as was the case with the mice, these studies do not contain experimental details such as strain or 

23 sex, number of animals exposed, or analytical methodology. These studies are summarized in 

24 Table 6.

25 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 19 of 73 

TABLE 6. Acute Lethality of Phosgene in Rats 

Strain Number/sex 

Exposure 

time (min) 

Concentration 

(ppm) Endpoint Reference 

NR NR 10 35 LC20 Shils, 1943 

NR NR 10 60 LC40 Shils, 1943 

NR NR 1 1625 LC50 Chasis, 1944 

NR 44/NR 10 38-75 LC50 Box and Cullumbine, 1947a 

NR NR 12 30 LC50 Chasis, 1944 

NR NR 15 35 LC50 Cameron and Foss, 1941 

NR NR 20 15 LC50 Kimmerle and Diller, 1977 

Wistar 40/NR 30 10-15 LC75 Henschler and Laux, 1960 

NR NR 20 25 LC50 Rothlin, 1941 

NR NR 12 85 LC60 Shils, 1943 

NR NR 10 40 LC70 Kimmerle and Diller, 1977 

NR 32/NR 10 39-103 LC75 Box and Cullumbine, 1947a 

Wistar 40/NR 20 25 LC50 Henschler and Laux, 1960 

NR NR 3 220 LC100 Winternitz et al., 1920 

NR 12/NR 10 147 LC100 Box and Cullumbine, 1947a 

NR 10/NR 13 73 LC100 Schultz, 1945 

NR NR 20 37 LC100 Rothlin, 1941 

NR NR 30 22 LC100 Winternitz et al., 1920 

NR=Not Reported 

1 

2 

3 Box and Cullumbine (1947b) investigated phosgene-induced lethality in rats after first 

4 receiving an exposure to a non-lethal concentration of phosgene. Rats were divided into two 

5 groups (12/group). Half of the groups were exposed to 19.2 ppm phosgene for 10 minutes and 

6 the other half served as a control group. Five days later, the pre-exposed and control rats were 

7 exposed to 55.2 , 60, 75.6, and 105.6 ppm of phosgene for 10 minutes. These rats were then 

8 observed for the next 48 hours for deaths. The pretreated rats had a reduced percentage of 

9 mortality (33%) compared to the control animals (74%). Thus, partial protection from 

10 phosgene-induced lethality was obtained by the phosgene pretreatment. 

11 

12 3.1.3. Guinea Pigs

13 

14 The few acute lethality studies of phosgene in guinea pigs do not contain experimental 

15 details such as strain or sex, number of animals exposed, or analytical methodology. These less 

16 than adequate studies are summarized in Table 7. 

17 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 20 of 73 

TABLE 7. Acute Lethality of Phosgene in Guinea Pigs 

Exposure Time 

(minute) Concentration (ppm) Endpoint Reference 

1 672 LC50 Chasis, 1944 

15 32 LC50 Underhill, 1920 

30 18 LC50 Chasis, 1944 

30 141 LC50 Moor and Gates, 1946 

9 85 LC99 Coman et al., 1947 

3 220 LC100 Winternitz et al., 1920 

30 20 LC100 Winternitz et al., 1920 

20 77 LC100 Ong, 1972 

1 

2 

3 3.1.4. Rabbits

4 

5 As was the case with guinea pigs, the few acute lethality studies of phosgene in rabbits 

6 do not contain experimental details such as strain or sex, number of animals exposed, or 

7 analytical methodology. These less than adequate studies are summarized in Table 8. 

8 

TABLE 8. Acute Lethality of Phosgene in Rabbits 

Exposure Time 

(minute) 

Concentration 

(ppm) Endpoint Reference 

30 17 LC40 Frosolono, 1977 

1 3200 LC50 Moor and Gates, 1946 

15 187 LC50 Underhill, 1920 

20 110 LC50 Cameron and Courtice, 1946 

20 20 LC50 Laquer and Magnus, 1921 

30 100-135 LC70 Halpern et al., 1950 

30 93 LC75 Frosolono, 1976 

30 82 LC90 Shils, 1943 

35 151 LC99 Coman et al., 1947 

15 220 LC100 Winternitz et al., 1920 

30 110 LC100 Winternitz et al., 1920 

9 

10 

11 3.1.5. Cats

12 

13 Wirth (1936) reported no deaths in cats exposed to 1.8 ppm phosgene for 470 minutes. 

14 A 1 min. LC50 of 1482 ppm phosgene was reported by Moor and Gates (1946), while a 15 min 

15 LC50 of 80 ppm was reported by Underhill (1920). No details such as number, sex, strain of cat, 

16 or methodology was provided in any of these studies. 

17 

18 3.1.6. Dogs

19 

20 Meek and Eyster (1920) exposed eight mongrel dogs (sex not specified) to 80 - 100 ppm 

21 phosgene for 30 minutes. All eight died within 24 hours post-exposure. Pulmonary edema with 

22 some evidence of cardiac effects was observed at necropsy. 

23 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 21 of 73 

1 Additional dog lethality information is presented in Table 9. 

2 

TABLE 9. Acute Lethality of Phosgene in Dogs 

Strain Number/sex 

Exposure 

time 

(minute) 

Concentration 

(ppm) Endpoint Reference 

NR 12/NR 10 110 LC25 Cameron and Courtice, 1946 

NR NR 1 2100 LC50 Chasis, 1944 

NR NR 10 45 LC50 Kimmerle and Diller, 1977 

NR 24/NR 15 60-70 LC50 Underhill, 1920 

NR NR 20 502 LC50 Chasis, 1944 

NR 6/NR 30 100-175 LC50 Patt et al., 1946 

NR NR 30 78 LC55 Postel and Swift, 1945 

Mongrel 18/NR 3 745-880 LC70 Coman et al., 1947 

NR 94/NR 20 135 LC70 Freeman et al., 1945 

NR 42/NR 30 98 LC70 Postel and Swift, 1945 

Mongrel 15/M,F 30 124 LC90 Schultz, 1945 

Mongrel 32/NR 10 39-103 LC75 Box and Collumbine, 1947 

Mongrel NR 3 734 LC99 Coman et al., 1947 

Mongrel NR 30 90 LC99 Coman et al., 1947 

NR=Not Reported 

3 

4 

5 3.1.7. Goats 

6 

7 Karel and Weston (1947) reported a 10 min. LC50 of 250 ppm phosgene for a group of 

8 30 female and 1 male goat, while Underhill (1920) reported a 15 min LC50 of 180 ppm for a 

9 group of 61 goats. All goats died when exposed to 8750 ppm phosgene for 1 minute (Tobias, 

10 1945), 500 ppm for 3 minutes, or 110 ppm phosgene for 30 minutes (Winternitz et al., 1920). 

11 No further experimental details were available. 

12 

13 3.1.8. Sheep

14 

15 A 10-minute LC50 value of 333 ppm phosgene was determined from exposing groups of 

16 two Dorset crossbred wethers to 135, 240, 427, or 758 ppm phosgene for 10 minutes, followed 

17 by a 24-hour observation period (Keeler et al., 1990b). Animals that died displayed a mixture 

18 of stringy mucous and frothy white material from the proximal trachea to the smaller 

19 bronchioles that filled the alveoli, perivascular spaces, and interlobular septa. Sheep that 

20 survived the 24-hour postexposure period were noted to have airways with scant amounts of 

21 mucus and frothy white material and mild to moderate alveolar edema.

22 

23 3.1.9. Non-human Primates

24 

25 Chasis (1944) reported a 1 minute LC50 of 240 ppm phosgene for a group of monkeys. 

26 The strain, sex, or number of animals was not reported. A 1 minute LC50 of 500 ppm was 

27 reported for 19 male and 18 female Rhesus monkeys (Weston and Karel, 1947). Moor and 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 22 of 73 

1 Gates (1946) found that all monkeys died when exposed to 1087 ppm phosgene for 1 minute. 

2 No other experimental details were available for either study. 

3 

4 3.2. Nonlethal Toxicity 

5 3.2.1. Mice

6 

7 Forty male CD-1 mice/group were exposed whole body for 20 minutes to either air or 

8 8 ppm phosgene (Sciuto et al., 2001). The chamber had a total volume of 15.8 L and a flow rate 

9 of 20 L/min. Phosgene was collected at the chamber’s outflow and concentrations were 

10 measured using an infrared spectrometer. Arterial blood samples were taken from the mice at 1, 

11 4, 8, 12 and 24 hours after the start of the exposure. Animals were sacrificed after blood was 

12 obtained and lung edema was estimated from lung wet weight/lung dry weight ratios 

13 (WW/DW). The exposure at 8 ppm caused pronounced acidosis indicated by decreasing arterial 

14 pH; this effect was significant (p<0.05) 8 to 12 hours after exposure. In the surviving mice, 

15 arterial pH was similar to that of controls by 24 hours. Arterial oxygen partial pressure (PO2)

16 and O2 saturation also decreased compared to controls beginning at 4 hours post-exposure. 

17 These parameters were also similar to controls by 24 hours. Partial pressure for carbon dioxide 

18 followed a similar path except it increased after exposure with the most significant increase at 

19 8 hours. The lung WW/DW ratio in treated mice increased significantly (p<0.05) compared to 

20 that of controls at all time points starting at 4 hours with the greatest increase at 8 hours post21 exposure (52%). 

22 

23 In another study, male CRL:CD-1 (ICR)BR mice were exposed whole-body to either air 

24 or 22 ppm phosgene for 20 minutes and were sacrificed immediately post-exposure for 

25 bronchoalveolar lavage (BAL) fluid analysis (Sciuto, 1998). The BAL fluid was analyzed for 

26 total glutathione (GSH), lipid peroxidation thiobarbituric acid reactive substances (TBARS) and 

27 protein. Lung edema was also assessed by obtaining lung wet weight and lung wet/dry ratios. 

28 The study did not report any deaths during exposure. There was a statistically significant 

29 (p<0.001) increase in protein levels in the BAL. 

30 

31 Hatch et al. (1986) exposed Swiss albino mice (8/group) to 0, 0.1, 0.2, 0.5, or 1 ppm 

phosgene for four hours in an 11.3 ft3 32 Rochester-type chamber. The phosgene was mixed with 

33 filtered room air before the metering orifice of the chamber and introduced into the chamber 

34 airstream. The chamber airstream had a flow rate of 1 chamber volume/minute, and the 

35 chamber air was sampled every 10 minutes. Phosgene concentrations were first determined by 

36 gas chromatography, and an infrared analyzer was used for a second check. Actual chamber 

37 concentrations were within 2 to 6% of target concentrations. Eighteen to 20 hours post38 exposure, the lungs were lavaged and analyzed for lavage fluid protein (LFP), an indicator of 

39 pulmonary edema. The LFP findings were 292  18, 302  21, 941  105, 1302  149, or 

40 2168  167 (units not provided) for 0, 0.1, 0.2, 0.5, or 1 ppm, respectively. The lowest 

41 exposure concentration producing a statistically significantly (p<0.05) altered protein 

42 concentration was 0.2 ppm. 

43 

44 In another study, Illing et al. (1988) exposed groups of 37-39 female CD-1 mice to 0.1 

45 to 0.5 ppm phosgene for 4 hours. Animals were exposed in stainless steel exposure chambers. 

46 Phosgene concentrations were monitored primarily by gas chromatography and double checked 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 23 of 73 

1 by infrared analysis. There was a significant (p<0.05) increase in pentobarbital-induced 

2 sleeping time in mice exposed to 0.15 to 0.5 ppm phosgene compared with air controls. No 

3 significant differences were observed in cytochrome P450 levels, body weights, or liver weights 

4 between phosgene exposed mice and air controls.

5 

6 Box and Cullumbine (1947b) exposed a group of 37 mice to 144 ppm phosgene for an 

7 unspecified period of time. Sub-groups of four or five of these mice were sacrificed on 

8 postexposure days 1, 2, 3, 4, 5, 7, 10, or 14. A histopathological examination was performed on 

9 the lungs of these animals. Varying degrees of edema, patches of leucocytic infiltration, and 

10 bronchial and bronchiolitic epithelia being lifted by edema were observed on post-exposure 

11 day 1. More severe edema and collapsed lungs with leukocytic infiltration were observed on 

12 post-exposure days 2-5. The lungs of the remaining mice were essentially normal by post13 exposure days 10 through 14.

14 

15 3.2.2. Rats 

16 

17 Adult male Wistar rats were exposed nose-only to phosgene gas in a GLP inhalation 

18 study for 30 or 240 minutes (Pauluhn, 2006b). The 30 minute exposures were to 0, 0.2, 0.5, 1.0, 

19 2.0 or 4.0 ppm and the 240 minute exposures to 0, 0.05, 0.1, 0.2, 0.4 or 1.0 ppm. Animals were 

20 observed for up to 84 days post-exposure. Chamber concentrations were monitored 

21 continuously by sampling from ports throughout the chamber using either an infrared analyzer 

22 or toxic gas paper tape monitor. Test atmospheres were also characterized using gas 

23 chromatography. No deaths occurred in any groups. 

24 

25 Six rats/group were sacrificed for bronchoalveolar lavage (BAL) and lung weight on 

26 post-exposure days 1, 3, 7, 14 and 84 and the rats exposed to 1 ppm for 4 hours were sacrificed 

27 on post-exposure days 1, 7, 14 and 28. In addition, 6 rats, not lavaged, were used for 

28 histopathological analysis on days 28 and 84. Clinical signs of irregular and labored breathing, 

29 tachypnea and decreased body weight were observed in the rats exposed to ≥ 2 ppm for 30 

30 minutes and ≥ 0.2 ppm for 240 minutes. At necropsy, rats exposed to 4.0 ppm for 30 minutes 

31 and ≥ 0.4 ppm for 240 minutes had noncollapsed lungs, focal discolorations and enlarged lung32 associated lymph nodes on post-exposure day 1 and to a lesser extent on days 3 and 7. Lung 

33 edema was observed in 3/6 rats exposed to 1.0 ppm for 240 minutes on post-exposure day 1. 

34 

35 Histopathology performed on day 84 showed similar lesions between treated and control 

36 rats in the lungs, but at day 28 in the 1.0 ppm group (240 minutes), 5/6 rats had minimal to 

37 slight hypercellularity of the terminal bronchioles with occasional peribronchial inflammatory 

38 infiltrates and septal thickening. There was no evidence of persistent inflammatory responses 

39 such as chronic pneumonia. Statistically significant (p<0.01 or 0.05) increases in lung weight 

40 were observed in the rats treated with 4.0 ppm for 30 minutes or ≥ 0.4 ppm for 240 minutes. 

41 The BAL fluid protein levels and polymorphonuclear leukocytes (PMNs) increased starting on 

42 post-exposure day 1 in rats exposed to ≥ 2 ppm for 30 minutes or ≥ 0.2 ppm for 240 minutes. 

43 

44 By 7 days post-exposure, parameters were similar to those of controls except in the 

45 highest concentration animals (1.0 ppm x 240 minutes). Tables 10 and 11 show the findings of 

46 lung wt/bwt ratio and in the BAL fluid. 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 24 of 73 

1 

TABLE 10. Group Means (±SD) of Findings in Rats Exposed for 4 Hours to Phosgene

Lung wt/body wt 

(mg/100g ) Protein in BAL (g/L) 

Collagen in BAL 

(mg/L) 

Neutrophilic 

granulocytes in BAL 

(%) 

Day 1 

Control 

0.1 

0.2 

0.4 

1.0 

466.0 ± 13.9 

479.2 ± 29.0 

521.3 ± 40.0 

571.5** ± 19.5 

1023.0** ± 162.0 

0.194 ± 0.012 

0.214 ± 0.037 

0.905* ± 0.690 

1.89** ± 0.65 

13.6** ± 3.0 

10.0 ± 2.7 

13.7 ± 3.9 

61.5 ± 81.1 

141.7** ± 73.8 

3203.0** ± 870 

0.111 ± 0.172 

0.500 ± 0.459 

4.00** ± 1.52 

7.33** ± 3.80 

36.9** ± 7.4 

Day 3 

Control 

0.1 

0.2 

0.4 

1.0 

453.5 ± 15.8 

472.2 ± 14.8 

472.8 ± 21.2 

536.9** ± 18.8 

– 

0.190 ± 0.075 

0.179 ± 0.025 

0.216 ± 0.025 

0.378* ± 0.084 

– 

10.6 ± 1.8 

7.32 ± 3.00 

9.00 ± 1.75 

35.6** ± 15.5 

– 

0.222 ± 0.272 

0.167 ± 0.408 

0.444* ± 0.544 

5.83 ± 3.32 

– 

Day 7 

Control 

0.1 

0.2 

0.4 

1.0 

438.4 ± 16.5 

429.0 ± 13.4 

432.6 ± 20.2 

464.3 ± 20.7 

627.8** ± 54.7 

0.163 ± 0.022 

0.169 ± 0.008 

0.183 ± 0.029 

0.175 ± 0.026 

0.302 ± 0.082 

10.0 ± 5.3 

9.97 ± 4.63 

11.9 ± 3.8 

14.2 ± 3.7 

49.3 ± 5.0 

0.222 ± 0.404 

0.167 ± 0.183 

0.389 ± 0.328 

0.167 ± 0.279 

0.722* ± 1.611 

Day 28 

Control 

0.1 

0.2 

0.4 

1.0 

402.7 ± 12.0 

420.6 ± 20.7 

420.1 ± 16.9 

431.4* ± 9.2 

438.3* ± 15.8 

0.223 ± 0.025 

0.204 ± 0.023 

0.183 ± 0.020 

0.212 ± 0.016 

0.195 ± 0.026 

11.5 ± 3.2 

12.6 ± 3.8 

14.7 ± 3.2 

13.4* ± 1.8 

13.9 ± 1.8 

0.278 ± 0.251 

0.111 ± 0.272 

0.111 ± 0.172 

0.222 ± 0.344 

0.000 ± 0.000 

Day 84 

Control 

0.1 

0.2 

0.4 

1.0 

334.6 ± 17.2 

321.8 ± 13.2 

324.0 ± 21.5 

320.6 ± 23.3 

– 

0.243 ± 0.025 

0.257 ± 0.008 

0.268 ± 0.032 

0.276 ± 0.024 

– 

10.3 ± 2.5 

15.6 ± 4.7 

21.4** ± 5.1 

10.2 ± 2.8 

– 

0.278 ± 0.328 

0.111 ± 0.272 

0.278 ± 0.251 

0.000 ± 0.000 

– 

a Data from Pauluhn, 2006b.

* Statistically significant at p<0.05 or ** p<0.01

2 

3 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 25 of 73 

TABLE 11. Group Means (±Sd) of Findings In Rats Exposed for 30 Minutes to Phosgene

Lung wt/body wt 

(mg/100g ) Protein in BAL (g/L) Collagen in BAL (mg/L) 

Neutrophilic 

granulocytes in BAL 

(%) 

Day 1 

Control*** 

0.2 

0.5 

1.0 

2.0 

4.0 

466.0 ± 13.9 

475.2 ± 25.2 

469.1 ± 11.0 

483.0 ± 26.5 

495.3 ± 21.6 

561.4** ± 34.1 

0.194 ± 0.012 

0.169 ± 0.020 

0.181 ± 0.031 

0.271 ± 0.064 

0.685** ± 0.083 

2.24** ± 1.01 

10.0 ± 2.7 

12.2 ± 2.1 

16.5 ± 4.8 

9.67 ± 3.37 

29.9* ± 4.2 

250.3** ± 229.2 

0.111 ± 0.172 

0.056 ± 0.136 

0.111 ± 0.172 

0.500 ± 0.506 

1.44** ± 0.69 

8.00** ± 3.14 

Day 3 

Control*** 

0.2 

0.5 

1.0 

2.0 

4.0 

453.5 ± 15.8 

453.5 ± 11.9 

452.0 ± 10.4 

464.2 ± 6.1 

475.3 ± 19.6 

538.6** ± 31.7 

0.190 ± 0.075 

0.184 ± 0.029 

0.184 ± 0.023 

0.190 ± 0.022 

0.252 ± 0.057 

0.349 ± 0.207 

10.6 ± 1.8 

13.3 ± 1.9 

10.5 ± 3.4 

13.7 ± 3.0 

13.7 ± 6.0 

22.4 ± 16.9 

0.222 ± 0.272 

0.278 ± 0.328 

0.056 ± 0.136 

0.056 ± 0.136 

2.39 ± 3.19 

7.22 ± 10.36 

Day 7 

Control*** 

0.2 

0.5 

1.0 

2.0 

4.0 

438.4 ± 16.5 

437.1 ± 27.3 

421.6 ± 15.7 

441.4 ± 22.7 

445.0 ± 12.7 

4..62 ± 11.4 

0.163 ± 0.022 

0.197 ± 0.019 

0.198 ± 0.027 

0.196 ± 0.016 

0.169 ± 0.023 

0.174 ± 0.024 

10.0 ± 5.3 

12.2 ± 3.6 

10.3 ± 4.6 

12.6 ± 2.2 

11.3 ± 2.5 

10.0 ± 4.9 

0.222 ± 0.404 

0.611 ± 0.647 

0.111 ± 0.172 

0.167 ± 0.279 

0.222 ± 0.272 

 0.278 ± 0.443 

Day 28 

Control*** 

0.2 

0.5 

1.0 

2.0 

4.0 

402.7 ± 12.0 

407.9 ± 19.6 

399.7 ± 18.2 

385.3 ± 15.4 

436.1* ± 12.4 

418.1 ± 20.1 

0.223 ± 0.025 

0.218 ± 0.015 

0.210 ± 0.027 

0.195 ± 0.024 

0.206 ± 0.019 

0.206 ± 0.024 

11.5 ± 3.2 

13.3 ± 4.7 

12.3 ± 4.9 

12.4* ± 2.9 

11.9 ± 3.7 

19.4 ± 4.2 

0.278 ± 0.251 

0.389 ± 0.491 

0.167 ± 0.279 

0.278 ± 0.534 

0.444 ± 0.779 

0.167 ± 0.279 

Day 84 

Control*** 

0.2 

0.5 

1.0 

2.0 

4.0 

334.6 ± 17.2 

324.6 ± 13.7 

336.4 ± 12.8 

328.2 ± 15.7 

330.3 ± 10.9 

327.1 ± 9.8 

0.243 ± 0.025 

0.298 ± 0.130 

0.248 ± 0.020 

0.236 ± 0.016 

0.289 ± 0.020 

0.262 ± 0.016 

10.3 ± 2.5 

15.3 ± 5.1 

14.3 ± 4.8 

21.8** ± 5.0 

12.4 ± 2.6 

14.6 ± 2.7 

0.278 ± 0.328 

0.056 ± 0.136 

0.056 ± 0.136 

0.056 ± 0.136 

0.200 ± 0.298 

0.167 ± 0.279 

a Data from Pauluhn, 2006b.

* Statistically significant at p<0.05 or ** p<0.01

*** Control (0 ppm) exposure was 4-hour duration. 

1 

2 

3 Male Sprague-Dawley rats were exposed whole-body to either air or 22 ppm phosgene 

4 for 20 minutes and were sacrificed immediately post-exposure for bronchoalveolar lavage 

5 (BAL) fluid analysis (Sciuto, 1998). The BAL was analyzed for total glutathione (GSH), lipid 

6 peroxidation thiobarbituric acid reactive substances (TBARS) and protein. Lung edema was 

7 also assessed by obtaining lung wet weight and lung wet/dry ratios. The study did not report 

8 any deaths during exposure. There was a statistically significant (p<0.001) increase in protein 

9 levels in the BAL. 

10 

11 A total of 118 male Wistar rats were exposed to 0.5 to 4.0 ppm phosgene for 5 minutes 

12 to 8 hours (Rinehart, 1962; Rinehart and Hatch, 1964). The exposures were varied to give CT 

13 products between 12 and 360 ppm-min and were carried out in 1700 L wooden exposure 

14 chambers, operating at a constant ventilation rate of 1000 L/min. The chamber surfaces were 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 26 of 73 

1 lacquered, and thus, potential loss of phosgene by reaction with the wooden surface was mini2 mized. This system provided for air Aturn-over@ every 2 minutes and a 99% equilibrium time 

3 of 8 minutes. Air samples were taken frequently during exposures, and adjustments were 

4 made when necessary to maintain constant phosgene concentrations. In addition to the lethality 

5 data presented in Section 3.1.2, several conclusions were also drawn concerning non-lethal 

6 endpoints. First, the CT product appears to be a valid way to express pulmonary irritation due 

7 to phosgene exposure. This is based on the finding of equal degrees of respiratory response, as 

8 measured by reduction in pulmonary gas exchange capacity, from exposures to various 

9 combinations of C and T that yield the same CT product. Second, there is no decrease in 

10 pulmonary performance from exposures less than CT= 30 ppm-min, but above this level, gas 

11 exchange capacity decreases directly with a log increase in CT. Finally, for low level exposures 

12 (below CT= 100), the major site of action is the respiratory bronchioles, while above this level, 

13 the alveoli are involved. 

14 

15 In a later publication of the above experiment (Gross et al., 1965), pulmonary pathology 

16 from the phosgene exposed-rats was described. Exposure to high concentrations of phosgene 

17 (2 ppm for 90 min) produced chemical pneumonia, while exposure to lower concentrations 

18 produced Achronic pneumonitis.@ The degree of pneumonitis produced by phosgene was rated 

19 as slight, moderate, or severe. Slight pneumonitis was defined as mural thickening of respira20 tory bronchioles with involvement of adjacent alveoli. Moderate pneumonitis was defined as 

21 alveolar involvement in a peribronchiolar zone that extends no more than one-third of the 

22 distance to the next bronchiole. Severe pneumonitis was defined as mural thickening of the 

23 respiratory bronchioles accompanied by obliteration of adjoining alveoli and air spaces con24 taining desquamated alveolar cells. The lowest 1-hr phosgene concentration producing 

25 moderate pneumonitis was 0.8 ppm. The same effect occurred with 1-hr exposures to 0.9, 2.5, 

26 or 3 ppm phosgene. This occurred in 2 of 3 rats, with the third rat displaying slight 

27 pneumonitis. 

28 

29 Hatch et al. (1986) exposed Sprague-Dawley rats (8/group) to 0, 0.1, 0.2, 0.5, or 1 ppm 

30 phosgene for four hours. The exposure system and parameters are similar to those described in 

31 Section 3.2.1 (Hatch et al., 1986). Actual chamber concentrations were within 2 to 6% of target 

32 concentrations. Eighteen to 20 hours post-exposure, the lungs were lavaged and analyzed for 

33 lavage fluid protein (LFP). The LFP findings were 340  38, 258  18, 506  54, 1642  116, 

34 or 2471  125 (units not provided) for 0, 0.1, 0.2, 0.5, or 1 ppm, respectively. The lowest 

35 exposure concentration producing a significantly (p<0.05) increased protein concentration was 

36 0.2 ppm.

37 

38 Male Sprague-Dawley rats were exposed to 0, 0.125, 0.25, 0.5, or 1 ppm phosgene for 

39 four hours and sacrificed on Day 0, 1, 2, or 3 post-exposure (Currie et al., 1987a). Animals 

were exposed in 0.32 m3 Rochester-type inhalation chambers. The air flow was 0.32 m3 40 /min, 

41 and the gas mixture passed downward through stainless steel wire cages holding the animals 

42 and was exhausted at the bottom through a water scrubber. Temperature in the chambers was 

23.03.4o 43 C and humidity was 6010% during exposures. The chambers were monitored by 

44 both infrared analysis and gas chromatography continuously during exposure, and even 

45 phosgene distribution was assured by sampling from various areas of the exposure chamber. 

46 Measured phosgene concentrations were within 2-6% of target concentrations. Exposure-
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 27 of 73 

1 related changes were observed in body weights, wet lung weights, LFP concentrations, and total 

2 cell count and differential cell count in lavage fluid. Body weights were decreased immediately 

3 after exposure through Day 2 for the 0.5 and 1 ppm exposure groups. Wet lung weights were 

4 increased in the 0.5 ppm exposure group on postexposure Days 1, 2, and 3 and in the 1 ppm 

5 exposure group immediately after exposure and on postexposure Days 1, 2, and 3. The relative 

6 wet lung to body weight ratios were increased immediately after exposure and on Days 1, 2, and 

7 3 in the 0.5 and 1 ppm exposure groups. LFP concentrations were increased in the 0.25 ppm 

8 exposure group on Day 1 and in the 0.5 and 1 ppm exposure groups immediately after exposure 

9 and on Days 1, 2, and 3. Total cell counts in lavage fluid were elevated in the 1 ppm exposure 

10 group on Days 2 and 3. Percentage of polymorphonuclear leukocytes were increased in the 

11 0.25 ppm exposure group on Days 1 and 2 and in the 0.5 and 1 ppm exposure groups on Days 1, 

12 2, and 3. The LFP and cellular parameters had their peak effect on day 1 post-exposure and had 

13 begun a return to control values by day 3 post-exposure, suggesting that the pulmonary damage 

14 was reversible or rapidly repairable. 

15 

16 In another study, Currie et al. (1987b) exposed male Sprague-Dawley rats to 0, 0.05, 

17 0.125, 0.25, 0.5, or 1 ppm phosgene for four hours. The exposure system and parameters are 

18 similar to those described in Currie et al. (1987a). Animals were sacrificed immediately after 

19 exposure and at days 1, 2, and 3 post-exposure. The ATP concentrations in lungs were 

20 significantly (p<0.05) decreased immediately after exposure at all exposure concentrations. 

21 The 1 ppm exposure group also had decreased ATP concentrations on Day 1 and increased ATP 

22 concentrations on Days 2 and 3. All other exposure groups had ATP concentrations similar to 

23 control values on Days 1, 2, and 3. LFP concentrations were only measured immediately after 

24 exposure and were linearly increased at 0.25, 0.5, and 1 ppm phosgene.

25 

26 Frosolono and Pawlowski (1977) exposed anesthetized male CFE Carworth rats to 0, 

27 100, 200, or 430 ppm phosgene for approximately 10 minutes. Animals were exposed in a 364 

28 L glass and stainless-steel chamber, and phosgene concentrations were estimated with a 

29 phosgene detector tube. The authors= stated that Athe analytical method for the determination 

30 of phosgene concentrations is not highly precise.... and concentrations given should be 

31 considered putative or nominal.@ Groups of 6 to 8 rats/concentration were sacrificed 0, 30, 60, 

32 or 90 minutes after exposure. No percentage change of lung water (used as a measure of 

33 pulmonary edema) was observed in rats exposed to 100 or 200 ppm phosgene and sacrificed 0 

34 and 30 minutes after exposure. However, 60 minutes post-exposure, the 100 ppm exposure 

35 group had a 6.7% increase in lung water and the 200 ppm exposure group had an 8.7% increase 

36 in lung water. Cytochrome C oxidase activities (specific and total) from the lungs were 

37 decreased, ranging from 30.1 to 79.8% after rats were exposed to 100 ppm and sacrificed 0, 30, 

38 and 60 minutes after exposure. After exposure to 200 ppm, relative serum lactic dehydrogenase 

39 (LDH) concentrations were increased from one to three fold over the postexposure time of 0 to 

40 90 minutes. An exposure to 430 ppm resulted in decreased lung LDH activities (specific and 

41 total) ranging from 3.3 to 70.8% in the organelle fractions (homogenate and soluble). The 

42 authors suggested that the decreased LDH activities were indicative of cellular damage resulting 

43 in increased serum LDH concentrations. 

44 

45 In a different report, Pawlowski and Frosolono (1977) describe pulmonary 

46 ultrastructural alterations in male CFE Carworth rats exposed to phosgene in a manner 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 28 of 73 

1 essentially identical to that described in Frosolono and Pawlowski (1977). Immediately after 

2 exposure, animals exposed to 100 ppm phosgene exhibited vesiculation of ciliated and Clara 

3 cell cytoplasm in the bronchiolar epithelium, while interstitial edema was observed 30 minutes 

4 post-exposure. In animals exposed to 200 ppm phosgene, interstitial edema was observed 

5 immediately after exposure, while focal Type I cell discontinuities and interstitial and 

6 intracellular edema were present 30 minutes post-exposure. At 48 minutes post-exposure to 

7 200 ppm phosgene, interstitial cellular edema with general septal thickening and involvement of 

8 type II cells was observed. At 430 ppm, cytoplasmic sequestration figures were observed in 

9 Type II cells 60 minutes post-exposure. 

10 

11 In another study, lavage protein concentrations and histopathological assessments of the 

12 lungs were determined in male Wistar rats (10-15/group) exposed to 0, 0.1, 0.15, 1, 2.5, or 

13 5 ppm phosgene for 10, 20, 50, 60, 250, 330, or 500 minutes (Diller et al., 1985). The exposure 

14 concentrations and durations were paired so as to provide different exposure scenarios corres15 ponding to 50 ppm-min. A special 7 L plexiglass chamber was constructed to achieve reliable 

16 exposures to low concentrations of phosgene. Air exchange was 8-fold/minute and consistency 

17 of phosgene concentration throughout the chamber was confirmed by a movable suction probe. 

18 Long-term mean phosgene concentrations were measured by collection of the gas samples in a 

19 glass bubbler and subsequent titration. Consistency throughout exposure was determined by a 

20 galvanometric analyzer, and concentration was checked using detector paper. Animals were 

21 sacrificed either 24 or 48 hours after the phosgene exposure. A phosgene concentration of 50 

22 ppm-min (5 ppm for 10 min) was required to produce alveolar edema. A concentration of 50 

23 ppm-min was also required to produce an increase in LFP, while widening of pulmonary 

24 interstices was observed at 25 ppm-min. No phosgene threshold was observed for the latter two 

25 parameters down to 0.1 ppm, indicating that the CT= k relationship is valid for these two 

26 parameters. However, under the conditions of this study, Haber=s rule appears to be valid for 

27 pulmonary edema only down to 5 ppm phosgene. 

28 

29 Franch and Hatch (1986) exposed male Sprague-Dawley rats to either 1 ppm phosgene 

30 for four hours with the sacrifices occurring immediately after exposure and on recovery period 

31 days 1, 2, 7, or 14 or 1 ppm of phosgene for seven hours with the sacrifices occurring hourly 

32 during the exposure period. The exposure system and parameters are similar to those described 

33 in Section 3.2.1 (Hatch et al., 1986). Actual chamber concentrations were 0.980.03 ppm for 

34 the 4 hour exposure regimen and 1.030.02 ppm for the 7 hour exposure regimen. Body 

35 weights of rats exposed to 1 ppm phosgene for 4 hours were significantly (p0.01) decreased to 

36 13% below controls on day 1 post-exposure. Body weights increased toward control values, 

37 achieving 3% below controls on day 14. Food consumption was also decreased compared to 

38 controls but was less than 10% below normal by day 4. Lung weights of exposed animals were 

39 60% greater than controls immediately after exposure and remained elevated through day 7 

40 post-exposure. Lung nonprotein sulfhydryl (NPSH) was similar in control and exposed rats on 

41 day 1, had increased to 80% above controls on day 2, and decreased back to control levels by 

42 day 7. Glucose-6-phosphate dehydrogenase (G6PD) activity was increased 40% in exposed 

43 animals compared to controls from days 1 through 14. Sequential examination every hour 

44 during a 7 hour exposure revealed lung weights increasing 4 hours into the exposure, reaching a 

45 maximum elevation of 60% above controls at 6 hours. Both the NPSH and G6PD activities 

46 were decreased in this exposure regimen. 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 29 of 73 

1 

2 Frosolono and Currie (1985) investigated the effect of phosgene on the pulmonary 

3 surfactant system (PSS) in groups of 6-14 rats exposed to 1 ppm phosgene for 4 hours. The 

4 exposure system and parameters are similar to those described in Section 3.2.1 (Hatch et al., 

5 1986). The actual chamber concentration was 1.00.06 ppm. Animals were sacrificed 

6 immediately after exposure, or on postexposure Days 1, 2, or 3. Pulmonary edema was present 

7 immediately after exposure and persisted through day 3. Phosphatidylinositol was significantly 

8 (p<0.05) decreased compared to controls immediately after exposure only. Phosphatidylserine 

9 and phosphatidylethanolamine were significantly increased compared to controls on days 1,2, 

10 and 3 post-exposure. Phosphatidylcholine was increased at all time points compared to 

11 controls. 

12 

13 Jaskot et al. (1989) exposed groups of male Sprague-Dawley rats (16/group) to 0 or 0.5 

14 ppm phosgene for 4 hours. The exposure system and parameters are similar to those described 

15 in Section 3.2.1 (Hatch et al., 1986). The actual chamber concentration was 0.540.05 ppm. 

16 The rats were sacrificed immediately or 24 hours post-exposure. Phosgene exposed rats 

17 showed no changes in angiotensin-converting enzyme (ACE) activity in lavage fluid or serum 

18 compared to controls. Whole-lung ACE activity was significantly increased immediately after 

19 exposure and 24 hours post-exposure, with increases of 55% and 44% above controls, 

20 respectively. Phosgene exposed rats also had increased ACE activity in lavage cell pellets, with 

21 increases of 50% and 54% above controls at 0 and 24 hours, respectively. 

22 

23 Assessment of pulmonary immunocompetence was determined by exposing male Fisher 

24 344 rats to 0.1, 0.5, or 1 ppm phosgene for 4 hours and measuring pulmonary natural killer cell 

25 activity on Day 1, 2, 4, or 7 post-exposure (Burleson and Keyes, 1989). The animals were 

exposed in a Rochester chamber, with temperature and humidity maintained at 23.3 1.7o 26 C and 

27 6010%, respectively. The chamber atmosphere was continuously monitored during exposures 

28 by both gas chromatography and infrared analysis. The actual chamber concentrations were 

29 0.97, 0.49, and 0.10 ppm for the 1, 0.5, or 0.1 ppm groups, respectively. The pulmonary natural 

30 killer activities in the rats exposed to 1 ppm were significantly (p<0.05) decreased on Days 1, 2, 

31 and 4. A decrease (p<0.05) in natural killer cell activity was also observed in the 0.5 ppm 

32 group. No effect was noted in the 0.1 ppm group. 

33 

34 Another immunological assessment, pulmonary cytotoxic T-lymphocyte (CTL) activity, 

35 was examined in male Fischer 344 rats exposed to 0 or 1 ppm phosgene for four hours. 

36 Animals were exposed in a Rochester exposure chamber, and the exposure atmosphere was 

37 monitored by gas chromatography and infrared analysis. The actual exposure concentration 

38 was 1.00.04 ppm. Twenty-four hours after phosgene exposure, subsets of both the control and 

39 phosgene-treated rats were infected with influenza virus. The remaining control and phosgene40 exposed rats were sham infected with uninfected lung homogenate. Animals were sacrificed on 

41 Day 2, 5, 7, 10, 15, or 20 post-infection (Ehrlich et al., 1989). 

42 

43 A significant suppression of CTL activity was noted in phosgene-exposed, influenza44 infected rats compared to air controls, air infected, and phosgene-treated sham-infected animals. 

45 This effect was observed only on Day 10 post-infection; however, this is a time when peak 

46 activity is normally detected in control rats. Body weights were significantly decreased 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 30 of 73 

1 (p<0.05) in phosgene exposed-infected and uninfected rats on day 2 post-infection and in 

2 phosgene-exposed, infected animals at day 5. Lung weights were significantly increased 

3 (p<0.05) in phosgene exposed-infected and uninfected rats on days 2 and 5 post-infection 

4 compared to air infected and air uninfected controls. 

5 

6 3.2.3. Guinea Pigs

7 

8 Cameron et al. (1942) exposed 10 guinea pigs to an average phosgene concentration of 

9 0.86 ppm for five hours. All survived an apparent 24-hour postexposure period. 

10 

11 Hatch et al. (1986) exposed Hartley guinea pigs (8/group) to 0, 0.1, 0.2, 0.5, or 1 ppm 

12 phosgene for four hours. The exposure system and parameters are similar to those described in 

13 Section 3.2.1 (Hatch et al., 1986). Actual chamber concentrations were within 2 to 6% of target 

14 concentrations. Eighteen to 20 hours post-exposure, the lungs were lavaged and analyzed for 

15 lavage fluid protein (LFP). The LFP findings were 305  19, 228  47, 407  75, 524  47, or 

16 1212  149 (units not provided) for 0, 0.1, 0.2, 0.5, or 1 ppm, respectively. The lowest 

17 exposure concentration producing a significantly (p<0.05) altered protein concentration was 0.5 

18 ppm. 

19 

20 In another study, Hartley guinea pigs (5/group) were exposed to 0, 0.25, or 0.5 ppm 

21 phosgene for 4 hours (Slade et al., 1989). The exposure chamber and atmosphere generation 

22 and measurement systems were similar to those used by Hatch et al. (1986). The LFP 

23 concentrations were measured 16 to 18 hours after exposure. These investigators found that the 

24 LFP concentrations were elevated by 90% in animals exposed to 0.25 ppm phosgene and 250% 

25 in animals exposed to 0.5 ppm phosgene, when compared to controls. 

26 

27 Male Hartley guinea pigs were exposed whole-body to either air or 22 ppm phosgene for 

28 20 minutes and scarificed immediately post-exposure for bronchoalveolar lavage (BAL) fluid 

29 analysis (Sciuto, 1998). The BAL fluid was analyzed for total glutathione (GSH), lipid 

30 peroxidation thiobarbituric acid reactive substances (TBARS) and protein. Lung edema was 

31 also assessed by obtaining lung wet weight and lung wet/dry ratios. The study did not report 

32 any deaths during exposure. In all three species, there was a statistically significant (p<0.001) 

33 increase in protein levels in the BAL. 

34 

35 3.2.4. Hamsters

36 

37 Hatch et al. (1986) exposed Syrian Golden hamsters (8/group) to 0, 0.1, 0.2, 0.5, or 1 

38 ppm phosgene for four hours. The exposure system and parameters are similar to those 

39 described in Section 3.2.1 (Hatch et al., 1986). Actual chamber concentrations were within 2 to 

40 6% of target concentrations. Eighteen to 20 hours post-exposure, the lungs were lavaged and 

41 analyzed for lavage fluid protein (LFP). The LFP findings were 319  6, 347  14, 520  63, 

42 1289  92, or 3035  111 (units not provided) for 0, 0.1, 0.2, 0.5, or 1 ppm, respectively. The 

43 lowest exposure concentration producing a statistically significantly (p<0.05) altered protein 

44 concentration was 0.2 ppm. 

45 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 31 of 73 

1 3.2.5. Rabbits

2 

3 Cameron et al. (1942) exposed 10 rabbits to an average phosgene concentration of 0.86 

4 ppm for five hours. All survived an apparent 24-hour postexposure period. 

5 

6 Hatch et al. (1986) exposed New Zealand white rabbits (8/group) to 0, 0.1, 0.2, 0.5, or 1 

7 ppm phosgene for four hours. The exposure system and parameters are similar to those 

8 described in Section 3.2.1 (Hatch et al., 1986). Actual chamber concentrations were within 2 to 

9 6% of target concentrations. Eighteen to 20 hours post-exposure, the lungs were lavaged and 

10 analyzed for lavage fluid protein (LFP). The LFP findings were 292  11, 309  20, 346  26, 

11 517  68, and 855  71 (units not provided) for 0, 0.1, 0.2, 0.5, or 1 ppm, respectively. The 

12 lowest exposure concentration producing a significantly (p<0.05) altered protein concentration 

13 was 0.5 ppm. 

14 

15 3.2.6. Dogs 

16 

17 Young adult (6-12 month old) male and female beagle dogs were exposed for 30 

18 minutes to phosgene in a head-only inhalation exposure at concentrations of 0 (5 dogs), 2.3, 4.1 

19 or 8.8 ppm (4 dogs/concentration) (Pauluhn, 2006c). The sexes of the dogs exposed were as 

20 follows: controls- 1 m and 4 f; 2.3 ppm- all males; 4.1 and 8.8 ppm- 2 m and 2 f. The target 

21 phosgene concentrations were attained by dilution cascades prior to being distributed to the 

22 directed-flow head-only chamber. The chamber had an internal volume of 11 L and was 

23 operated in a well-ventilated room. The stability, homogeneity and the time to achieve steady 

24 state were all continuously monitored using either an infrared process analyzer or a CM4 toxic 

25 paper tape monitor and by the 2-HMP derivatization method with subsequent gas 

26 chromatographic determination. Dogs were exposed while suspended in slings by placing their 

27 heads into a size-adjustable exposure port. Parameters measured included respiratory minute 

28 volume (pre-exposure, just after exposure and prior to sacrifice); arterial blood gas analysis 

29 (pre-exposure and pre-sacrifice); bronchoalveolar lavage (BAL) (24 hrs post-exposure) and 

30 necropsy and histopathology (24 hrs post-exposure). 

31 

32 During exposure, dogs exposed to 2.3 and 4.1 ppm displayed signs of irritation: minor 

33 nasal discharge, salivation and lacrimation. The dogs in the 8.8 ppm group displayed labored 

34 breathing, reddened conjunctiva/mucosa and vomitus and rales on day 1 post-exposure. 

35 Measured respiratory minute volume indicated interdog variability that was higher in the mid36 and high-concentration males than the females and appeared to be a result of distress-related 

37 hyperventilation. Statistically significant increases (p<0.05) in wet lung weight to body weight 

38 ratio, absolute lung weight and the level of BAL protein were observed in the 8.8 ppm exposed 

39 dogs. The BAL PMNs were elevated in both the 4.1 and 8.8 ppm exposed groups. Alveolar gas 

40 exchange was impaired slightly in the highest concentration dogs as evidenced by decreased 

41 arterial pO2. At necropsy, 3/4 dogs exposed to 8.8 ppm had pulmonary fibrinous inflammation, 

42 epithelial necrosis, hemorrhages, intra-alveolar fibrin exudation, minimal to slight focal septal 

43 thickening and positive Sirius-red reaction. Lung edema was also observed in these dogs. 

44 

45 Coman et al. (1947) exposed adult mongrel dogs to 108-197 ppm phosgene for 30 

46 minutes and sacrificed the animals from 0.63 to 8.58 hours after exposure or to 71-80 ppm 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 32 of 73 

1 phosgene for 3 minutes and sacrificed the animals from 0.13 to 5.32 hours after exposure. Mild 

2 to severe emphysema was observed in all dogs, with severity generally correlating to exposure 

3 concentration and time. Swelling and sloughing of the bronchiolar mucosa were then observed 

4 and were usually confined to bronchioles proximal to the respiratory bronchioles. Transient 

5 bronchiolar constriction, followed by dilatation of the bronchioles, was also observed. 

6 Congestion of the lung and alveolar edema usually followed in the lower exposure 

7 concentrations at the 30-minute exposure time with the lung congestion preceding alveolar 

8 edema in the higher exposure concentrations at the three-minute exposure time. Lung/body 

9 weight ratios increased as both exposure concentration and/or sacrifice time after exposure 

10 increased. 

11 

12 In another study, adult mongrel dogs were exposed to phosgene concentrations that 

13 fluctuated between 24 and 40 ppm for 30 minutes (Clay and Rossing, 1964). The experimental 

14 design was as follows: (1) two dogs served as controls, (2) seven dogs were exposed one or two 

15 times and sacrificed one or two days after the last exposure, (3) seven dogs were exposed four 

16 to 10 times and sacrificed from one to seven days after the last exposure, (4) five dogs were 

17 exposed 15 to 25 times and sacrificed immediately and from 1 to 14 days after the last exposure, 

18 and (5) four dogs were exposed 30 to 40 times and sacrificed immediately or from 1 to 12 

19 weeks after the last exposure. For all animals exposed one or two times, acute bronchiolitis or 

20 peribronchiolitis developed. Pulmonary emphysema was produced in dogs receiving more than 

21 two exposures. 

22 

23 3.2.7. Sheep

24 

25 Groups of ten unanesthetized, adult sheep were exposed to 0 or 767 ppm phosgene for 

26 10 minutes (Assaad et al., 1990). Blood samples were collected immediately before the 

27 exposure and 15, 30, 60, 120, 180, or 240 minutes after the exposure; and plasma prostacyclin 

28 and thromboxane metabolites (6-keto-PGFla and TXB2) concentrations were measured. Levels 

29 of both metabolites were significantly (p<0.05) increased in the exposed animals compared to 

30 pre-exposure baseline values and air control values. The 6-keto-PGFla returned to control 

31 values by 180 minutes, whereas the TXB2 did not. The authors concluded that (1) acute lung 

32 injury occurred immediately following exposure even though pulmonary edema and symptoms 

33 of pulmonary toxicity developed 4 to 8 hours after exposure, (2) phosgene may induce 

34 pulmonary edema by injuring cell membranes, and (3) arachidonic acid metabolites may be 

35 useful as early, non-specific markers for phosgene-induced lung injury. 

36 

37 In a subsequent study (Assaad et al., 1991), 10 unanesthetized adult sheep were exposed 

38 to 0 or 767 ppm phosgene for 10 minutes and were sacrificed four hours post-exposure. Gross 

39 examination of the lungs revealed congestion and edema, while the light microscopic evaluation 

40 demonstrated alveolar and interstitial edema, fibrin and neutrophil exudation in the air spaces, 

41 and increased alveolar macrophages. The electron microscopic examination revealed that Type 

42 I pneumocytes had intracellular swelling, necrosis, and denuding of basement membrane with 

43 the preservation of the tight junctions. Type II pneumocytes showed loss of lamellar bodies, 

44 cytoplasmic swelling, and damage to the endoplasmic reticulum. Endothelial cells showed 

45 increased density and vesicular activity, cytoplasmic swelling, and displacement of the 

46 basement membrane. 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 33 of 73 

1 

2 Five Dorset-crossbred wether sheep underwent surgery in order to provide simultaneous 

3 information concerning phosgene exposure and pulmonary vascular and interstitial fluid 

4 dynamics (Keeler et al., 1990a). The efferent duct of the caudal mediastinal lymph node was 

5 cannulated to monitor pulmonary lymph flow. Additionally, a carotid arterial catheter, a 

6 pulmonary artery catheter, and a left atrial catether were implanted to monitor systemic and 

7 pulmonary hemodynamics. After a 5- to 7-day recovery period, the sheep were exposed to 

8 480-600 ppm phosgene for 10 minutes. The control pulmonary lymph flow rate was 10.32.2 

9 g/hour, and the exposed sheep values were 19.56.0, 21.56.0, 22.56.0, 24.05.9, 26.55.3, 

10 26.96.0, or 27.35.8 g/hour for 1, 1.5, 2, 2.5, 3, 3.5, or 4 hours post-exposure, respectively. 

11 There was a small increase in mean pulmonary microvascular pressure, but no change in the 

12 ratio of lymph to plasma protein concentration. Sheep were sacrificed four hours after 

13 exposure. Histopathological evaluations of the lungs revealed diffuse, moderate alveolar and 

14 interlobular edema. 

15 

16 3.2.8. Goats

17 

18 Cameron et al. (1942) exposed two goats to an average phosgene concentration of 0.86 

19 ppm for five hours. Both survived an apparent 24-hour postexposure period. 

20 

21 3.2.9. Cats

22 

23 Cameron et al. (1942) exposed two cats to an average phosgene concentration of 0.86 

24 ppm for five hours. One cat became Avery ill@ with considerable labored breathing, but both 

25 survived an apparent 24-hour postexposure period. 

26 

27 3.2.10. Monkeys

28 

29 Cameron et al. (1942) exposed two monkeys to an average phosgene concentration of 

30 0.86 ppm for five hours. One of the monkeys became Avery ill@ with considerable labored 

31 breathing, but both survived an apparent 24-hour postexposure period. 

32 

33 3.3. Repeated Exposure Studies 

34 

35 Franch and Hatch (1986) exposed male Sprague-Dawley rats (10 weeks old) to 0.125 or 

36 0.25 ppm phosgene, 4 hours/day, 5 days/week for a total of 17 days; rats were sacrificed on 

days 3, 7, 10, 13, 17 and after a 2 or 20 day recovery period. Animals were exposed in 0.32 m3 37 

38 Rochester-type chambers while in individual wire-mesh cages. Chamber air was measured 

39 every 10-minutes and analyzed with a gas chromatograph. Lungs from exposed rats were 

40 weighed and then prepared for histopathology or biochemical assays. No changes in body 

41 weight were observed in any treated rats. In the 0.25 ppm group, lung wet weight was 

42 approximately 25% greater than controls (p ≤0.01) on day 7 but was similar to control by day 2 

43 of recovery. An increase in NPSH content and G6PD activity was noted in the 0.25 ppm group. 

44 All values were similar to controls by day 2 post-exposure. Hydroxyproline content was not 

45 affected by exposure. Lung lesions in the 0.125 ppm rats were only described as “minimal” on 

46 histopathologic examination after 17 days of exposure; lungs of the 0.25 ppm rats had moderate 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 34 of 73 

1 multifocal mononuclear-cell accumulation in the walls of the terminal bronchioles and alveoli. 

2 Some alveolar cell hyperplasia and macrophages were also observed. 

3 

4 Male Fischer 344 rats (60 days old) were exposed to either clean air (controls; n=12) or 

5 to phosgene (n=8/concentration) gas 6 hrs/day at concentrations of 0.1 ppm (5 days/week), 0.2 

6 ppm (5 days/week), 0.5 ppm (2 days/week) or 1.0 ppm (1 day/week) for 4 or 12 weeks 

7 (Kodavanti et al.,1997). One group of rats at each exposure concentration was allowed clean air 

8 recovery for 4 additional weeks after the 12 week exposure. Rats were exposed whole-body in 

9 either Hazelton 2000 chambers (0, 0.1, 0.2 or 0.5 ppm) or Rochester chambers (0 and 1.0 ppm) 

10 with a control group placed in each chamber; 8 controls were exposed in the Hazelton chamber 

11 and 4 in the Rochester. Animals in the Hazelton chamber remained in the chamber even during 

12 non-exposure times but the animals in the Rochester chamber were moved in and out from an 

13 animal room; no differences were observed in any parameters between the two control groups. 

14 Phosgene was controlled in the chambers using a mass-flow controller and chamber 

15 concentrations were monitored from samples taken every 20 minutes using gas 

16 chromatography. At the scheduled sacrifice, the lungs were removed, weighed and the left lung 

17 was used for histopathology and the right for biochemical analysis. Biochemical analysis 

18 included hydroxyproline and prolyl hydroxylase activity to measure collagen synthesis and 

19 desmosine concentration to measure an index of elastin in the lungs. No mortality was reported 

20 at any exposure level. A small but significant decrease in mean body weight (p<0.05) was 

21 observed in the 0.5 and 1.0 ppm rats at 4 and 12 weeks. A concentration-dependent increase in 

22 the mean lung to body weight ratio was seen following both 4 and 12 weeks of exposure 

23 (statistically significant at 0.2 ppm or greater). Mean lung displacement volume (used as index 

24 of change in lung volume) was statistically significantly increased in a concentration-dependent 

25 manner beginning at 0.1 ppm at 4 weeks and at 0.2 ppm or greater at 12 weeks of exposure. 

26 The mean values for the parameters measured (body weight, lung weight and lung displacement 

27 volume) were provided in bar graphs; individual data were not provided.Histopathological 

28 examination of the lung was conducted in all groups after 4, 12 and 16 (4- week recovery) 

29 weeks. In animals exposed for 4 weeks, there were changes in the bronchiolar regions, with a 

30 small but apparent thickening and mild inflammation seen at 0.1 ppm that progressed in severity 

31 with concentration to extensive inflammation and thickening of the terminal bronchiolar regions 

32 and alveolar walls at 1 ppm, although the samples for 0.5 ppm were lost. An increase in 

33 collagen indicated by trichrome staining was seen in the 0.2 and 1 ppm animals, although no 

34 elevation of total hydroxyproline, a measure of collagen deposition, was observed after 4 

35 weeks. Similar changes were seen following 12 weeks of exposure; the lesions did not appear to 

36 have progressed beyond those seen at 4 weeks. Both pulmonary prolyl hydroxylase activity and 

37 pulmonary desmosine were elevated at 4 and 12 weeks of exposure in the 1.0 ppm animals. The 

38 intensity of collagen staining in the bronchiolar region was increased, compared to controls, in 

39 the 0.2 and 1 ppm groups. The pulmonary hydroxyproline level was significantly elevated only 

40 in the 1 ppm animals after 12 weeks of exposure. 

41 

42 Only the 1.0 ppm rats had a small but significant increase in lung to body weight ratio 

43 and significant decrease in body weight after the 4 week recovery. Resolution of almost all 

44 histopathological findings occurred after the 4 week recovery. Prolyl hydrolase activity and 

45 desmosine concentration returned to normal with recovery, but hydroxyproline activity was still 

46 statistically significantly increased in the 0.5 and 1.0 ppm rats. Collagen staining remained at 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 35 of 73 

1 the same level of intensity as seen in the 12-week groups dosed at 0.2 and 1 ppm. Overall, the 

2 changes induced by phosgene were not amplified with 12 weeks of treatment compared to 4 

3 weeks and most pulmonary alterations were reversible after a 4 week recovery. 

4 

5 3.4. Developmental/Reproductive Toxicity 

6 

7 Developmental and reproductive toxicity studies regarding animal exposure to phosgene 

8 were not available. 

9 

10 3.5. Genotoxicity 

11 

12 Genotoxic studies regarding animal exposure to phosgene were not available. However, 

13 the two highly reactive chlorines of phosgene suggest that it could act on DNA in a similar 

14 manner to that of bifunctional alkylating agents (Shah et al., 1979). 

15 

16 3.6. Carcinogenicity 

17 

18 A study by Selgrade et al. (1989) showed that exposure to very low levels of phosgene 

19 enhances the susceptibility of mice to lung tumor formation. Female C57BL/6 mice were 

20 exposed for 4 h to 0.01 (N=13), 0.025 (N=28), or 0.05 ppm phosgene (N=35) and injected 

21 intravenously with syngeneic B16 melanoma cells on the following day. Controls were injected 

22 with tumor cells and exposed to air. The lungs were removed 2-3 weeks after tumor cell injec23 tion and the tumors were counted. Compared with controls, there was a statistically significant 

24 (p<0.05) increase in the number of B16 melanoma tumors in the lungs of mice treated with 

25 0.025 or 0.05 ppm phosgene. The number of tumors/lung were 105, 110, or 185 in mice treated 

26 with 0.01, 0.025, or 0.05 ppm, respectively, compared with 90, 75, or 100 in the respective 

27 control groups. Exposure to 0.025 ppm was considered the lowest-observed-effect level. 

28 Extending the exposure time from 4 to 8 h did not alter the susceptibility to B16 tumors at 

29 0.01 ppm. 

30 

31 In other experiments using a higher concentration, mice were exposed by inhalation to 

32 0.5 ppm phosgene for 4 h and injected intravenously with melanoma tumor cells on the 

33 following day or injected with tumors and then exposed to 0.5 ppm for 4 h/day for 4 

34 consecutive days. There was a significant increase (p<0.05) in the number of lung tumors in the 

35 group exposed to phosgene prior to inoculation (96 tumors/lung compared with 38 tumors/lung 

36 for controls). Although the number of tumors in mice exposed to phosgene on 4 consecutive 

37 days beginning immediately after tumor injection was higher than in controls (65 tumors/lung 

38 compared with 48 tumors/lung for controls), the difference was not statistically significant. 

39 These experiments showed that exposure following tumor injection had little effect on tumor 

40 susceptibility compared with phosgene exposure prior to tumor injection. 

41 

42 3.7. Summary

43 

44 Animal lethality studies are abundant; however, the studies are of varying quality and 

45 many are incompletely reported. Thus, the utility of the lethality studies must be considered on 

46 a case by case basis. Even though there are limitations concerning these studies, there appears 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 36 of 73 

1 to be little species variability between rats, mice, and guinea pigs, and the CT=k relationship 

2 appears to be generally valid (although at very high or very low concentrations or exposure 

3 times so short that the animal can hold it=s breath, the CT=k relationship may not hold). 

4 

5 Many nonlethal acute inhalation studies exist, and are of generally good quality. These 

6 studies also suggest that there are few differences between species after acute exposure to 

7 phosgene and that the type and sequence of effects are similar in humans and experimental 

8 animals. Many of the nonlethal toxicity studies describe biochemical changes in lung fluid, 

9 whose pathogenesis is likely due to acylation (see Section 4.2). Selected biochemical and other 

10 nonlethal effects are summarized in Table 12. 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 37 of 73 

TABLE 12. Summary of Non-Lethal Animal Inhalation Studies With Phosgene 

Concentration (ppm) Time Species Effect 

0 or 8 20 min Mouse LOAEL ≥ 8 ppm, based on acidosis, clinical 

signs and ↓ body wt., ↑ lung ww/dw 

0 or 22 20 min Mouse, rat and 

guinea pig 

LOAEL ≥ 22 ppm, based on ↑ LFP 

0, 2.1, 4.3 or 8.8 30 min 

*dogs sacrificed 24-hr 

post-exposure 

Dog LOAEL= 4.3 ppm, based on increased PMNs 

in BAL fluid NOAEL = 2.3 ppm 

P

0.2, 0.5, 1.0, 2.0 or 4.0 30 min Rat LOAEL = 2.0 ppm, based on clinical signs 

and ↓ body wt., ↑ LFP 

NOAEL = 1. 0 ppm 

P

2 90 min Rat Chemical pneumonia 

0, 0.05, 0.1, 0.2, 0.4 or 1.0 240 min Rat LOAEL = 0.2 ppm, based on based on 

clinical signs and ↓ body wt., ↑ LFP NOAEL = 0.1 ppm 

P

0, 0.1, 0.5 or 1.0 240 min Rat LOAEL = 0.5 ppm based on decrease in NK 

cell activity NOAEL = 0.1 ppm 

B

0 or 1.0 240 min Rat LOAEL ≥ 1.0 ppm based on ↓ body wt., ↑

lung wts 

E

0 or 0.5 240 min Rat LOAEL ≥ 0.5 ppm based on ↑ LFP and lung 

wts, 

J

0, 0.25 or 0.5 240 min Guinea pig LOAEL ≥ 0.25 ppm based on ↑ LFP 

0.1 to 0.5 240 min mouse LOAEL = 0.15 ppm based on ↑ phenobarbital 

induced sleeping times NOAEL = 0.10 

I

0, 0.125, 0.25, 0.5 or 1.0 240 min Rat LOAEL = 0.25 ppm based on ↑ PMNs in 

lavage fluid NOAEL = 0.125 ppm 

C

0, 0.05, 0.125, 0.25, 0.5 or 1.0 240 min Rat LOAEL ≥ 0.05 ppm based on ↓ ATP in lungs 

0, 0.1, 0.2, 0.5 or 1.0 240 min rat, mouse and 

hamster 

LOAEL = 0.2 ppm based on ↑ LFP NOAEL = 0.1 ppm 

H

0, 0.1, 0.2, 0.5 or 1.0 240 min rabbit and guinea 

pig 

LOAEL = 0.5 ppm based on ↑ LFP NOAEL = 0.2 ppm 

H

0 or 1.0 240 min Rat LOAEL ≥ 1.0 ppm based on ↓ body wt., ↑

lung wts 

F

0 or 1.0 240 min Rat LOAEL ≥ 1.0 ppm based on ↑ pulmonary 

edema 

F

0 or 1.0 420 min Rat LOAEL ≥ 1.0 ppm based on ↑ lung wts F
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 38 of 73 

TABLE 12. Summary of Non-Lethal Animal Inhalation Studies With Phosgene 

Concentration (ppm) Time Species Effect 

0.125 or 0.25 4 hrs/day, 5 days/week for 

17 days 

Rat LOAEL = 0.25 ppm based on ↑ lung wts and 

↑ NPSH and G6PD activity NOAEL = 0.125 ppm 

F

0, 0.1, 0.2, 0.5 or 1.0 0.1 ppm for 5 days/week; 

0.2 ppm for 5 days/week; 0.5 ppm for 2 days/week; 

1.0 ppm for 1 day/week 

All exposed 6 hrs/day for 

up to 12 weeks 

Rat LOAEL = 0.1 ppm based on reversible lung 

histopathology; ↑ lung displacement volume NOAEL = none 

K

1 2 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 39 of 73 

1 4. SPECIAL CONSIDERATIONS

2 4.1. Metabolism and Disposition

3 

4 Following inhalation exposure, a small portion of phosgene hydrolyzes to hydrochloric 

5 acid (HCl) and carbon dioxide (CO2) in the mucous coating of the upper respiratory tract 

6 (Diller, 

7 1985), but in the moist atmosphere of the terminal spaces of the lungs more extensive hydroly8 sis is thought to occur (Beard, 1982). Although phosgene is only slightly soluble in water, once 

9 in solution it rapidly hydrolyzes to HCl and CO2. However, phosgene reacts even faster with 

10 other functional groups such as amino, hydrazino, and sulfhydril groups (Jaskot et al., 1991; 

11 Diller, 1985). 

12 

13 4.2. Mechanism of Toxicity 

14 

15 The toxicity of phosgene is due to both acylation and hydrolysis. The acylation is most 

16 important and results from the reaction of phosgene with nucleophiles such as amino, hydroxyl, 

17 and sulfhydryl groups of macromolecules. The acylation causes lipid and protein denaturation, 

18 irreversible membrane changes, and disruption of enzymatic function. Phosgene depletes lung 

19 glutathione, and glutathione reductase and superoxide dismutase increase as a result of the 

20 lung=s response to injury. Cellular glycolysis and oxygen uptake are decreased following 

21 exposure to phosgene, and there is a decrease of intracellular ATP and cyclic AMP associated 

22 with increased permeability of pulmonary vessels and pulmonary edema. Phosgene exposure 

23 also causes increased lipid peroxidation and increased leukotriene synthesis, but no change in 

24 cyclooxygenase metabolism (TEMIS, 1997). 

25 

26 The hydrogen chloride formed by the hydrolysis of phosgene causes the initial irritation 

27 to the eyes, nasopharynx, and respiratory tract. However, because of phosgene=s poor water 

28 solubility, only a minimal amount of hydrogen chloride is formed (TEMIS, 1997). 

29 

30 4.3. Structure-Activity Relationships

31 

32 Phosgene is a reactive intermediate of both chloroform and carbon tetrachloride 

33 metabolism. Chloroform is metabolized by oxidative dehydrochlorination of its carbon34 hydrogen bond to form the highly unstable trichloromethanol (Cl3COH) which is then 

35 spontaneously converted to phosgene. This reaction is catalyzed by cytochrome P-450 and 

36 occurs both in the liver and kidneys. The evidence for phosgene formation from chloroform 

37 was the isolation of 2-oxothioazolidine-4-carboxylic acid from the microsomal incubation of 

38 chloroform in the presence of cysteine. This compound is the expected product of the reaction 

39 of phosgene with cysteine (Pohl et al., 1977; Mansuy et al., 1977). The electrophilic phosgene 

further reacts with water to yield CO2 and Cl- 40 (major end products of chloroform metabolism), 

41 but significant amounts of phosgene bind covalently with proteins and lipids, or conjugate with 

42 cysteine or glutathione (GSH) (U.S. EPA, 1985). 

43 

44 Covalent binding of phosgene with cellular macromolecules has been proposed as a 

45 mechanism of chloroform-induced hepatic and renal toxicity (Pohl et al., 1980a,b) and it is 

46 generally accepted that the carcinogenic activity of chloroform resides in its highly reactive 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 40 of 73 

1 intermediate metabolites such as phosgene. Irreversible binding of reactive chloroform 

2 metabolites to cellular macromolecules support several theoretical concepts as a mechanism for 

3 its carcinogenicity (U.S. EPA, 1985). 

4 

5 Covalent macromolecular binding of phosgene may be prevented to some extent by 

6 endogenous glutathione (GSH) (Sipes et al., 1977). Phosgene reacts with two molecules of 

7 GSH to form diglutathionyl dithiocarbonate (GSCOSG), a compound identified as a metabolite 

8 of chloroform in rat liver microsomes and mouse kidney homogenates incubated with chloro9 form in the presence of GSH (Pohl et al., 1981; Branchflower et al., 1984). In mouse kidney 

10 homogenates, GSCOSG was shown to be further metabolized by kidney α-glutamyl 

11 transpeptidase to N-(2-oxothiazolidine-4-carbonyl)-glycine, which in turn is hydrolyzed, 

12 possibly in the presence of cysteinyl glycinase, to 2-oxothiazolidine-4-carboxylic acid 

13 (Branchflower et al., 1984). 

14 

15 The metabolism of carbon tetrachloride proceeds via cytochrome P-450-dependent 

16 dehalogenation (Sipes et al., 1977). The first step involves cleavage of one carbon-chlorine 

bond to yield Cl- 17 and a trichloromethyl free radical which is then oxidized to the unstable 

18 intermediate trichloromethanol, the precursor of phosgene. Hydrolytic dechlorination of 

19 phosgene yields CO2 and HCl (Shah et al., 1979). Although there are similarities in the 

20 metabolism of chloroform and carbon tetrachloride, metabolic activation of chloroform 

21 produces primarily phosgene, whereas the level of phosgene production from carbon 

22 tetrachloride appears to be small. Pohl et al. (1981) compared the amount of phosgene (as 

23 diglutathionyl dithiocarbamate) produced by the aerobic metabolism of carbon tetrachloride and 

24 chloroform by liver microsomes from phenobarbital-treated rats. The results indicate that 

25 phosgene production from carbon tetrachloride is only 4% of that produced from chloroform. 

26 The reactive metabolites of both chloroform and carbon tetrachloride covalently bind to 

27 proteins and lipids, but only minimally to DNA and nucleic acids. The failure of the reactive 

28 species, e.g. phosgene, trichloromethyl free radical, and other metabolites, to significantly bind 

29 to DNA has been ascribed to their short half-lives and to their lack of nuclear penetration (U.S. 

30 EPA, 1985). 

31 

14 32 C-Phosgene given to intact rats labeled liver proteins and to a smaller extent lipids 

(Reynolds, 1967). The pattern of labeling was different from that of 14 33 C-carbon tetrachloride 

and was similar to that of 14C-chloroform. It was also shown that 36 34 Cl-carbon tetrachloride 

35 radioactivity was stably incorporated into liver lipid and protein, pointing to the trichloromethyl 

36 radical rather than phosgene as the reactive form of carbon tetrachloride. Cessi et al. (1966) 

37 reported that phosgene labeled the terminal amino groups of polypeptides in a manner similar to 

38 in vivo protein labeling produced by carbon tetrachloride. However, after inhalation, phosgene 

39 reacts completely with lavage fluid, lung tissue, and lung capillary blood so that it is unlikely 

40 that phosgene will reach tissue beyond the lung (Diller, 1974). 

41 

42 4.4. Other Relevant Information

43 4.4.1. Haber=s Law and Time-Scaling 

44 

45 The concept of a Adeath product@ was introduced by Haber to explain the relationship 

46 between the extent of exposure to phosgene and death (Haber, 1924). According to AHaber=s 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 41 of 73 

1 Law,@ the biological effect of phosgene is directly proportional to the exposure expressed as the 

2 product of the atmospheric concentration (C) and the time of exposure (T) or CT = k, where k 

3 can be death, pulmonary edema, or other biological effects of phosgene exposure (US EPA, 

4 1986). Haber=s Law has subsequently been shown by other investigators to be valid for both 

5 nonlethal and lethal effects within certain limits. 

6 

7 For example, Rinehart (1962) and Rinehart and Hatch (1964) showed that the CT 

8 product appears to be a valid way to express pulmonary irritation due to phosgene exposure in 

9 rats. This is based on the finding of equal degrees of respiratory response, as measured by 

10 reduction in pulmonary gas exchange capacity, from exposures to various combinations of C 

11 and T that yield the same CT product. 

12 

13 Furthermore, rat and mouse lethality data from more recent well-conducted studies 

14 (Pauluhn, 2006a; Zwart et al.; 1990) also suggest that Haber=s Law may be valid for phosgene. 

15 ten Berge et al. (1986) have shown that the concentration-exposure time relationship for many 

irritant and systemically-acting vapors and gasses can be described by the relationship cn 16 x t = 

17 k. 

18 When the 10- to 60-minute rat LC50 data of Pauluhn (2006a) are utilized in a linear regression 

19 analysis, a value of the exponent, n, of 1.15 is obtained; similarly, use of the 10- to 60-minute 

20 rat LC50 data of Zwart et al. (1990) yields an ‘n’ value of 0.93. The mouse 10- to 60-minute 

21 lethality data of Zwart et al. (1990) yield a value of 1.3 for the exponent, n. Thus, the fact that 

22 these emperically-derived values of the exponent n approximate 1, is further support that 

23 Haber=s Law is valid for phosgene. 

24 

25 However, the validity of Haber’s Law for derivation of AEGL values is complicated by 

26 the fact that high concentrations of phosgene stimulate protective reflexes in rodents; whereas, 

27 similar changes do not occur in humans and larger animals (dog) (Pauluhn, 2006c). Thus, it 

28 may be difficult to extrapolate to humans from high phosgene exposure concentrations of short 

29 duration in rodents. Rats exhibited a transient decrease in respiration during the first 10-15 

30 minutes of exposure, leading to a decreased inhaled concentration of phosgene (Pauluhn, 

31 2006a). Thus, the c x t products noted at short duration and high concentration may be higher 

32 than those obtained at longer exposure durations, suggesting an apparent lower toxicity at the 

33 short-duration x high-concentration exposures. Thus, for purposes of AEGL value derivation 

34 from rodent data, it is more appropriate to utilize rodent studies of at least 30-minutes so that a 

35 stable breathing pattern has been achieved (Pauluhn, 2006a). 

36 

37 4.4.2. Species Variability

38 

39 An increase BAL fluid protein is a sensitive marker of phosgene-induced 

40 noncardiogenic pulmonary high-permeability edema following acute inhalation exposure 

41 (Pauluhn et al., 2007). In rats, c x t products of between 48 ppm·min and 60 ppm·min induced 

42 increased protein in BAL fluid. [Exposures were 2.0 ppm for 30 min (Pauluhn, 2006b), or 0.2 

43 ppm for 240 min (Pauluhn, 2006b; Hatch et al., 1986)], and no increase was noted from 24-30 

44 ppm·min [Exposures were 0.1 ppm for 240 min or 1 ppm for 30 min (Pauluhn, 2006b)] . 

45 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 42 of 73 

1 In mice and hamsters, a c x t product of 48 ppm·min induced an increase of protein in 

2 BAL fluid. [Exposure was 0.2 ppm for 240 min (Hatch et al., 1986)], and no increase was noted 

3 at 24 ppm·min. [Exposure was 0.1 ppm for 240 min (Hatch et al., 1986)]. 

4 

5 However, in dogs, a c x t product of 129 ppm·min was necessary to cause an increase in 

6 protein in BAL fluid. [Exposure was 4.3 ppm for 30 min (Pauluhn, 2006c)], and no increase 

7 was observed at 63 ppm·min (Pauluhn, 2006c). Thus, the CT product required to induce an 

8 increase in protein in BAL fluid in dogs is approximately two-fold greater than in rodents, and 

9 the NOAEL for increased BAL protein in dogs (63 ppm·min) is higher than the LOAEL values 

10 in rodents (48-60 ppm·min). Additionally, with regard physiology of the respiratory tract and 

11 acinar structure of the lung, dogs are more similar to humans than rodents (Pauluhn, 2006a, 

12 2006b, 2006c; Pauluhn et al., 2007). 

13 

14 Therefore, these data, summarized in Table 13, suggest that an interspecies uncertainty 

15 factor of no more than 1 is justified when extrapolating from laboratory animals to humans. 

16 

17 

TABLE 13. Mean BAL Protein Values for Various Species 

Species BAL Protein CT NOAEL 

(ppm· min) 

BAL Protein CT LOAEL 

(ppm· min) 

BAL Study Quality 

(Reference) 

Mouse 24 ( 0.1 x 240) 48 (0.2 x 240) Well-conducted study, 

analytical methods 

(Hatch et al., 1986) 

Rat 24 (0.1 x 240) 

30 (1 x 30) 

48 (0.2 x 240) 

60 (2 x 30) 

GLP Study 

(Pauluhn, 2006b) 

Hamster 24 (0.1 x 240) 48 (0.2 x 240) Well-conducted study, 

analytical methods 

(Hatch et al., 1986) 

Dog 63 (2.1 x 30) 129 (4.3 x 30) GLP Study 

(Pauluhn, 2006c) 

18 

19 

20 5. RATIONALE AND PROPOSED AEGL-1 

21 5.1. Human Data Relevant to AEGL-1 

22 

23 No human data were relevant for establishing AEGL-1 values. 

24 

25 5.2. Animal Data Relevant to AEGL-1 

26 

27 No animal data were relevant for establishing AEGL-1 values. 

28 

29 5.3. Derivation of AEGL-1

30 

31 Appropriate data were not available for derivation of AEGL-1 values for phosgene. 

32 Odor cannot be used as a warning for potential exposure. The odor threshold is reported to be 

33 between 0.5 to 1.5 ppm, a value above or approaching AEGL-2 and AEGL-3 values, and 

34 tolerance to the pleasant odor of phosgene occurs rapidly. Furthermore, following odor 

35 detection and minor irritation, serious effects may occur after a clinical latency period of 24 

36 hours. Therefore, AEGL-1 values are not recommended (Table 14). 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 43 of 73 

1 

TABLE 14. AEGL-1 Values for Phosgene 

Classification 10-min 30-min 1-hr 4-hr 8-hr 

AEGL-1 NR NR NR NR NR 

NR: Not Recommended. Absence of AEGL-1 values does not imply that exposure to concentrations below 

AEGL-2 are without effect.

2 

3 

4 6. RATIONALE AND PROPOSED AEGL-2

5 6.1. Human Data Relevant to AEGL-2 

6 

7 No human data were relevant to establishing the AEGL-2 values. 

8 

9 6.2. Animal Data Relevant to AEGL-2

10 

11 Biochemical markers of phosgene exposure such as increased protein in BAL fluid were 

12 observed in rats exposed to ≥2 ppm for 30 minutes or ≥0.2 ppm for 4 hours (Pauluhn, 2006b). 

13 BAL protein levels were similar to those of controls by 7-days post-exposure. Increased LFP 

14 was also observed in mice, rats, guinea pigs, hamsters, and rabbits exposed to up to 1 ppm 

15 phosgene for 4 hours (Hatch et al., 1986; Diller et al., 1985). Increased PMN counts in BAL 

16 fluid were observed in dogs exposed to ≥4.3 ppm for 30 minutes; no effect was noted in dogs 

17 exposed to 2.3 ppm for 30 minutes (Pauluhn, 2006c). Chemical pneumonia was observed in 

18 rats exposed to 2.0 ppm phosgene for 90 minutes (Gross et al., 1965). Other effects defined by 

19 AEGL-2 included Avery ill@ monkeys with labored breathing (Cameron et al., 1942) and acute 

20 bronchiolitis or peribroncholitis in dogs (Clay and Rossing, 1964). However, a lack of 

21 experimental details in these monkey and dog studies renders them inappropriate for AEGL 

22 derivation. 

23 

24 6.3. Derivation of AEGL-2

25 

26 The NOAEL for increased PMNs in BAL fluid observed in dogs (2.3 ppm for 30 

27 minutes) (Pauluhn, 2006c) will be used as the basis for deriving AEGL-2 values. The dog was 

28 chosen over rodents because, with regard physiology of the respiratory tract and acinar structure 

29 of the lung, dogs are more similar to humans than rodents. This endpoint was chosen because 

30 BAL fluid changes are a sensitive marker of phosgene-induced noncardiogenic pulmonary high31 permeability edema following acute inhalation exposure (Pauluhn et al., 2007). 

32 

33 An uncertainty factor of 1 will be applied for interspecies extrapolation. In rats, c x t 

34 products of between 48 ppm·min and 60 ppm·min induced increased protein in BAL fluid , and 

35 no increase was noted from 24-30 ppm·min. In mice and hamsters, a c x t product of 48 

36 ppm·min induced an increase of protein in BAL fluid, and no increase was noted at 24 ppm·min. 

37 However, in dogs, a c x t product of 129 ppm·min was necessary to cause an increase in protein 

38 in BAL fluid, and no increase was observed at 63 ppm·min. Thus, the CT product required to 

39 induce an increase in protein in BAL fluid in dogs is approximately two-fold greater than in 

40 rodents, and the NOAEL for increased BAL protein in dogs (63 ppm·min) is higher than the 

41 LOAEL values in rodents (48-60 ppm·min). Additionally, with regard physiology of the 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 44 of 73 

1 respiratory tract and acinar structure of the lung, dogs are more similar to humans than rodents 

2 (Pauluhn, 2006a, 2006b, 2006c; Pauluhn et al., 2007). Collectively, these data suggest that an 

3 interspecies uncertainty factor of no more than 1 is justified when extrapolating from laboratory 

4 animals to humans. 

5 

6 An uncertainty factor of 3 will be applied to account for sensitive human 

7 subpopulations. The intraspecies UF of 3 is considered sufficient due to the steep 

8 concentration-response curve (death in 2/10 rats exposed to 52.3 ppm and 6/10 exposed to 61.9 

9 ppm for 10 min; 4/10 exposed to 13.4 ppm and 10/10 exposed to 16.7 ppm for 30-min; 4/10 

10 exposed to 7.4 ppm and 10/10 exposed to 11.8 ppm for 1-hr; Pauluhn, 2006a) which implies 

11 limited intra-individual variability. Also, the mechanism of phosgene toxicity (binding to 

12 macromolecules and irritation) is not expected to vary greatly between individuals. The 

13 concentration-time relationship for many irritant and systemically-acting vapors and gases may 

be described by cn 14 x t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et al., 1986). 

15 Haber=s Law c x t = k; n=1 has been shown to be valid for phosgene within certain limits and 

16 will be used for scaling of the AEGL values. The AEGL-2 values for phosgene are presented in 

17 Table 15, and the calculations for these AEGL-2 values are presented in Appendix A. 

18 

TABLE 15. AEGL-2 Values for Phosgene 

Classification 10-min 30-min 1-hr 4-hr 8-hr 

AEGL-2 2.3 ppm 

(9.5 mg/m3

)

0.77 ppm 

(3.2 mg/m3) 

0.38 ppm 

(1.6 mg/m3) 

0.096 ppm 

(0.39 mg/m3) 

0.048 ppm 

(0.19 mg/m3) 

19 

20 

21 The AEGL-2 values are considered protective. No significant treatment-related effects 

22 were noted in rats exposed to 0.125 ppm phosgene 4 hours/day, 5 days/week for 17 weeks 

23 (Franch and Hatch, 1986). 

24 

25 7. RATIONALE AND PROPOSED AEGL-3

26 7.1. Human Data Relevant to AEGL-3 

27 

28 No human data were relevant to establishing the AEGL-3 values. 

29 

30 7.2. Animal Data Relevant to AEGL-3

31 

32 Many lethality data exist in a variety of species (mouse, rat, guinea pig, rabbit, cat, dog, 

33 goat, sheep, and monkeys). However, in most cases, experimental parameters are poorly 

34 described and the quality of data are questionable for AEGL derivation. The mouse and rat 

35 LC50 studies of Zwart et al. (1990) ant rat studies of Pauluhn (2006a) are the exception and are 

36 appropriate for AEGL-3 derivation. 

37 

38 7.3. Derivation of AEGL-3

39 

40 The AEGL-3 values will be based on an estimated 1-hour lethality threshold (BMCL05) 

41 in rats from the Pauluhn (2006a) study (3.9 ppm). The Pauluhn (2006a) study is selected over 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 45 of 73 

1 the Zwart et al. (1990) study because it utilized a nose-only protocol; whereas, Zwart utilized a 

2 whole-body protocol. An uncertainty factor of 1 will be applied for interspecies extrapolation. 

3 

4 An increase BAL fluid protein is a sensitive marker of phosgene-induced 

5 noncardiogenic pulmonary high-permeability edema following acute inhalation exposure 

6 (Pauluhn et al., 2007). In rats, c x t products of between 48 ppm·min and 60 ppm·min induced 

7 increased protein in BAL fluid , and no increase was noted from 24-30 ppm·min. In mice and 

8 hamsters, a c x t product of 48 ppm·min induced an increase of protein in BAL fluid, and no 

9 increase was noted at 24 ppm·min. However, in dogs, a c x t product of 129 ppm·min was 

10 necessary to cause an increase in protein in BAL fluid, and no increase was observed at 63 

11 ppm·min. Thus, the CT product required to induce an increase in protein in BAL fluid in dogs 

12 is approximately two-fold greater than in rodents, and the NOAEL for increased BAL protein in 

13 dogs (63 ppm·min) is higher than the LOAEL values in rodents (48-60 ppm·min). 

14 Additionally, with regard physiology of the respiratory tract and acinar structure of the lung, 

15 dogs are more similar to humans than rodents (Pauluhn, 2006a, 2006b, 2006c; Pauluhn et al., 

16 2007). Collectively, these data suggest that an interspecies uncertainty factor of no more than 1 

17 is justified when extrapolating from laboratory animals to humans. 

18 

19 An uncertainty factor of 3 will be applied to account for sensitive human 

20 subpopulations. The intraspecies UF of 3 is considered sufficient due to the steep 

21 concentration-response curve (death in 2/10 rats exposed to 52.3 ppm and 6/10 exposed to 61.9 

22 ppm for 10 min; 4/10 exposed to 13.4 ppm and 10/10 exposed to 16.7 ppm for 30-min; 4/10 

23 exposed to 7.4 ppm and 10/10 exposed to 11.8 ppm for 1-hr; Pauluhn, 2006a) which implies 

24 limited intra-individual variability. Also, the mechanism of phosgene toxicity (binding to 

25 macromolecules and irritation) is not expected to vary greatly between individuals. The 

26 concentration-time relationship for many irritant and systemically-acting vapors and gases may 

be described by cn 27 x t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et al., 1986). 

28 Haber=s Law c x t = k; n=1 has been shown to be valid for phosgene within certain limits and 

29 will be used for scaling of the AEGL values for phosgene. The AEGL-3 values for phosgene 

30 are presented in Table 16, and the calculations for these AEGL-3 values are presented in 

31 Appendix A. 

32 

TABLE 16. AEGL-3 Values for Phosgene 

Classification 10-min 30-min 1-hr 4-hr 8-hr 

AEGL-3 7.8 ppm 

(32 mg/m3

) 

2.6 ppm 

(11 mg/m3) 

1.3 ppm 

(5.3 mg/m3) 

0.33 ppm 

(1.4 mg/m3) 

0.16 ppm 

(0.66 mg/m3) 

33 

34 

35 The AEGL-3 values may be considered protective. No deaths were noted in 

36 approximately 200 workers exposed to phosgene concentrations ranging from 50 to 300 

37 ppm·min (Kaerkes, 1992), and calculated AEGL-3 values are approximately 79 ppm·min. 

38 Furthermore, no deaths were noted in rats exposed to phosgene 6 hrs/day at concentrations of 

39 0.1 ppm (5 days/week), 0.2 ppm (5 days/week), 0.5 ppm (2 days/week) or 1.0 ppm (1 day/week) 

40 for 4 or 12 weeks (Kodavanti et al.,1997). 

41 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 46 of 73 

1 8. SUMMARY OF PROPOSED AEGLS

2 8.1. AEGL Values and Toxicity Endpoints

3 

4 The derived AEGL values for various levels of effects and durations of exposure are 

5 summarized in Table 17. Data were insufficient for deriving AEGL-1 values. Increased BAL 

6 fluid protein in rats was used as the basis for AEGL-2, and estimated lethality thresholds in rats 

7 (BMCL05) were used for AEGL-3. 

8 

TABLE 17. Summary of AEGL Values for Phosgene 

Classification 10-min 30-min 1-hr 4-hr 8-hr 

AEGL-1 

(Nondisabling) 

NR NR NR NR NR 

AEGL-2 

(Disabling) 

2.3 ppm 

(9.5 mg/m3

)

0.77 ppm 

(3.2 mg/m3) 

0.38 ppm 

(1.6 mg/m3) 

0.096 ppm 

(0.39 mg/m3) 

0.048 ppm 

(0.19 mg/m3) 

AEGL-3 

(Lethal) 

7.8 ppm 

(32 mg/m3

) 

2.6 ppm 

(11 mg/m3) 

1.3 ppm 

(5.3 mg/m3) 

0.33 ppm 

(1.4 mg/m3) 

0.16 ppm 

(0.66 mg/m3) 

NR: Not Recommended. Absence of AEGL-1 values does not imply that exposure to concentrations below 

AEGL-2 are without effect. 

9 

10 8.2. Comparison with Other Standards and Guidelines

11 

TABLE 18. Extant Standards and Guidelines for Phosgene 

Exposure Duration

Guideline 10 min 30 min 1 hr 4 hr 8 hr 

AEGL-1 NR NR NR NR NR 

AEGL-2 2.3 ppm 0.77 ppm 0.38 ppm 0.096 ppm 0.048 ppm 

AEGL-3 7.8 ppm 2.6 ppm 1.3 ppm 0.33 ppm 0.16 ppm 

ERPG-1a NA 

ERPG-2a 0.5 ppm 

ERPG-3a 1.5 ppm 

EEGL (NRC)b 

0.2 ppm 0.02 ppm (24-hr) 

NIOSH IDLHc 2 ppm 

NIOSH STELd 0.2 ppm (15-min ceiling) 

NIOSH RELd 0.1 ppm (10-hr) 

OSHA PELTWAe

 0.1 ppm 

ACGIH TLVf 0.1 ppm 

MAK (Germany)g 0.1 ppm 

MAC 

(Netherlands)h 

 0.02 ppm 

a 12 ERPG (Emergency Response Planning Guidelines, American Industrial Hygiene Association (AIHA 2009) 

13 The ERPG-1 is the maximum airborne concentration below which it is believed nearly all individuals could be 

14 exposed for up to one hour without experiencing other than mild, transient adverse health effects or 

15 without perceiving a clearly defined objectionable odor. The ERPG-1 for Phosgene is not derived. 

16 

17 The ERPG-2 is the maximum airborne concentration below which it is believed nearly all individuals could be 

18 exposed for up to one hour without experiencing or developing irreversible or other serious health effects 

19 or symptoms that could impair an individual=s ability to take protective action. The ERPG-2 for Phosgene 

20 is based on increased protein in BAL fluid from time-adjusted dog studies. 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 47 of 73 

1 The ERPG-3 is the maximum airborne concentration below which it is believed nearly all individuals could be 

2 exposed for up to one hour without experiencing or developing life-threatening health effects. The ERPG3 3 for Phosgene is based on acute animal inhalation data. 

4 b 5 EEGL (Emergency Exposure Guidance Levels, National Research Council (NRC 1985) 

6 The EEGL is the concentration of contaminants that can cause discomfort or other evidence of irritation or 

7 intoxication in or around the workplace, but avoids death, other severe acute effects and long-term or 

8 chronic injury. The EEGL for Phosgene is based on the Amost relevant animal exposure studies (Gross et 

9 al., 1965; Rinehart & Hatch, 1964)@ and studies suggesting that animals do not tolerate phosgene at 0.2 

10 ppm administered 5 hr/day for 5 days (Cameron & Foss, 1941; Cameron et al., 1942). 

11 

C 12 IDLH (Immediately Dangerous to Life and Health, National Institute of Occupational Safety and Health)

13 (NIOSH 2005) represents the maximum concentration from which one could escape within 30 minutes 

14 without any escape-impairing symptoms, or any irreversible health effects. The IDLH for Phosgene is 

15 based on acute inhalation toxicity data in humans. 

16 d 17 NIOSH REL-STEL (Recommended Exposure Limits - Short Term Exposure Limit) (NIOSH 2005) 

18 is defined analogous to the ACGIH TLV-TWA. 

19 e 20 OSHA PEL-TWA (Occupational Health and Safety Administration, Permissible Exposure Limits - Time 

21 Weighted Average) (OSHA 1994) is defined analogous to the ACGIH-TLV-TWA, but is for exposures of 

22 no more than 10 hours/day, 40 hours/week. 

23 f 24 ACGIH TLV-TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value - 

25 Time Weighted Average) (ACGIH 2000) is the time-weighted average concentration for a normal 8-hour 

26 workday and a 40-hour workweek, to which nearly all workers may be repeatedly exposed, day after day, 

27 without adverse effect. 

28 

29 gMAK (Maximale Argeitsplatzkonzentration [Maximum Workplace Concentration]) Deutsche 

30 Forschungsgemeinschaft (German Research Association) 2007 is defined analogous to the ACGIH-TLV31 TWA. 

32 

33 hMAC (Maximaal Aanvaaarde Concentratie [Maximal Accepted Concentration]). SDU Uitgevers (under the 

34 auspices of the Ministry of Social Affairs and Employment), The Hague, The Netherlands 2000. is defined 

35 analogous to the ACGIH-TLV-TWA.

36 

37 8.3 Data Adequacy and Research Needs

38 

39 No reliable, quantitative human data exist. Human data are limited to descriptive effects 

40 from accidental exposure and are thus inappropriate for derivation of AEGL values. There are, 

41 however, a plethora of acute inhalation data in many experimental species. The database is 

42 sufficient to have good confidence in AEGL-2 and AEGL-3 values. 

43 

44 9. REFERENCES

45 

46 ACGIH (American Conference of Governmental Industrial Hygienists, Inc). 2000. Documentation of 

47 the Threshold Limit Values and Biological Exposure Indices. 6th Edition. 

48 

49 AIHA (American Industrial Hygiene Association). 2009. Emergency Response Planning Guidelines. 

50 AIHA, Fairfax, VA. 

51 

52 Assaad, A., Trotz, M., Moore, D., Nold, J, Corcoran, K., Hurt, H., Keeler, J., Phillips, K., and Said, S.I. 

53 1990. Arachidonic acid metabolites as early markers of phosgene-induced acute lung injury and 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 48 of 73 

1 pulmonary edema. World Conference on Lung Health. Boston, MA. May 20-24. Am. Rev. 

2 Respir. Dis. 141: A420. 

3 

4 Assaad, A., Nold, J., Petrali, J., Moore, D., Mitcheltree, L., Corcoran, K., and Phillips, K. 1991. 

Pulmonary pathological alterations in sheep exposed to lethal dose of phosgene. 75th 5 Annual 

6 Meeting of the American Societies for Experimental Biology, Atlanta, Georgia. April 21-25. 

7 FASEB J. 5:A484. 

8 

9 Beard, R.R. 1982. Inorganic compounds of oxygen, nitrogen, and carbon. In: Patty=s Industrial 

10 Hygiene and Toxicology, Vol 2C, Clayton, G.D. and Clayton, F.E., Eds. John Wiley & Sons, 

11 New York. Pp. 4126-4128. 

12 

13 Box, G.E.P. and Cullumbine, H. 1947a. The relationship between survival time and dosage with certain 

14 toxic agents. Br. J. Pharmacol. 2:27-37. 

15 

16 Box, G.E.P. and Cullumbine, H. 1947b. The effect of exposure to sub-lethal doses of phosgene on the 

17 subsequent L(Ct)50 for rats and mice. Brit. J. Pharmacol. 2:38-55. 

18 

19 Bradley, B.L. and Unger, K.M. 1982. Phosgene inhalation: A case report. Texas Med. 78:51-53. 

20 

21 Branchflower, R.V., Nunn, D.S., Highet, R.J., et al. 1984. Nephrotoxicity of chloroform: metabolism to 

22 phosgene by the mouse kidney. Toxicol. Appl. Pharmacol. 72:159-168. 

23 

24 Burleson, G.R. and Keyes, L.L. 1989. Natural killer activity in Fischer 344 rat lungs as a method to 

25 assess pulmonary immunocompetence: Immunosuppression by phosgene inhalation. 

26 Immunopharmacol. Immunotoxicol. 11:421-443. 

27 

28 Cameron, G.R. and Courtice, F.C. 1946. The production and removal of oedema fluid in the lung after 

29 exposure to carbonyl chloride (phosgene). J. Physiol. 105:175-185. (Cited in U.S. EPA, 1986) 

30 

31 Cameron, G.R. and Foss, G.L. 1941. Effect of low concentrations of phosgene for 5 hours on 5 

32 consecutive days in groups of different animals. Washington, DC: British Embassy Defense 

33 Staff; Porton report no. 2316, serial no. 63. (Cited in U.S. EPA, 1986) 

34 

35 Cameron, G.R., Courtice, F.C., and Foss, G.L. 1942. Effects of exposing different animals to a low 

concentration of phosgene 1:1,000,000 (4 mg/m3 36 ) for 5 hours. (Chapter IX in First Report on 

37 Phosgene Poisoning. Portion Report No. 2339.) Washington, D.C. British Defense Staff. British 

38 Embassy. (Cited in U.S. EPA, 1986) 

39 

40 Cessi, C., Columbini, C., and Mameli, L. 1966. The reaction of liver proteins with a metabolite of 

41 carbon tetrachloride. Biochem. J. 101:46-47c. 

42 

43 Chasis, H. 1944. Phosgene: Review of Literature on the effect of exposure in man and experimental 

44 animals. Contract W-49-036-CWS-1. 

45 

46 Clay, J.R. and Rossing, R.G. 1964. Histopathology of exposure of phosgene: An attempt to produce 

47 pulmonary emphysema experimentally. Arch. Pathol. 78:544-551. 

48 

49 Coman, D.R., Bruner, H.D., Horn, R.C., Friedman, M., Boche, R.D., McCarthy, M.D. Gibbon, M.H., 

50 and Schultz, J. 1947. Studies on experimental phosgene poisoning: I. The pathologic anatomy of 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 49 of 73 

1 phosgene poisoning with special reference to the early and late phases. Am. J. Pathol. 23:1037-

2 1074. 

3 

4 Currie, W.D., Hatch, G.E., and Frosolono, M.F. 1987a. Pulmonary alterations in rats due to acute 

5 phosgene inhalation. Fundam. Appl. Toxicol. 8:107-114. 

6 

7 Currie, W.D., Hatch, G.E., and Frosolono, M.F. 1987b. Changes in lung ATP concentration in the rat 

8 after low-level phosgene exposure. J. Biol. Toxicol. 2:105-114. 

9 

10 Delephine, S. 1922. Summary notes on two fatalities due to inhaling phosgene. J. Ind. Hygiene. 4:433-

11 440. 

12 

13 Diller, W.F. 1974. Klinik und Pathologie der phosgenvergiftung. Pneumonologie. 150:139-148. 

14 

15 Diller, W.F. 1978. Medical phosgene problems and their possible solution. J. Occup. Med. 20:189-193. 

16 

17 Diller, W. F., Bruch, J., and Dehnen, W. 1985. Pulmonary changes in the rats following low phosgene 

18 exposure. Arch. Toxicol. 57:184-190. 

19 

20 Diller, W.F. 1985. Pathogenesis of phosgene poisoning. Toxicol. Ind. Health. 1: 7-15. 

21 

22 Diller, W.F., Schnellbaecher, F., and Wuestefeld, E. 1979. Late pulmonary sequelae of phosgene 

23 poisoning or inhalation-toxic pulmonary edema. Arbeitsmed. Arbeitsschultz Prophyl. 29: 5-16. 

24 (Cited in U.S. EPA, 1986) 

25 

26 Diller, W.F. and Zante, R. 1982. Dosis-wirkungs-beziehungen bei phosgen-einwirkung auf mensch und 

27 tier. Zbl. Arbeitsmed. 32: 360-368 

28 

29 Ehrlich, J.P., Gunnison, A.F., and Burleson, G.R. 1989. Influenza virus-specific cytotoxic T-lymphocyte 

30 activity in Fischer 344 rat lungs as a method to assess pulmonary immunocompetence: Effect of 

31 phosgene inhalation. Inhalation Toxicol. 1:129-138. 

32 

33 Everett, E.D. and Overholt, E.L. 1968. Phosgene poisoning. JAMA. 205: 243-245. 

34 

35 Franch, S. and Hatch, G.E. 1986. Pulmonary biochemical effects of inhaled phosgene in rats. J. Toxicol. 

36 Environ. Health 19:413-423. 

37 

38 Freeman, S., Grodins, F.S., and Kosman, A.J. 1945. The use of helium in the treatment of phosgene 

39 poisoning. In: Fasciculus on chemical warfare medicine: v. II, respiratory tract. Washington, 

40 DC: National Research Council, Committee on Treatment of Gas Casualities; pp. 541-550. 

41 (Cited in U.S. EPA, 1986) 

42 

43 Frosolono, M.F. 1976. Basic Mechanism, diagnostic procdures and therapeutic countermeasures for 

44 phosgene poisoning in animals. Final report, MCA. (Cited in U.S. EPA, 1986) 

45 

46 Frosolono, M.F. 1977. Basic Mechanism, diagnostic procedures and therapeutic countermeasures for 

47 phosgene poisoning in animals. Final report, MCA. (Cited in U.S. EPA, 1986) 

48 

49 Frosolono, M.F. and Currie, W.D. 1985. Response of the pulmonary surfactant system to phosgene. 

50 Toxicol. Ind. Health. 1: 29-35. 

51 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 50 of 73 

1 Frosolono, M.F. and Pawlowski, R. 1977. Effect of phosgene on rat lungs after single high-level 

2 exposure: I. Biochemical alterations. Arch. Environment Health 32: 271-277. 

3 

4 Frosolono, M.F. and Currie, W.D. 1985. Effect of phosgene on the pulmonary surfactant system (PSS): 

5 Dose-response relationships. Biochemistry 24:3386. 

6 

7 Galdston, M., Leutscher, J.A., Longcope, W.T., et. al. 1947a. A study of the residual effects of 

8 phosgene poisoning in human subjects: I. After acute exposure. J. Clin. Invest. 26:145-168. 

9 

10 Galdston, M., Leutscher, J.A., Longcope, W.T., and Ballich, N.L. 1947b. A study of the residual effects 

11 of phosgene poisoning in human subjects: II. After chronic exposure. J. Clin. Invest. 26:169-

12 181. 

13 

14 Gross, P., Rinehart, W.E., and Hatch, T. 1965. Chronic pneumonitis caused by phosgene. Arch. 

15 Environ. Health. 10: 768-775. 

16 

17 Haber, F.R. 1924. Zur geschichte des gaskrieges [On the history of the gas war]. In: Fuenf Vortraege 

18 aus den Jahren 1920-23 [Five lectures from the years 1920-1923]. Berlin, Germany: Verlag von 

19 Julius Springer; pp. 76-92. (Cited in U.S. EPA, 1986) 

20 

21 Halpern, B.N., Cruchaud, S., Vermeil, G., and Roux, J.L. 1950. Experimental study on the pathogenesis 

22 and treatment of acute pulmonary edema. Arch. Int. Pharmacodyn. Ther. 82:425-476. (Cited in 

23 U.S. EPA, 1986) 

24 

25 Hatch, G.E., Slade, R., Stead, A.G., and Graham, J.A. 1986. Species comparison of acute inhalation 

26 toxicity of ozone and phosgene. J. Toxicol. Environmental Health 19:43-53. 

27 

28 Hedlund, L.W., and Putman, C.E. 1985. Methods for detecting pulmonary edema. Toxicol. Ind. 

29 Health. 1:59-67. 

30 

31 Hegler, C. 1928. On the mass poisoning by phosgene in Hamburg. I. Clinical observations. 54:1551-

32 1553. 

33 

34 Henschler, D. 1971. German MAK Criteria. (From Ehrlicher, H. 1971. Personal Communication, 

35 Department of Medicine, Bayer AG, Leverkusen). 

36 

37 Henschler, D. and Laux, W. 1960. On the specificity of a tolerance increase by repeated inhalation of 

38 pulmonary edema-producing gases. Naunyn-Schmiedbergs Arch. Exp. Pathol. Pharmakol. 

39 239:433-441. (Cited in U.S. EPA, 1986) 

40 

41 Herzog, H. And Pletscher, A. 1955. Die wirkung von industriellen reizgasen auf die 

42 bronchialschleimhaut des menschen. Schweizerische Medizinische Wochenschrift. 85:477-481. 

43 

44 Illing, J.W., Mole, M.L., Graham, J.A, et al. 1988. Influence of phosgene inhalation on extrapulmonary 

45 effects in mice. Inhalation Toxicol. 1:13-20. 

46 

47 Jaskot, R.H., Grose, E.C., and Stead, A.G. 1989. Increase in angiotensin-converting enzyme in rat lungs 

48 following inhalation of phosgene. Inhalation Toxicol. 1:71-78. 

49 

50 Jaskot, R.H., Grose, E.C., Richards, J.H., and Doerfler, D.L. 1991. Effects of inhaled phosgene on rat 

51 lung antioxidant systems. Fund. Appl. Toxicol. 17:666-674. 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 51 of 73 

1 

2 Kaerkes, B. 1992. Experiences with a phosgene indicator badge during an eleven-year period. M.D. 

3 Dissertation, Heinrich-Heine University. Duesseldorf, Germany. 

4 

5 Karel, L. and Weston, R.E. 1947. The biological assay of inhaled substance by the dosimetric method: 

6 The retained median lethal dose and the respiratory response in unanesthetized, normal goats 

7 exposed to different concentrations of phosgene. J. Ind. Hyg. Toxicol. 29:23-28. 

8 

9 Kawai, M. 1973. [Inhalation toxicity of phosgene and trichloronitromethane (chloropicrin)]. J. Sangyo 

10 Igaku 15:406-407. 

11 

12 Keeler, J.R., Hurt, H.H., Nold, J.B., Corcoran, K.D., and Tezak-Reid, T.M. 1990a. Phosgene-induced 

13 lung injury in sheep. Inhalation Toxicol. 2:391-406. 

14 

15 Keeler, J.R., Hurt, H.H., Nold, J.B., and Lennox, W.J. 1990b. Estimation of the LCt50 of phosgene in 

16 sheep. Drug Chem Toxicol. 13:229-239. 

17 

18 Kimmerle, G. and Diller, W. 1977. Unveroffentilichte Untersuchungen. (Cited in U.S. EPA, 1986) 

19 

20 Kirk-Othmer.. 1991. Encyclopedia of Chemical Technology. Fourth Edition. Volume 18. John Wiley 

21 & Sons. New York. Phosgene. pp. 645-655. 

22 

23 Kodavanti, U.P., D.L. Costa, S.N. Giri, B. Starcher and G.E. Hatch. 1997. Pulmonary structural and 

24 extracellular matrix alterations in Fischer 344 rats following subchronic exposure. Fundamental 

25 and Applied Toxicology 37:54-63. 

26 

27 

28 Laquer, E. and Magnus, R. 1921. Combat gas poisoning. III. Experimental pathology of phosgene 

29 poisoning. Z. Gesamte Exp. Med. 13:31-107. 

30 

31 Leonardos, G., Kendall, D.A., and Barnard, N.J. 1968. Odor threshold determinations of 53 odorant 

32 chemicals. Presented at the 61th Annual Meeting of the Air Pollution Control Association, St. 

33 Paul, Minn., June 23-27. [Requested. NIOSH, 1976, page 29] 

34 

35 Lipsett, M.J., Shusterman, D.J., and Beard, R.R. 1994. Phosgene. In: Industrial hygiene and toxicology, 

36 4th ed. Vol. II, part F. Clayton, G.D. and Clayton, F.E. editors, J. Wiley & Sons, Inc. pp. 4557-

37 4563. 

38 

39 MAC (Maximaal Aanvaaarde Concentratie [Maximal Accepted Concentration]). 2000. SDU Uitgevers 

40 (under the auspices of the Ministry of Social Affairs and Employment), The Hague, The 

41 Netherlands. 

42 

43 MAK (Maximale Argeitsplatzkonzentration [Maximum Workplace Concentration]) 2007. Deutsche 

44 Forschungsgemeinschaft (German Research Association). 

45 

46 Mansuy, D., Beaune, P., Crestell, T., Lange, M., and Leroux, M. 1977. Evidence for phosgene 

47 formation during liver microsomal oxidation of chloroform. Biochem. Biophys. Res. Comm. 

48 79:513-517. 

49 

50 Meek, W.J. and Eyster, J.A.E. 1920. Experiments on the pathological physiology of acute phosgene 

51 poisoning. Am. J. Physiol. 51:303-320. 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 52 of 73 

1 

2 Misra, N.P., Manoria, P.C., and Saxena, K. 1985. Fatal pulmonary oedema with phosgene poisining. J. 

3 Assoc. Physicians India. 33:430-431. 

4 

5 Moor, S. and Gates, M. 1946. Technical report of division G/NDRC. (Cited in U.S. EPA, 1986) 

6 

7 NIOSH (National Institute of Occupational Safety and Health). 1976. Criteria for a recommended 

8 standard: occupational exposure to phosgene. NIOSH-76-137. 

9 

10 NIOSH (National Institute of Occupational Safety and Health). 2005. Phosgene. NIOSH Publication 

11 2005-149. NIOSH Pocket Guide to Chemical Hazards. www.cdc.gov/niosh. 

12 

13 NRC (National Research Council). 1985. Emergency and Continuous Exposure Limits for Selected 

14 Airborne Contaminants. Phosgene. pp. 69-86. National Academy Press. Washington, D.C. 

15 

16 Ong, S.G. 1972. Treatment of phosgene poisoning with antiserum: anaphylactic shock by phosgene. 

17 Arch. Toxicol. 29:267-278. (Cited in U.S. EPA, 1986) 

18 

19 OSHA (Occupational Safety and Health Administration). 1994. Limits for Air Contaminants. U. S. 

20 Department of Labor. 29 CFR 1910.1000. 

21 

22 Pauluhn, J. 2006a. Acute nose-only exposure of rats to phosgene. Part I. Concentration x time 

23 dependence of LC50s, non-lethal-threshold concentrations and analysis of breathing patterns. 

24 Inhalation Toxicology 18:423-435. 

25 

26 Pauluhn, J. 2006b. Acute nose-only exposure of rats to phosgene. Part II. Concentration x time 

27 dependence of changes in bronchoalveolar lavage during a follow-up period of 3 months. 

28 Inhalation Toxicology 18:595-607. 

29 

30 Pauluhn, J. 2006c. Acute head-only exposure of dogs to phosgene. Part III. Comparison of indicators of 

31 lung injury in dogs and rats. Inhalation Toxicology 18:609-621. 

32 

33 Pauluhn, J., et al. 2007. Workshop Summary: Phosgene-induced pulmonary toxicity revisited: appraisal 

34 of early and late markers of pulmonary injury from animal models with emphasis on human 

35 significance. Inhalation Toxicology: 19: 10, 789-810. 

36 

37 Patt, H.M., Tobias, J.M., Swift, M.N., Postel, S., and Gerard, R.W. 1946. Hemodynamics in pulmonary 

38 irritant poisoning. Am. J. Physiol. 147:329-339. 

39 

40 Pawlowski, R. and Frosolono, M.F. 1977. Effect of phosgene on rat lungs after single high-level 

41 exposure. II. Ultrastructural alternations. Arch. Environ. Health 32:278-283. 

42 

43 Pohl, L.R., Bhooshan, B., Whittaker, N.F., and Krishna, G. 1977. Phosgene: a metabolite of 

44 chloroform. Biochem. Biophys. Res. Comm. 79:684-691. 

45 

46 Pohl, L.R., Martin, J.L., and George, J.W. 1980a. Mechanism of metabolic activation of chloroform by 

47 rat liver microsomes. Biochem. Pharmacol. 29:3271-3276. 

48 

49 Pohl, L.R., Martin, J.L., Taburet, A.M. and George, J.W. 1980b. Oxidative bioactivation of haloforms 

50 into hepatotoxins. In: Microsomes, Drug Oxidations, and Chemical Carcinogenesis, Vol. II. 

51 Coon, M.J., et al., Eds. Academic Press, New York. Pp. 881-884. 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 53 of 73 

1 

2 Pohl, L.R., Branchflower, R.V., Highet, R. J., et al. 1981. The formation of diglutathionyl 

3 dithiocarbonate as a metabolite of chloroform, bromotrichloromethane, and carbon tetrachloride. 

4 Drug. Metab. Dispos. 9:334-338. 

5 

6 Polednak, A.P. and Hollis, D.R. 1985. Mortality and causes of death among workers exposed to 

7 phosgene in 1943-1945. Toxicol. Ind. Health. 1:137-148. 

8 

9 Polednak, A.P. 1980. Mortality among men occupationally exposed to phosgene in 1943-1945. Environ. 

10 Res. 22:357-367. 

11 

12 Postel, S. and Swift, M. 1945. Evaluation of the bleeding-transfusion treatment of phosgene poisoning. 

13 In: Fasciculus on chemical warfare medicine: v. II, respiratory tract. Washington, DC: National 

14 Research Council, Committee on Treatment of Gas Casualties; pp. 664-690. (Cited in U.S. 

15 EPA, 1986) 

16 

17 Regan, R.A. 1985. Review of clinical experience in handling phosgene exposure cases. Toxicol. Ind. 

18 Health. 1:69-71. 

19 

20 Reynolds, E.S. 1967. Liver parenchymal cell injury. IV. Pattern of incorporation of carbon and 

21 chlorine from carbon tetrachloride into chemical constituents of liver in vivo. J. Pharmacol. 

22 Exp. Ther. 155:126-127. 

23 

24 Rinehart, W.E. 1962. A study of the concentration x time (CT) relationship in sub-lethal exposures to 

25 phosgene (dissertation). Pittsburgh, PA. University of Pittsburgh. Publication No. 62-6675. 

26 University Microfilms, Inc. Ann Arbor, MI. 

27 

28 Rinehart, W.E. and Hatch, T. 1964. Concentration-time product (CT) as an expression of dose in 

29 sublethal exposures to phosgene. AIHA Journal. 25:545-553. 

30 

31 Rothlin, E. 1941. Pathogenesis and treatment for phosgene intoxication. Schweiz. Med. Wochenschr. 

32 71:1526-1535. (Cited in U.S. EPA, 1986) 

33 

34 Sandall, T.E. 1922. The later effects of gas poisoning. Lancet. 203: 857-859. (Cited in U.S. EPA, 

35 1986) 

36 

37 Schultz, J. 1945. The prophylactic action of hexamethylenetetramine in phosgene poisoning. In: 

38 Fasciculus on chemical warfare medicine: v. II, Respiratory tract. Washington, DC: National 

39 Research Council, Committee on Treatment of Gas Casualties; pp. 691-712. 

40 

41 Sciuto, A.M. 1998. Assessment of early acute lung injury in rodents exposed to phosgene. Arch 

42 Toxicology 72:283-288. 

43 

44 Sciuto, A.M., T.S. Moran, A. Narula and J.S. Forster. 2001. Disruption of gas exchange in mice after exposure to 

45 the chemical threat agent phosgene. Military Medicine 166, 9:809-814. 

46 

47 Selgrade, M.K., Starnes, D.M., Illing, J.W., Daniels, M.J., and Graham, J.A. 1989. Effects of phosgene 

48 exposure on bacterial, viral, and neoplastic lung disease susceptability in mice. Inhalation 

49 Toxicol. 1:243-259. 

50 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 54 of 73 

1 Shah, H., Hartman, S.P., and Weinhouse, S. 1979. Formation of carbonyl chloride in carbon 

2 tetrachloride metabolism by rat liver in vitro. Cancer Res. 39:3942-3947. 

3 

4 Shils, S.E. 1943. The therapeutic and prophylactic value of hexamethylenetetramine in phosgene 

5 poisoning. MD (EA) Memorandum report Nr. 81 V. 19. (Cited in U.S. EPA, 1986) 

6 

7 Sipes, I.G., Krishna, G., and Gillette, J.R. 1977. Bioactivation of carbon tetrachloride, chloroform, and 

8 bromotrichloromethane: role of cytochrome P-450. Life Sciences. 20: 1541-1548. 

9 

10 Slade, R., Highfill, J.W., and Hatch, G.E. 1989. Effects of depletion of ascorbic acid or nonprotein 

11 sulfhydryls on the acute inhalation toxicity of nitrogen dioxide, ozone, and phosgene. Inhalation 

12 Toxicol. 1:261-271. 

13 

14 Stavrakis, P. 1971. The use of hexamethylenetetramine (HMT) in treatment of acute phosgene 

15 poisoning. Ind. Med. 40:30-31. 

16 

17 TEMIS (Trauma Emergency Medical Information System). 1997. Phosgene. 

18 

19 ten Berge, W.F., Zwart, A. and Appleman, L.M. 1986. Concentration-time mortality response 

20 relationship of irritant and systemically acting vapours and gases. J. Hazardous Materials 

21 13:301-309. 

22 

23 Tobias, J.M. 1945. The pathological physiology of the lung after phosgene. In: Fasciculus on chemical 

24 warfare medicine: v. II, respiratory tract. Washington, DC: National Research Council, 

25 Committee on Treatment of Gas Casualties; pp. 331-391. (Cited in U.S. EPA, 1986) 

26 

27 Underhill, F.P. 1920. The lethal war gases. Physiology and experimental treatment. New Haven Yale 

28 University Press. 

29 

30 U.S. DHEW (U.S. Department of Health, Education, and Welfare). 1968. Eighth revision international 

31 classification of diseases, adapted for use in the United States. Public Health Services 

32 Publication No. 1693:1. 

33 

34 U.S. EPA, 1985. Health Assessment Document for Chloroform. Prepared by the Office of Health and 

35 Environmental Assessment, Environmental Criteria and Assessment Office, Research Triangle 

36 Park, NC, for the Office of Air Quality Planning and Standards. EPA 600/8-84-004F. 

37 

38 U.S. EPA. 1986. Health Assessment Document for Phosgene. Office of Health and Environmental 

39 Assessment. EPA/600/8-86/022A. 

40 

41 Weston, R.E. and Karel, L. 1946. An application of the dosimetric method for biologically assaying 

42 inhaled substances: The determination of the retained median lethal dose, percentage retention, 

43 and respiratory response in dogs exposed to different concentrations of phosgene. J. Pharmacol. 

44 Exptl. Ther. 88:195. 

45 

46 Weston, R.E. and Karel, L. 1947. An adaptation of the dosimeteric method for use in smaller animals. 

47 The retained median lethal dose and the respiratory response in normal, unanesthetized, Rhesus 

48 monkeys (Macaca mulatta) exposed to phosgene. J. Ind. Hyg. Toxicol. 29:29-33. 

49 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 55 of 73 

1 Winternitz, M.C, Lambert, R.A., and Jackson, L. 1920. The pathology of phosgene poisoning. In: 

2 Collected studies on the pathology of was gas poisoning. New Haven, CT: Yale Univ. Press; pp. 

3 35-66. 

4 

5 Wirth, W. 1936. Uber die wirkung kleinster phosgenmengen. Arch. Exp. Pathol. Pharmacol. 181:198-

6 206. 

7 

8 Zwart, A., Arts, J.H.E., Klokman-Houweling, J.M., and Schoen, E.D. 1990. Determination of 

9 concentration-time-mortality relationships to replace LC50 values. Inhalation Toxicol. 2:105-

10 117. 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 56 of 73 

1 APPENDIX A: DERIVATION OF AEGL VALUES

2 

3 AEGL-1 for Phosgene

4 

5 Data were insufficient for derivation of AEGL-1 values for phosgene. 

6 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 57 of 73 

1 Derivation of AEGL-2 for Phosgene

2 

3 Key study: Pauluhn, 2006c 

4 

5 Toxicity endpoint: Increased PMNs in BAL fluid, dog (2.3 ppm for 30 min) 

6 

Scaling: C1 7 x t = k 

 (2.3 ppm)1 8 x 0.5 hr = 1.15 ppmhr 

9 

10 

11 Uncertainty factors: 1 for interspecies variability 

12 3 for intraspecies variability 

13 

10-min AEGL-2 C1 14 x 0.167 hr = 1.15 ppmhr 

15 C = 6.9 ppm 

16 10-min AEGL-2 = 6.9/3 = 2.3 ppm 

17 

18 30-min AEGL-2 C = 2.3 ppm 

19 30-min AEGL-2 = 2.3/3 = 0.77 ppm 

20 

1-hr AEGL-2 C1 21 x 1 hr = 1.15 ppmhr 

22 C = 1.15 ppm 

23 1-hr AEGL-2 = 1.15 ppm/3 = 0.38 ppm 

24 

4-hr AEGL-2 C1 25 x 4 hrs = 1.15 ppmhr 

26 C = 0.29 ppm 

27 4-hr AEGL-2 = 0.29 ppm/3 = 0.096 ppm 

28 

8-hr AEGL-2 C1 29 x 8 hrs = 1.15 ppmhr 

30 C = 0.14 ppm 

31 8-hr AEGL-2 = 0.14 ppm/3 = 0.048 ppm 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 58 of 73 

1 Derivation of AEGL-3 for Phosgene

2 

3 Key study: Pauluhn (2006a) 

4 

5 Toxicity endpoint: Estimated threshold for lethality in rats: BMCL05

6 3.9 ppm for 1-hr 

7 

Scaling: C1 8 x t = k 

 (3.9 ppm)1 9 x 1 hr = 3.9 ppmhr 

10 

11 Uncertainty factors: 1 for interspecies variability 

12 3 for intraspecies variability 

13 

10-min AEGL-3 C1 14 x 0.167 hr = 3.9 ppmhr 

15 C = 23.35 ppm 

16 10-min AEGL-3 = 23.35/3 = 7.8 ppm 

17 

30-min AEGL-3 C1 18 x 0.5 hr = 3.9 ppmhr 

19 C = 7.8 ppm 

20 10-min AEGL-3 = 7.8/3 = 2.6 ppm 

21 

22 1-hr AEGL-3 C = 3.9 ppm 

23 1-hr AEGL-3 = 3.9 ppm/3 = 1.3 ppm 

24 

4-hr AEGL-3 C1 25 x 4 hrs = 3.9 ppmhr 

26 C = 0.975 ppm 

27 4-hr AEGL-3 = 0.975 ppm/3 = 0.33 ppm 

28 

8-hr AEGL-3 C1 29 x 8 hrs = 3.9 ppmhr 

30 C = 0.488 ppm 

31 8-hr AEGL-3 = 0.488 ppm/3 = 0.16 ppm 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 59 of 73 

1 APPENDIX B: DERIVATION SUMMARY FOR PHOSGENE AEGLS 

2 

3 ACUTE EXPOSURE GUIDELINE LEVELS FOR PHOSGENE 

4 DERIVATION SUMMARY

5 

AEGL-1 VALUES FOR PHOSGENE

10-min 30-min 1-hr 4-hr 8-hr 

NR NR NR NR NR 

Key Reference: NA 

Test Species/Strain/Number: NA 

Exposure Route/Concentrations/Durations: NA 

Effects: NA 

Endpoint/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 to 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 hours. 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 60 of 73 

1 

AEGL-2 VALUES FOR PHOSGENE

10-min 30-min 1-hr 4-hr 8-hr 

2.3 ppm 

(9.5 mg/m3

)

0.77 ppm 

(3.2 mg/m3) 

0.38 ppm 

(1.6 mg/m3) 

0.096 ppm 

(0.39 mg/m3) 

0.048 ppm 

(0.19 mg/m3) 

Key Reference: Pauluhn, J. 2006c. Acute head-only exposure of dogs to phosgene. Part III. Comparison of 

indicators of lung injury in dogs and rats. Inhalation Toxicology 18:609-621. 

Test Species/Strain/Number: Dog/ Beagle/4-5 males and/or females/concentration 

Exposure Route/Concentrations/Durations: Dogs/Inhalation: 30 minute exposures to 0, 2.3, 4.1, or 8.8 ppm 

Effects: 

2.3 ppm: nasal discharge, salivation lacrimation 

4.1 ppm: nasal discharge, salivation lacrimation, increased BAL PMNs 

8.8 ppm: labored breathing, rales, increased BAL PMNs, increased lung weight, pulmonary pathology edema 

Endpoint/Concentration/Rationale: NOAEL for increased PMNs in BAL fluid / BAL fluid changes are a 

sensitive marker of phosgene-induced noncardiogenic pulmonary high-permeability edema following acute 

inhalation exposure 

Uncertainty Factors/Rationale: 

Total uncertainty factor: 3 

Interspecies: 1 An increase BAL fluid protein is a sensitive marker of phosgene-induced 

noncardiogenic pulmonary high-permeability edema following acute inhalation exposure (Pauluhn et al., 2007). 

In rats, c x t products of between 48 ppm·min and 60 ppm·min induced increased protein in BAL fluid , and no 

increase was noted from 24-30 ppm·min. In mice and hamsters, a c x t product of 48 ppm·min induced an increase 

of protein in BAL fluid, and no increase was noted at 24 ppm·min. However, in dogs, a c x t product of 129 

ppm·min was necessary to cause an increase in protein in BAL fluid, and no increase was observed at 63 

ppm·min. Thus, the CT product required to induce an increase in protein in BAL fluid in dogs is approximately 

two-fold greater than in rodents, and the NOAEL for increased BAL protein in dogs (63 ppm·min) is higher than 

the LOAEL values in rodents (48-60 ppm·min). Additionally, with regard physiology of the respiratory tract and 

acinar structure of the lung, dogs are more similar to humans than rodents (Pauluhn, 2006a, 2006b, 2006c; 

Pauluhn et al., 2007). Collectively, these data suggest that an interspecies uncertainty factor of no more than 1 is 

justified when extrapolating from laboratory animals to humans.

Intraspecies: 3 - considered sufficient due to the steep concentration-response curve (death in 2/10 rats 

exposed to 52.3 ppm and 6/10 exposed to 61.9 ppm for 10 min; 4/10 exposed to 13.4 ppm and 10/10 exposed 

to 16.7 ppm for 30-min; 4/10 exposed to 7.4 ppm and 10/10 exposed to 11.8 ppm for 1-hr; Pauluhn, 2006a) 

which implies limited intra-individual variability. Also, the mechanism of phosgene toxicity (binding to 

macromolecules and irritation) is not expected to vary greatly between individuals. 

Modifying Factor: Not applicable 

Animal to Human Dosimetric Adjustment: Insufficient data 

Time Scaling: Cn x t = k where n = 1. Haber=s Law c x t = k; n=1 has been shown to be valid for phosgene 

within certain limits and was used for scaling of the AEGL values for phosgene. 

Data adequacy: The database is rich. The calculated AEGL-2 values are supported by repeated-exposure rat 

studies where No significant treatment-related effects were noted in rats exposed to 0.125 ppm phosgene 4 

hours/day, 5 days/week for 17 weeks (Franch and Hatch, 1986). 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 61 of 73 

1 

AEGL-3 VALUES FOR PHOSGENE

10-min 30-min 1-hr 4-hrs 8-hrs 

7.8 ppm 

(32 mg/m3

) 

2.6 ppm 

(11 mg/m3) 

1.3 ppm 

(5.3 mg/m3) 

0.33 ppm 

(1.4 mg/m3) 

0.16 ppm 

(0.66 mg/m3) 

Reference: Pauluhn, J. 2006a. Acute nose-only exposure of rats to phosgene. Part I. Concentration x time 

dependence of LC50s, non-lethal-threshold concentrations and analysis of breathing patterns. Inhalation 

Toxicology 18:423-435. 

Test Species/Strain/Sex/Number: Wistar rats/ 5 males and 5 females/ concentration 

Exposure Route/Concentrations/Durations: Rats/Inhalation: 41.1, 44.8, 52.3, 61.9 ppm for 10-min; 12.6, 

13.4, 16.7, 21.4 ppm for 30-min; 0, 7.4, 9.7, 11.8 ppm for 1-hr; 2.2 and 2.7 ppm for 4-hr. 

Effects: 

Concentration Mortality LC50 BMCL05 BMC01

(ppm) 

Exposure 

duration 

(min) 

M F 

41.1 10 2/5 1/5 

44.8 10 0/5 0/5 

52.3 10 1/5 1/5 

61.9 10 3/5 3/5 

62.5 ppm 24.3 ppm 32.6 ppm 

 

12.6 30 3/5 1/5 

13.4 30 3/5 1/5 

16.7 30 5/5 5/5 

21.4 30 5/5 4/5 

13.5 ppm 5.0 ppm 7.4 ppm 

 

0 60 0/5 0/5 

7.4 60 2/5 2/5 

9.7 60 5/5 4/5 

11.8 60 5/5 5/5 

7.7 ppm 3.9 ppm 5.3 ppm 

 

2.2 240 5/5 1/5 

2.7 240 5/5 4/5 

2.1 ppm - - 

Endpoint /Concentration/Rationale: Estimated lethality threshold (BMCL05) in rats/ 3.9 ppm for 1-hr 

Uncertainty Factors/Rationale: 

Total uncertainty factor: 3 

Interspecies: 1- An increase BAL fluid protein is a sensitive marker of phosgene-induced 

noncardiogenic pulmonary high-permeability edema following acute inhalation exposure (Pauluhn et al., 

2007). In rats, c x t products of between 48 ppm·min and 60 ppm·min induced increased protein in BAL fluid 

, and no increase was noted from 24-30 ppm·min. In mice and hamsters, a c x t product of 48 ppm·min 

induced an increase of protein in BAL fluid, and no increase was noted at 24 ppm·min. However, in dogs, a c x 

t product of 129 ppm·min was necessary to cause an increase in protein in BAL fluid, and no increase was 

observed at 63 ppm·min. Thus, the CT product required to induce an increase in protein in BAL fluid in dogs 

is approximately two-fold greater than in rodents, and the NOAEL for increased BAL protein in dogs (63 

ppm·min) is higher than the LOAEL values in rodents (48-60 ppm·min). Additionally, with regard physiology 

of the respiratory tract and acinar structure of the lung, dogs are more similar to humans than rodents (Pauluhn, 

2006a, 2006b, 2006c; Pauluhn et al., 2007). Collectively, these data suggest that an interspecies uncertainty 

factor of no more than 1 is justified when extrapolating from laboratory animals to humans. 

Intraspecies: 3 - considered sufficient due to the steep concentration-response curve (death in 2/10 rats 

exposed to 52.3 ppm and 6/10 exposed to 61.9 ppm for 10 min; 4/10 exposed to 13.4 ppm and 

10/10 exposed to 16.7 ppm for 30-min; 4/10 exposed to 7.4 ppm and 10/10 exposed to 11.8 ppm 

for 1-hr; Pauluhn, 2006a) which implies limited intra-individual variability. Also, the mechanism 

of phosgene toxicity (binding to macromolecules and irritation) is not expected to vary greatly 

between individuals. 

Modifying Factor: Not applicable 

Animal to Human Dosimetric Adjustment: Insufficient data 

Time Scaling: Cn x t = k where n = 1. Haber=s Law c x t = k; n=1 has been shown to be valid for phosgene 

within certain limits and was used for scaling of the AEGL values for phosgene. 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 62 of 73 

Data Adequacy: The AEGL-3 values are based on a well-conducted study in rats and the database is rich. 

AEGL-3 values are considered protective. No deaths were noted in rats exposed to phosgene 6 hrs/day at 

concentrations of 0.1 ppm (5 days/week), 0.2 ppm (5 days/week), 0.5 ppm (2 days/week) or 1.0 ppm (1 

day/week) for 4 or 12 weeks (Kodavanti et al.,1997). Also, no deaths were noted in approximately 200 

workers exposed to phosgene concentrations ranging from 50 to 300 ppm·min (Kaerkes, 1992), and 

calculated AEGL-3 values are approximately 79 ppm·min. 

1 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 63 of 73 

1 APPENDIX C: CATEGORY PLOT FOR PHOSGENE 

2 

3 

0 

0 

1 

10 

100 

ppm

0 60 120 180 240 300 360 420 480 

Minutes

Human - No Effect

Human - Discomfort

Human - Disabling

Animal - No Effect

Animal - Discomfort

Animal - Disabling

Animal - Some Lethality

Animal - Lethal

AEGL

Chemical Toxicity - TSD All Data

Phosgene

AEGL-3

AEGL-2

4 

5 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 64 of 73 

1 

Phosgene N 

For Category 

0 = No effect, 

1 = Discomfort, 

2 = Disabling, 

PL = Partially 

Lethal, 

3 = Lethal 

 

Source Species Sex # Exposures ppm Minutes Category Comments 

NAC/AEGL-1 NR 10 AEGL 

NAC/AEGL-1 NR 30 AEGL 

NAC/AEGL-1 NR 60 AEGL 

NAC/AEGL-1 NR 240 AEGL 

NAC/AEGL-1 NR 480 AEGL 

 

NAC/AEGL-2 2.3 10 AEGL 

NAC/AEGL-2 0.77 30 AEGL 

NAC/AEGL-2 0.38 60 AEGL 

NAC/AEGL-2 0.096 240 AEGL 

NAC/AEGL-2 0.048 480 AEGL 

 

NAC/AEGL-3 7.8 10 AEGL 

NAC/AEGL-3 2.6 30 AEGL 

NAC/AEGL-3 1.3 60 AEGL 

NAC/AEGL-3 0.33 240 AEGL 

NAC/AEGL-3 0.16 480 AEGL 

 mouse 1 77 10 pl LC50 (Zwart, 1990) male 

 mouse 1 61 10 pl LC50 (Zwart, 1990) female 

 mouse 1 18 30 pl LC50 (Zwart, 1990) male 

 mouse 1 11 30 pl LC50 (Zwart, 1990) female 

 mouse 1 9 10 pl LC50 (Zwart, 1990) male 

 mouse 1 5 15 pl LC50 (Zwart, 1990) female 

 rat 1 0.29 30 1 transient decreased minute 

volume 

(Pauluhn, 2006a) 

 rat 1 1 240 pl increased lung weight, BAL 

protein 

(Pauluhn, 2006a) 

 rat 1 41.1 10 pl mortality 3/10; lung edema, 

pulmonary hemorrhage, 

foamy trachael exudate (Pauluhn, 

2006a) 

 rat 1 44.8 10 2 mortality 0/10; lung edema, 

pulmonary hemorrhage, 

foamy trachael exudate (Pauluhn, 

2006a) 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 65 of 73 

 rat 1 52.3 10 pl mortality 2/10; lung edema, 

pulmonary hemorrhage, 

foamy trachael exudate (Pauluhn, 

2006a) 

 rat 1 61.9 10 pl mortality 6/10; lung edema, 

pulmonary hemorrhage, 

foamy trachael exudate (Pauluhn, 

2006a) 

 rat 1 12.6 30 pl mortality 4/10; lung edema, 

pulmonary hemorrhage, 

foamy trachael exudate (Pauluhn, 

2006a) 

 rat 1 13.4 30 pl mortality 4/10; lung edema, 

pulmonary hemorrhage, 

foamy trachael exudate (Pauluhn, 

2006a) 

 rat 1 16.7 30 3 mortality 10/10; lung edema, 

pulmonary hemorrhage, 

foamy trachael exudate (Pauluhn, 

2006a) 

 rat 1 21.4 30 pl mortality 9/10; lung edema, 

pulmonary hemorrhage, 

foamy trachael exudate (Pauluhn, 

2006a) 

 rat 1 7.4 60 pl mortality 4/10; lung edema, 

pulmonary hemorrhage, 

foamy trachael exudate (Pauluhn, 

2006a) 

 rat 1 9.7 60 pl mortality 9/10; lung edema, 

pulmonary hemorrhage, 

foamy trachael exudate (Pauluhn, 

2006a) 

 rat 1 11.8 60 3 mortality 10/10; lung edema, 

pulmonary hemorrhage, 

foamy trachael exudate (Pauluhn, 

2006a) 

 rat 1 2.2 240 pl mortality 6/10; lung edema, 

pulmonary hemorrhage, 

foamy trachael exudate (Pauluhn, 

2006a) 

 rat 1 2.7 240 pl mortality 9/10; lung edema, 

pulmonary hemorrhage, 

foamy trachael exudate (Pauluhn, 

2006a) 

 rat 1 80 10 pl LC50 (Zwart, 1990) 

 rat 1 20 30 pl LC50 (Zwart, 1990) 

 rat 1 12 60 pl LC50 (Zwart, 1990) 

 rat 1 4 75 pl LC50 (Rinehart & Hatch, 1964)) 

 rat 1 4 125 3 LC100 (Rinehart & Hatch, 1964) 

 mouse 1 8 20 2 Increased lung weight, acidosis 

(Sciuto, 2001) 

 mouse 1 22 20 2 Increased protein in BAL fluid 

(Sciuto, 1998) 

 rat 1 22 20 2 Increased protein in BAL fluid 

(Sciuto, 1998) 

 gp 1 22 20 2 Increased protein in BAL fluid 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 66 of 73 

(Sciuto, 1998) 

 mouse 1 0.2 240 2 Increased protein in BAL fluid 

(Hatch, 1986) 

 mouse 1 0.15 240 2 Increased phenobarbital-induced 

sleep time 

(Illing, 1988) 

 rat 1 0.2 30 0 no effect reported (Pauluhn 

2006b) 

 rat 1 0.5 30 0 no effect reported (Pauluhn 

2006b) 

 rat 1 1 30 0 no effect reported (Pauluhn 

2006b) 

 

 rat 1 2 30 2 labored breathing, tachypnea, 

decreased BW, 

increased BAL protein (Pauluhn, 

2006b) 

 rat 1 4 30 2 lung pathology, labored breathing, 

tachypnea, 

decreased BW, increased BAL 

protein 

 (Pauluhn, 2006b) 

 rat 1 2 90 2 chemical pneumonia (Gross, 

1965) 

 rat 1 0.05 240 0 no effect reported (Pauluhn 

2006b) 

 rat 1 0.1 240 0 no effect reported (Pauluhn 

2006b) 

 rat 1 0.2 240 2 labored breathing, tachypnea, 

decreased BW, 

 increased BAL protein (Pauluhn, 

2006b) 

 rat 1 0.4 240 2 labored breathing, tachypnea, 

decreased BW, 

 increased BAL protein (Pauluhn, 

2006b) 

 rat 1 1 240 2 lung pathology, labored breathing, 

tachypnea, 

 decreased BW, increased BAL 

protein 

(Pauluhn, 2006b) 

 rat 1 1 240 2 decreased BW, increased lung 

weight 

(Erlich, 1989) 

 gp 1 0.25 240 2 increased protein in BAL fluid 

(Slade, 1989) 

 gp 1 0.5 240 2 increased protein in BAL fluid 

(Slade, 1989) 

 rat 1 0.125 240 0 no effect reported (Currie, 1987a) 

 rat 1 0.25 240 2 increased protein BAL fluid 

(Currie, 1987a) 

 rat 1 0.5 240 2 increased protein BAL fluid, 

increased lung weight (Currie, 

1987a) 

 rat 1 1 240 2 increased protein BAL fluid, 

 increased lung weight (Currie, 

1987a) 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 67 of 73 

 rat 1 0.1 240 0 no effect reported (Hatch, 1986) 

 rat 1 0.2 240 2 increased lBAL protein (Hatch, 

1986) 

 mouse 1 0.1 240 0 no effect reported (Hatch, 1986) 

 mouse 1 0.2 240 2 increased BAL protein (Hatch, 

1986) 

 hamster 1 0.1 240 0 no effect reported (Hatch, 1986) 

 hamster 1 0.2 240 2 increased BAL protein (Hatch, 

1986) 

 rabbit 1 0.2 240 0 no effect reported (Hatch, 1986) 

 rabbit 1 0.5 240 2 increased BAL protein (Hatch, 

1986) 

 gp 1 0.2 240 0 no effect reported (Hatch, 1986) 

 gp 1 0.5 240 2 increased BAL protein (Hatch, 

1986) 

 dog 1 2.3 30 1 nasal discharge, salivation, 

lacrimation 

(Pauluhn, 2006c) 

 dog 1 4.1 30 1 nasal discharge, salivation, 

lacrimation; 

increased BAL PMNs (Pauluhn, 

2006c) 

 dog 1 8.8 30 2 labored breathing, rales, increased 

lung 

weight, pulmonary pathology and 

edema 

(Pauluhn, 2006c) 

1 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 68 of 73 

1 BMDS MODEL RUN Phosgene 30 min 

2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

3 

4 The form of the probability function is: 

5 

6 P[response] = Background 

7 + (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), 

8 

9 where CumNorm(.) is the cumulative normal distribution function 

10 

11 

12 Dependent variable = COLUMN3 

13 Independent variable = COLUMN1 

14 Slope parameter is not restricted 

15 

16 Total number of observations = 5 

17 Total number of records with missing values = 0 

18 Maximum number of iterations = 250 

19 Relative Function Convergence has been set to: 1e-008 

20 Parameter Convergence has been set to: 1e-008 

21 

22 

23 

24 User has chosen the log transformed model 

25 

26 

27 Default Initial (and Specified) Parameter Values 

28 background = 0 

29 intercept = -8.93912 

30 slope = 3.47228 

31 

32 

33 Asymptotic Correlation Matrix of Parameter Estimates 

34 

35 ( *** The model parameter(s) -background 

36 have been estimated at a boundary point, or have been specified by the user, 

37 and do not appear in the correlation matrix ) 

38 

39 intercept slope 

40 

41 intercept 1 -1 

42 

43 slope -1 1 

44 

45 

46 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 69 of 73 

1 Parameter Estimates 

2 

3 Variable Estimate Std. Err. 

4 background 0 NA 

5 intercept -10.2513 3.55375 

6 slope 3.95309 1.32526 

7 

8 NA - Indicates that this parameter has hit a bound 

9 implied by some inequality constraint and thus 

10 has no standard error. 

11 

12 Analysis of Deviance Table 

13 

14 Model Log(likelihood) Deviance Test DF P-value 

15 Full model -16.7111 

16 Fitted model -19.5263 5.63053 3 0.131 

17 Reduced model -34.4972 35.5722 4 <.0001 

18 

19 AIC: 43.0527 

20 Goodness of Fit 

21 

22 Scaled 

23 Dose Est._Prob. Expected Observed Size Residual 

24 ------------------------------------------------------------------------ 

25 0.0000 0.0000 0.000 0 10 0 

26 12.6000 0.4070 4.070 4 10 -0.04492 

27 13.4000 0.5032 5.032 4 10 -0.6527 

28 16.7000 0.8101 8.101 10 10 1.531 

29 21.4000 0.9685 9.685 9 10 -1.239 

30 

31 Chi-square = 4.31 DF = 3 P-value = 0.2302 

32 

33 

34 Benchmark Dose Computation 

35 

36 Specified effect = 0.05 

37 

38 Risk Type = Extra risk 

39 

40 Confidence level = 0.95 

41 

42 BMD = 8.82098 

43 

44 BMDL = 5.01841 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 70 of 73 

0

0.2

0.4

0.6

0.8

1

0 5 10 15 20

Fraction Affected

dose

Probit Model with 0.95 Confidence Level

11:01 08/13 2009

BMDL BMD

 

Probit

1 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 71 of 73 

1 BMDS MODEL RUN Phosgene 1 hr 

2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

3 

4 The form of the probability function is: 

5 

6 P[response] = Background 

7 + (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), 

8 

9 where CumNorm(.) is the cumulative normal distribution function 

10 

11 

12 Dependent variable = COLUMN3 

13 Independent variable = COLUMN1 

14 Slope parameter is not restricted 

15 

16 Total number of observations = 4 

17 Total number of records with missing values = 0 

18 Maximum number of iterations = 250 

19 Relative Function Convergence has been set to: 1e-008 

20 Parameter Convergence has been set to: 1e-008 

21 

22 

23 

24 User has chosen the log transformed model 

25 

26 

27 Default Initial (and Specified) Parameter Values 

28 background = 0 

29 intercept = -8.66339 

30 slope = 4.25842 

31 

32 

33 Asymptotic Correlation Matrix of Parameter Estimates 

34 

35 ( *** The model parameter(s) -background 

36 have been estimated at a boundary point, or have been specified by the user, 

37 and do not appear in the correlation matrix ) 

38 

39 intercept slope 

40 

41 intercept 1 -1 

42 

43 slope -1 1 

44 

45 

46 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 72 of 73 

1 Parameter Estimates 

2 

3 Variable Estimate Std. Err. 

4 background 0 NA 

5 intercept -12.3592 4.62176 

6 slope 6.03934 2.18595 

7 

8 NA - Indicates that this parameter has hit a bound 

9 implied by some inequality constraint and thus 

10 has no standard error. 

11 

12 

13 

14 Analysis of Deviance Table 

15 

16 Model Log(likelihood) Deviance Test DF P-value 

17 Full model -9.98095 

18 Fitted model -10.0476 0.133401 2 0.9355 

19 Reduced model -27.2742 34.5865 3 <.0001 

20 

21 AIC: 24.0953 

22 

23 

24 Goodness of Fit 

25 

26 Scaled 

27 Dose Est._Prob. Expected Observed Size Residual 

28 ------------------------------------------------------------------------ 

29 0.0000 0.0000 0.000 0 10 0 

30 7.4000 0.3930 3.930 4 10 0.04559 

31 9.7000 0.9135 9.135 9 10 -0.1524 

32 11.8000 0.9946 9.946 10 10 0.2339 

33 

34 Chi-square = 0.08 DF = 2 P-value = 0.9608 

35 

36 

37 Benchmark Dose Computation 

38 Specified effect = 0.05 

39 Risk Type = Extra risk 

40 

41 Confidence level = 0.95 

42 

43 BMD = 5.89496 

44 

45 BMDL = 3.90643 
PHOSGENE DRAFT REVISED 1: 10/2009 

Page 73 of 73 

0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12

Fraction Affected

dose

Probit Model with 0.95 Confidence Level

11:09 08/13 2009

BMDL BMD

 

Probit

1 

2 

3