PHOSGENE OXIME Page 1 of 31 Proposed 06/2009 v.1 

1 

2 

3 

4 ACUTE EXPOSURE GUIDELINE LEVELS 

5 (AEGLs) 

6 

7 PROPOSED 

8 

9 

10 PHOSGENE OXIME 

11 (CAS Reg. No. 1794-86-1) 

12 

13 

14 

15 
PHOSGENE OXIME Page 2 of 31 Proposed 06/2009 v.1 

1 

2 PREFACE

3 

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

5 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous 

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

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

8 chemicals. 

9 

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

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

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

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

14 The three AEGLs are defined as follows: 

15 

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

cubic meter [ppm or mg/m3 17 ]) of a substance above which it is predicted that the general 

18 population, including susceptible individuals, could experience notable discomfort, irritation, or 

19 certain asymptomatic, non-sensory effects. However, the effects are not disabling and are 

20 transient and reversible upon cessation of exposure. 

21 

AEGL-2 is the airborne concentration (expressed as ppm or mg/m3 22 ) of a substance above 

23 which it is predicted that the general population, including susceptible individuals, could 

24 experience irreversible or other serious, long-lasting adverse health effects or an impaired ability 

25 to escape. 

26 

AEGL-3 is the airborne concentration (expressed as ppm or mg/m3 27 ) of a substance above 

28 which it is predicted that the general population, including susceptible individuals, could 

29 experience life-threatening health effects or death. 

30 

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

32 mild and progressively increasing but transient and nondisabling odor, taste, and sensory 

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

34 above each AEGL, there is a progressive increase in the likelihood of occurrence and the 

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

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

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

38 that individuals, subject to unique or idiosyncratic responses, could experience the effects 

39 described at concentrations below the corresponding AEGL. 

40 

41 
PHOSGENE OXIME Page 3 of 31 Proposed 06/2009 v.1 

1 TABLE OF CONTENTS 

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

3 LIST OF TABLES........................................................................................................................................5 

4 EXECUTIVE SUMMARY...........................................................................................................................6 

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

6 2. HUMAN TOXICITY DATA...............................................................................................................9 

7 2.1. Acute Lethality ............................................................................................................................9 

8 2.2 Nonlethal Toxicity.......................................................................................................................9 

9 2.3. Developmental/Reproductive Effects........................................................................................10 

10 2.4. Genotoxicity ..............................................................................................................................10 

11 2.5. Carcinogenicity..........................................................................................................................10 

12 2.6. Summary....................................................................................................................................10 

13 3. ANIMAL TOXICITY DATA............................................................................................................10 

14 3.1. Acute Lethality ..........................................................................................................................10 

15 3.1.1 Dogs ......................................................................................................................................10 

16 3.2. Nonlethal Toxicity.....................................................................................................................11 

17 3.2.1. Mice, Guinea Pigs, Rabbits...................................................................................................11 

18 3.3 Summary of Toxicity in Animals ..............................................................................................11 

19 3.4. Developmental/Reproductive Effects........................................................................................12 

20 3.5. Genotoxicity ..............................................................................................................................12 

21 3.6. Carcinogenicity..........................................................................................................................12 

22 4. SPECIAL CONSIDERATIONS ........................................................................................................12 

23 4.1. Metabolism and Disposition......................................................................................................12 

24 4.2. Mechanism of Toxicity..............................................................................................................12 

25 4.3. Structure-Activity Relationships ...............................................................................................13 

26 4.4. Other Relevant Information.......................................................................................................13 

27 4.4.1. Species Variability ................................................................................................................13 

28 4.4.2. Susceptible Populations ........................................................................................................13 

29 4.4.3. Concurrent Exposure Issues..................................................................................................13 
PHOSGENE OXIME Page 4 of 31 Proposed 06/2009 v.1 

1 5. DATA ANALYSIS FOR AEGL-1 ....................................................................................................13 

2 5.1. Human Data Relevant to AEGL-1.............................................................................................13 

3 5.2. Animal Data Relevant to AEGL-1 ............................................................................................13 

4 5.3. Derivation of AEGL-1 Values...................................................................................................14 

5 6. DATA ANALYSIS FOR AEGL-2 ....................................................................................................14 

6 6.1. Human Data Relevant to AEGL-2.............................................................................................14 

7 6.2. Animal Data Relevant to AEGL-2 ............................................................................................14 

8 6.3. Derivation of AEGL-2 Values...................................................................................................15 

9 7. DATA ANALYSIS FOR AEGL-3 ....................................................................................................15 

10 7.1. Human Data Relevant to AEGL-3.............................................................................................15 

11 7.2. Animal Data Relevant to AEGL-3 ............................................................................................15 

12 7.3. Derivation of AEGL-3 Values...................................................................................................15 

13 8. SUMMARY OF AEGLs....................................................................................................................16 

14 8.1. AEGL Values and Toxicity Endpoints......................................................................................16

15 8.2. Comparisons with Other Standards and Guidelines ..................................................................16 

16 8.3. Data Adequacy and Research Needs .........................................................................................16 

17 9. REFERENCES...................................................................................................................................17 

18 APPENDIX A: Derivation of AEGL Values..............................................................................................18 

19 APPENDIX B: Time Scaling Calculations.................................................................................................24 

20 APPENDIX C: Derivation Summary Tables..............................................................................................26 

21 APPENDIX D: Category Plot.....................................................................................................................30 
PHOSGENE OXIME Page 5 of 31 Proposed 06/2009 v.1 

1 LIST OF TABLES 

2 

S- 1. AEGL Values for phosgene oxime (mg/m3 3 ) .............................................................................7 

4 TABLE 1. Chemical and Physical Data for Phosgene 

5 Oxime.....................................................9 

6 TABLE 2. Summary of inhalation toxicity of phosgene oxime toxicity in animals.................................12 

7 TABLE 3. AEGL-1 values for phosgene oxime .......................................................................................14 

TABLE 4. AEGL-2 values for phosgene oxime (mg/m3 8 ).........................................................................15 

TABLE 5. AEGL-3 values for phosgene oxime (mg/m3 9 ).........................................................................16 

TABLE 6. AEGL values for phosgene oxime (mg/m3 10 ) ............................................................................16 

11 
PHOSGENE OXIME Page 6 of 31 Proposed 06/2009 v.1 

1 

2 EXECUTIVE SUMMARY 

3 

4 Phosgene oxime (CX) is an urticant or nettle agent causing instant intolerable pain, 

5 erythema, wheals and urticaria. It is very corrosive, capable of causing extensive tissue damage. 

6 Phosgene oxime was first produced by the Germans in 1929 as a possible warfare agent. The 

7 mechanism of action is not fully understood but the lesions produced in the skin are similar to 

8 those caused by a strong acid. Phosgene oxime will penetrate ordinary clothing and surgical 

9 gear. 

10 

11 Data regarding inhalation exposure of humans to phosgene oxime are limited to a 

controlled study with informed volunteers exposed for 1 minute (3 mg/m3 12 ) or 10 minutes (1 

mg/m3 13 ); the former resulting in unpleasant irritation of the nose, eyes and skin during exposure, 

14 and the latter resulting in immediate detection of compound but no notable effects (Malatesta et 

15 al., 1983). 

16 

17 Inhalation toxicity data in animals are also limited. Results of experiments in dogs 

18 showed high mortality rates following 30-minute exposures to phosgene oxime concentrations of 

1500-3000 mg/m3 19 . These studies also reported a latency period of up to three days between 

20 cessation of exposure and death. Exposure of mice, rabbits and guinea pigs for 30 minutes to 

100-500 mg phosgene oxime/m3 21 resulted in agitation, respiratory difficulty, and extreme 

22 lacrimation but no lethality. All of these reports lacked detail and provided no long-term follow23 up, gross pathology, or histopathology findings. 

24 

25 No information is available regarding metabolism and disposition, mechanism of action, 

26 reproductive/developmental toxicity, mutagenicity or carcinogenicity of phosgene oxime. 

27 

28 AEGL-1 values for phosgene oxime were based upon awareness of the chemical as 

29 determined by ocular, nasal and dermal sensations by volunteers exposed for 10 minutes to 1 

mg/m3 30 (Malatesta et al., 1983). This sensory perception was not considered to be disabling. The 

31 use of data obtained from exposures of informed human volunteers eliminates the animal-to32 human extrapolation concerns allowing an interspecies uncertainty factor of 1. Because the 

33 initial effects of phosgene oxime appear to be the result of direct-contact with exposed tissue 

34 (eyes, nasal mucosae, skin), an uncertainty factor of 3 was considered sufficient to account for 

35 possible individual variability. Metabolism and disposition processes would not be critical in 

36 such immediate responses. Rigorous empirical data regarding exposure concentration-duration 

37 relationship are not available for phosgene oxime, and more severe effects appear to occur with 

increasing concentration. Therefore, time scaling where n =1 in the relationship Cn 38 x t = k was 

39 applied to obtain AEGL values for time points greater that 10 minutes. A modifying factor of 2 

40 was applied in derivation of the AEGL-1 values to account for limited information on the 

41 inhalation toxicity of phosgene oxime as well as the lack of methodologic detail in the Malatesta 

42 et al. (1983) report. 

43 

44 AEGL-2 values were based upon the same point-of-departure (POD) used for deriving 

45 AEGL-1 values; irritation (ocular, dermal, nasal) in volunteers exposed to phosgene oxime at a 

concentration of 1 mg/m3 46 for 10 minute (Malatesta et al., 1983). No uncertainty factor for 

47 sensitive individuals was applied with the implication that the exposure may result in effects 

48 approaching AEGL-2 severity for these individuals. This approach was considered more 
PHOSGENE OXIME Page 7 of 31 Proposed 06/2009 v.1 

1 defensible than utilizing notable irritation reported by Malatesta et al. (1983) for volunteers 

exposed to 3 mg/m3 2 for only 1 minute. Data from volunteers precluded the need for an 

3 interspecies uncertainty factor greater than 1. As for AEGL-1 derivation, a modifying factor of 2 

4 was applied for overall data deficiencies as well as study deficiencies. Time scaling was applied 

as described for AEGL-1; Cn 5 x t = k, where n=1. 

6 

7 Lethality data for phosgene oxime were limited to animal studies reporting 100% 

8 lethality and were inappropriate for estimating a lethality threshold and derivation of AEGL-3 

values. In lieu of lethality data, the highest nonlethal exposure (500 mg/m3 9 for 30 minutes) 

10 reported by Malatesta et al. (1983) for mice, guinea pigs and rabbits was considered the POD for 

11 AEGL-3 derivation. Malatesta et al. (1983) observed agitation, respiratory difficulty, and 

12 intense lacrimation in these animals during the 30-minute exposure to phosgene oxime at 

concentrations of 100-500 mg/m3 13 . Total uncertainty factor application was 10. The uncertainty 

14 factor for interspecies extrapolation was limited to 3 because all of the species tested by 

15 Malatesta et al. (1983) exhibited a similar response. The uncertainty factor of 3 for individual 

16 variability was considered sufficient for direct-contact damage attributed to the actions of the 

17 parent molecule. A modifying factor of 2 was applied for data deficiencies (NRC, 2001). 

18 In the absence of an empirically derived exponent (n), temporal scaling from the 30-minute 

19 experimental duration to AEGL-specific durations was performed using n = 3 when 

20 extrapolating to shorter time points and n = 1 when extrapolating to longer time points using the 

Cn 21 x t = k equation (NRC, 2001). 

22 

23 The AEGL values for phosgene oxime are summarized in Table S-1. 

24 

S- 1. AEGL Values for phosgene oxime expressed as mg/m3 [ppm] 

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

AEGL-1 

(Nondisabling) 

0.17 

[0.036] 

0.056 

[0.012] 

0.028 

[0.0059] 

0.0069 

[0.0014] 

0.0035 

[0.00074] 

Awareness (ocular, 

nasal, dermal sensation) 

by human volunteers; 1 

mg/m3

 for 10 min.; 

UF=1 x 3; MF=2; n=1 

(Malatesta et al., 1983) 

AEGL-2 

(Disabling) 

0.50 

[0.011] 

0.17 

[0.036] 

0.083 

[0.017] 

0.021 

[0.0044] 

0.010 

[0.0021] 

Awareness (ocular, 

nasal, dermal 

sensation) by human 

volunteers; 1 mg/m3

 for 

10 min.; UF=1 x 1; 

 MF=2; n=1 (Malatesta 

 et al., 1983) 

AEGL-3 

(Lethality) 

36 

[7.6] 

25 

[5.3] 

13 

[2.7] 

3.1 

[0.65] 

1.6 

[0.34]

Highest nonlethal 

exposure in animals 

(500 mg/m3 for 30 min.; 

UF= 3 x 3; MF=2; n=1 

or 3 (Malatesta et al., 

1983) 

25 

26 

27 References 

28 

29 Malatesta, P., B. Bianchi and C. Malatesta. 1983. Contributo allo studio delle sostanze orticanti: Nota 1. 

30 Boll. Chim. Farm 122: 96-103. (Translated from Italian) 
PHOSGENE OXIME Page 8 of 31 Proposed 06/2009 v.1 

1 1. INTRODUCTION

2 

3 Phosgene oxime (CX) is an urticant or nettle agent causing instant intolerable pain, 

4 erythema, wheals and urticaria (USACHPPM, 1996). Due to its corrosive properties, damage to 

5 tissue is extensive. Phosgene oxime was first produced by the Germans in 1929 as a possible 

6 warfare agent. The precise mechanism of action is not fully understood but the lesions produced 

7 in the skin are similar to those made by a strong acid. Phosgene oxime penetrates ordinary 

8 clothing and surgical gear. The physical/chemical properties of phosgene oxime are summarized 

9 in Table 1. 

10 

11 

TABLE 1. Chemical and Physical Data for Phosgene Oxime 

Parameter Value Reference 

Synonyms CX; dichloroformoxime Sidell et al., 1997 

Chemical formula CHCl2NOH Sidell et al., 1997 

Molecular weight 113.9 USACHPPM, 1996 

CAS Registry No. 1794-86-1 

Physical state Colorless solid; yellowish-brown in liquid form 

Solid form can sublime 

Sidell et al., 1997 

Solubility in water 70% in water and very soluble in most organic solvents Sidell et al., 1997 

Vapor pressure 11.2 mm Hg at 25°C (solid) 

13 mm Hg at 40°C (liquid) 

Sidell et al., 1997 

Density <3.9 Sidell et al., 1997 

Boiling point/Freezing 

point 

53-54 °C/35- 40 °C USACHPPM, 1996 

Conversion factors in air 1 ppm = 4.66 mg/m3 

1 mg/m3 = 0.21 ppm 

12 

13 

14 2. HUMAN TOXICITY DATA 

15 2.1. Acute Lethality 

16 

 An estimated LCt50 of 3200 mg•min/m3 17 (based upon a 10-minute exposure) for phosgene 

18 oxime vapor has been reported by the U.S. Army (2005). 

19 

20 2.2 Nonlethal Toxicity 

21 

22 Phosgene oxime has been described as having a disagreeable, intensely irritating odor 

23 (Sidell et al., 1997). The U.S. Armed Forces (U.S. Army, 2005) report a provisional odor 

detection ECt50 of 1 mg•min/m3 24 (10 minutes). A provisional inhalation exposure value of 3 

mg•min/m3 25 for 1 minute was considered an incapacitating/intolerable exposure (U.S. Army, 

26 2005). 

27 

28 Malatesta et al. (1983) conducted a study in which six informed adults, including the 

29 investigators, were exposed to phosgene oxime. The exposure chamber was described as a 

30 hermetically sealed room (with precisely calculated capacity) that was equipped with a fan to 

31 enhance homogeneity of the test atmosphere. Phosgene oxime was introduced by high-pressure 

32 (200 atm) nebulization using gas cylinders and stainless steel cylinders. Methods for 

33 determination of exposure concentrations were not specified. A “threshold of physiologic 

sensitivity” of 1 mg/m3 34 (0.21 ppm) was reported which was also the minimal concentration 
PHOSGENE OXIME Page 9 of 31 Proposed 06/2009 v.1 

1 achieved in the closed environment over a 10-minute period. The physiological response 

2 apparently referred to awareness of the chemical by ocular sensitivity, taste, and odor. The 

author also reported a “threshold of pathologic sensitivity” of ~3 mg/m3 3 (0.63 ppm). This value 

4 was defined as the minimal concentration causing an unpleasant or irritating sensation on the 

5 conjunctiva, nose (assumed to refer to nasal passage surfaces), or intact skin after one minute of 

6 exposure. 

7 

8 2.3. Developmental/Reproductive Effects 

9 

10 Data on potential developmental/reproductive toxicity of phosgene oxime in humans 

11 were not available. 

12 

13 2.4. Genotoxicity 

14 

15 No information regarding potential genotoxicity of phosgene oxime in humans was 

16 available. 

17 

18 2.5. Carcinogenicity 

19 

20 No information regarding the carcinogenic potential of phosgene oxime in humans was 

21 available. 

22 

23 2.6. Summary

24 

25 No information regarding inhalation toxicity of phosgene oxime in humans was 

26 available. 

27 

28 3. ANIMAL TOXICITY DATA 

29 3.1. Acute Lethality 

30 3.1.1 Dogs

31 

32 In a Bulgarian study, dogs (breed, number, and sex not provided) were exposed to 1.5-3 

mg phosgene oxime/L air (1500-3000 mg/m3 33 ) for 30 minutes (Balev and Andreev, 1957). 

34 Cage-side observations included: general behavior, weight, body temperature, blood (no further 

35 details), pulse (rhythm, frequency and “fullness”), respiration (frequency, rhythm and 

36 “deepness”), and urination. Assessments were performed at pre-exposure, every 10-15 minutes 

37 during the 3-4 hours following exposure, and once daily until the animals died. Dogs in the 

38 study held their breath upon entering the chamber after which respiration became rapid and 

39 shallow. Animals appeared distressed and exhibited frequent movement. Increased lacrimation, 

40 salivation and coughing were observed. The oral mucosae and the skin turned red and, later 

41 during the exposure, became violet. Upon removal from the chamber, the dogs remained 

42 agitated and continuously rubbed their eyes. At a later (unspecified) time, the dogs became 

43 calmer, exhibited more normal coloration of the oral mucosae, and resumed normal breathing 

44 for 30 minutes to 24 hours (rarely), after which their condition deteriorated. This second phase 

45 was characterized by increased pulse, increased respiration, foaming of the mouth, cyanosis, and 

46 death 2-3 days post-exposure. Based upon these findings, the investigators defined three main 

47 stages of phosgene oxime toxicity: reflective, latent and manifest. These same stages were 

48 observed after phosgene oxime was administered intravenously at 10 mg/kg bw. 
PHOSGENE OXIME Page 10 of 31 Proposed 06/2009 v.1 

1 

2 Two dogs/treatment group (breed, age, and gender not specified) were exposed to 1.5-2.0 

3 mg phosgene oxime/L of air for 30 minutes in four treatment groups (Tschanatschev and 

4 Dronzin, 1957). In each of the four groups, one dog was administered a pre-exposure treatment 

5 to assess the effects on phosgene oxime-induced toxicity, while an untreated dog was exposed to 

6 phosgene oxime (designated as “control” in the study report). The treatment protocols included 

7 using a combination of Novacain neck blocks, calcium, glucose, Vitamin K and oxygen. 

8 Animals were placed in a dynamic flow chamber. No further detail was provided. Prior to and 

9 during the exposure, the dogs were monitored for body temperature, pulse, respiratory 

10 rate/pattern, blood chemistry and general behavior. Once exposures started, all dogs 

11 demonstrated anxiety, lacrimation, salivation, moving or shaking the head, coughing and 

12 increased respiration. Out of all four groups, only 1 of 8 dogs survived. The dog was treated 

13 with a vagosympathetic neck block using novacaine, a 2% sodium bicarbonate solution rinse in 

14 the eyes, oxygen, Cardiazol/Lobelin, calcium chloratum, Vitamin K, glucose supplementation 

15 and a tannic acid enema after exposure. The “control dog” exposed in this scenario died 10 

16 hours post-exposure. The study demonstrated that aggressive supportive care post-exposure to 

17 phosgene oxime, possibly in combination with the pre-exposure treatment, could prevent 

18 mortality at this concentration. 

19 

20 3.2. Nonlethal Toxicity 

21 3.2.1. Mice, Guinea Pigs, Rabbits 

22 

23 In a study by Malatesta et al. (1983), mice, guinea pigs and rabbits (number of animals, 

24 species and gender were not provided) were exposed by inhalation to phosgene oxime at 

concentrations of 100 to 500 mg/m3 25 (only the range was provided). The experiments were 

26 conducted with an aqueous solution of phosgene oxime which was nebulized at 200 atm. using 

27 gas cylinders and stainless steel sprayers. The experiments were carried out in a tightly closed 

28 room with a precisely calculated capacity. Homogeneity of the test atmosphere was attempted 

29 using fans, although actual concentration and homogeneity of the vapor within the chamber were 

30 not confirmed analytically. No further details were provided. No deaths occurred at any 

31 concentration. Agitation, respiratory difficulty, and intense lacrimation during exposure were 

32 reported. No signs of phosgene oxime toxicity were observed in any animals at 3 days following 

33 exposure. 

34 

35 3.3 Summary of Toxicity in Animals

36 

37 The limited inhalation toxicity data for phosgene oxime in animals is summarized in 

38 Table 2. 

39 
PHOSGENE OXIME Page 11 of 31 Proposed 06/2009 v.1 

1 

TABLE 2. Summary of inhalation toxicity of phosgene oxime in animals 

Concentration 

Exposure 

Duration Species Effect Reference 

100-500 mg/m3 30 min. Mice, guinea 

pigs, rabbits 

All concentrations: no deaths; 

lacrimation, agitation and respiratory 

difficulty resolved by day 3 postexposure 

Malatesta et al., 1983 

1.5- 2.0 mg/L 

(1,500-2,000 mg/m3

) 

30 min. Dogs (n =8) 7 of 8 dogs died; survivor received 

intensive support therapy 

Tschanatschev and 

Dronzin, 1957 

1.5-3 mg/L 

(1,500-3,000 mg/m3

) 

30 min. Dogs 100% lethality Balev and Andreev, 

1957 

2 

3 

4 3.4. Developmental/Reproductive Effects 

5 

6 No information is available in the open literature regarding potential developmental and 

7 reproductive toxicity of phosgene oxime following inhalation exposure. 

8 

9 3.5. Genotoxicity 

10 

11 Information regarding the potential genotoxicity of phosgene oxime following inhalation 

12 exposure is not available. 

13 

14 3.6. Carcinogenicity 

15 

16 Information regarding the potential carcinogenicity of phosgene oxime following 

17 inhalation exposure is not available. 

18 

19 4. SPECIAL CONSIDERATIONS 

20 4.1. Metabolism and Disposition 

21 

22 There are no data regarding the metabolism and disposition of phosgene oxime.

23 

24 4.2. Mechanism of Toxicity 

25 

26 The mechanism of phosgene oxime toxicity is unknown. Damage is often instantaneous 

27 and may be the result of the necrotizing effects of the chlorine, direct effect of the oxime, or 

28 associated with the carbonyl group (Sidell et al., 1997). The tissue damage is very similar to that 

29 caused by a concentrated mineral acid. Within 5-30 minutes of exposure, edema develops at the 

30 initial site of contact and the tissues become necrotic. Over the course of 24 hours, the edema 

31 regresses and the blanched area becomes pigmented with an eschar forming over the next 7 days. 

32 In some cases, healing may require more than 6 months. Ocular exposure results in pain, 

33 conjunctivitis, and keratitis. Phosgene oxime appears to affect the first capillary bed 

34 encountered. With the exception of supportive care, there is no antidote or recommended 

35 therapeutic regimen once exposure has occurred. 

36 
PHOSGENE OXIME Page 12 of 31 Proposed 06/2009 v.1 

1 4.3. Structure-Activity Relationships 

2 

3 There are no data with which to assess structure-activity relationships with respect to 

4 development of AEGL values. There is no evidence that phosgene is involved in the toxicity of 

5 phosgene oxime. 

6 

7 4.4. Other Relevant Information 

8 4.4.1. Species Variability 

9 

10 Because the most significant and immediate effects of acute exposure to phosgene oxime 

11 are the result of direct-contact with ocular and respiratory tract tissue, variability across species 

12 is expected to be limited. These tissues represent the most sensitive targets for phosgene oxime 

13 vapor exposure. 

14 

15 4.4.2. Susceptible Populations 

16 

17 Phosgene oxime toxicity occurs after direct contact with the skin, eyes or respiratory 

18 tract, which would not vary between healthy individuals. However, those with compromised 

19 respiratory function such as asthma or COPD experience more severe responses to phosgene 

20 oxime exposure than otherwise healthy people. As the vapor is heavier than air, phosgene oxime 

21 can accumulate in low-lying areas and enclosed spaces. 

22 

23 4.4.3. Concurrent Exposure Issues 

24 

25 Concurrent exposure to other irritant chemicals affecting the eyes or respiratory tract may 

26 be of concern regarding exposure to phosgene oxime. No data are available with which to 

27 quantify such exposure with respect to development of AEGL values for phosgene oxime. 

28 

29 5. DATA ANALYSIS FOR AEGL-1 

30 5.1. Human Data Relevant to AEGL-1 

31 

32 Data regarding AEGL-1 tier effects in humans following vapor exposure to phosgene 

33 oxime are limited. 

34 

35 Malatesta et al. (1983) conducted a study in which six informed volunteers, including the 

investigator, were exposed to phosgene oxime. A concentration of 1 mg/m3 36 (0.21 ppm) was 

37 considered the “threshold of physiologic sensitivity”; this was also the minimal concentration 

38 achieved in the closed environment over a 10-minute period. Higher concentrations resulted in 

the identification/characterization of a “threshold of pathologic sensitivity” of ~3 mg/m3 39 (0.63 

40 ppm). This was defined as the minimal concentration causing an unpleasant or irritating 

41 sensation on the conjunctiva, nose, or skin after one minute of exposure. 

42 

43 5.2. Animal Data Relevant to AEGL-1 

44 

45 The responses of mice, guinea pigs, and rabbits described by Malatesta et al. (1983) 

46 included agitation, respiratory difficulty, and intense lacrimation, all of which are of greater 

47 severity than that consistent with the AEGL-1 definition. 

48 
PHOSGENE OXIME Page 13 of 31 Proposed 06/2009 v.1 

1 5.3. Derivation of AEGL-1 Values 

2 

3 The most appropriate data for derivation of AEGL-1 values for phosgene oxime are the 

4 responses of the human volunteers exposed for 10 minutes to phosgene oxime at a concentration 

of 1 mg/m3 5 (Malatesta et al., 1983). The physiological responses (awareness based upon ocular, 

nasal and dermal responses) over a 10-minute exposure to 1 mg/m3 6 were considered an 

7 appropriate point-of-departure (POD) and the critical endpoint for AEGL-1 development. 

8 Although deficient in details regarding the analysis of the test atmosphere these findings provide 

9 the only information regarding exposure-response data for AEGL-1 tier effects following acute 

10 inhalation exposure to phosgene oxime. Further, the information comes from humans, thereby 

11 eliminating the need for animal-to-human extrapolation. Because the initial effects of phosgene 

12 oxime result from direct-contact with exposed tissues (eyes, nasal mucosae, skin), an uncertainty 

13 factor of 3 to account for possible individual variability is appropriate. Metabolism and 

14 disposition processes would not be critical in such responses. 

15 

16 Because rigorous empirical data regarding exposure concentration-duration relationship 

17 were not available for phosgene oxime, and because more severe effects appear to occur with 

increasing concentration, time scaling (where n =1 in the relationship Cn 18 x t = k) was applied to 

19 obtain AEGL values for time points greater than 10 minutes (NRC, 2001). A modifying factor 

20 of 2 has also been applied in the derivation of the AEGL-1 values to account for limited 

21 information on the inhalation toxicity of phosgene oxime as well as the recognized deficiencies 

22 in the Malatesta et al. (1983) report. The AEGL-1 values for phosgene oxime are presented in 

23 Table 3 and the derivation summarized in Appendices A and C. 

24 

TABLE 3. AEGL-1 values for phosgene oxime

Classification 10-min 30-min 1-h 4-h 8-h 

AEGL-1 0.17 mg/m3 

0.036 ppm 

0.056 mg/m3

0.012 ppm 

0.028 mg/m3

0.0059 ppm 

0.0069 mg/m3

0.0014 ppm 

0.0035 mg/m3

0.00074 ppm 

25 

26 

27 6. DATA ANALYSIS FOR AEGL-2

28 6.1. Human Data Relevant to AEGL-2 

29 

30 In a study using six informed volunteers, Malatesta et al. (1983) reported that a 1-minute 

exposure to phosgene oxime at 3 mg/m3 31 resulted in unpleasant or irritating sensations in the eyes 

32 (conjunctiva), nose (assumedly nasal epithelium), and skin (termed threshold of pathologic 

33 sensitivity by the investigators). The U.S. Army (2005) reported a provisional inhalation 

exposure value of 3 mg•min/m3 34 (derived based upon 1-minute exposure duration) which was 

35 considered incapacitating/intolerable, but the U.S. Army assessment appears to have been based 

36 upon the Malatesta et al. (1983) study. 

37 

38 6.2. Animal Data Relevant to AEGL-2 

39 

40 Mice guinea pigs and rabbits exposed to phosgene oxime at concentrations of 100 to 500 

mg/m3 41 (21 to 105 ppm) for 30 minutes displayed agitation, respiratory difficulty, and intense 

42 lacrimation during exposure (Malatesta et al., 1983). Although these changes occurred during 

43 exposure and resolved within 3 days following cessation of exposure, no gross pathology or 

44 histopathology findings were reported. 
PHOSGENE OXIME Page 14 of 31 Proposed 06/2009 v.1 

1 

2 6.3. Derivation of AEGL-2 Values 

3 

4 AEGL-2 values were based upon the same point-of-departure (POD) used for deriving 

5 AEGL-1 values; irritation (ocular, dermal, nasal) in volunteers exposed to phosgene oxime at a 

concentration of 1 mg/m3 6 for 10 minutes (Malatesta et al., 1983). No uncertainty factor for 

7 sensitive individuals was applied with the implication that the exposure may result in effects 

8 approaching AEGL-2 severity for these individuals. This approach was considered more 

9 defensible than utilizing notable irritation reported by Malatesta et al. (1983) for volunteers 

exposed to 3 mg/m3 10 for only 1 minute. Data from human volunteers precluded the need for an 

11 interspecies uncertainty factor greater than 1. As for AEGL-1 derivation, a modifying factor of 2 

12 was applied for overall data deficiencies as well as study deficiencies. Time scaling was applied 

as described for AEGL-1; Cn 13 x t = k, where n=1. 

14 

15 The AEGL-2 values for phosgene oxime are presented in Table 4 and the derivation 

16 summarized in Appendices A and C. 

17 

TABLE 4. AEGL-2 values for phosgene oxime

Classification 10-min 30-min 1-h 4-h 8-h 

AEGL-2 0.50 mg/m3

0.011 ppm 

0.17 mg/m3

0.036 ppm 

0.083 mg/m3

0.017 ppm 

0.021 mg/m3

0.0044 ppm 

0.010 mg/m3

0.0021 ppm 

18 

19 

20 7. DATA ANALYSIS FOR AEGL-3

21 7.1. Human Data Relevant to AEGL-3 

22 

23 No human data were available for derivation of AEGL-3 values for phosgene oxime. 

24 

25 7.2. Animal Data Relevant to AEGL-3 

26 

27 Animal lethality data were limited to two studies in dogs (Balev and Andreev, 1957; 

28 Tschanatschev and Dronzin, 1957) that used very high exposure concentrations (1500-300 

mg/m3 29 ) for exposure durations of 30 minutes. These exposures caused death. The study reports 

30 provided no data with which to empirically determine a lethality threshold 

31 

32 

33 7.3. Derivation of AEGL-3 Values 

34 

35 Lethality data for phosgene oxime were limited to animal studies reporting 100% 

lethality. In lieu of lethality data, the highest nonlethal exposure (500 mg/m3 36 for 30 minutes) 

37 reported by Malatesta et al. (1983) for mice, guinea pigs and rabbits was considered the POD for 

38 AEGL-3 derivation. Malatesta et al. (1983) observed agitation, respiratory difficulty, and 

39 intense lacrimation in these animals during the 30-minute exposure to phosgene oxime at 

concentrations of 100-500 mg/m3 40 . In the absence of an empirically derived exponent (n), 

41 temporal scaling from the 30-minute experimental duration to AEGL-specific durations was 

42 performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to 

longer time points using the Cn 43 x t = k equation (NRC, 2001). Total uncertainty factor 

44 application was 10. The uncertainty factor for interspecies extrapolation was limited to 3 
PHOSGENE OXIME Page 15 of 31 Proposed 06/2009 v.1 

1 because all of the species tested by Malatesta et al. (1983) exhibited a similar response. The 

2 uncertainty factor of 3 for individual variability was considered sufficient for direct-contact 

3 damage attributed to the actions of the parent molecule. A modifying factor of 2 was applied for 

4 data deficiencies (NRC, 2001). 

5 

6 The AEGL-3 values for phosgene oxime are presented in Table 5 and the derivation 

7 summarized in Appendices A and C. 

8 

9 

TABLE 5. AEGL-3 values for phosgene oxime 

Classification 10-min 30-min 1-h 4-h 8-h 

AEGL-3 36 mg/m3 

7.6 ppm 

25 mg/m3

5.3 ppm 

13 mg/m3

2.7 ppm 

3.1 mg/m3

0.65 ppm 

1.6 mg/m3

0.34 ppm 

10 

11 

12 8. SUMMARY OF AEGLs

13 8.1. AEGL Values and Toxicity Endpoints 

14 

15 Information regarding the toxicity of phosgene oxime following inhalation exposure is 

16 limited. A single study using informed volunteers provided data for very short exposure 

17 durations. These data were sufficient for deriving AEGL-1 and AEGL-2 values based upon the 

18 potent irritant effects of phosgene oxime. No data were available for empirical determination of 

19 a lethality threshold. AEGL-3 values were developed based upon the highest nonlethal 

20 concentration in several laboratory species. The AEGL values for phosgene oxime are 

21 summarized in Table 6. 

22 

TABLE 6. AEGL values for phosgene oxime expressed as mg/m3 [ppm]

Classification 10-min 30-min 1-h 4-h 8-h 

AEGL-1 

(Nondisabling) 

0.17 

[0.036] 

0.056 

 [0.012] 

0.028 

[0.0059] 

0.0069 

[0.0014] 

0.0035 

[0.00074] 

AEGL-2 

(Disabling) 

0.50 

[0.011] 

0.17 

[0.036] 

0.083 

[0.017] 

0.021 

[0.0044] 

0.010 

[0.0021] 

AEGL-3 

(Lethality) 

36 

[7.6] 

25 

[5.3] 

13 

[2.7] 

3.1 

[0.65] 

1.6 

[0.34]

23 

24 

25 8.2. Comparisons with Other Standards and Guidelines 

26 

27 There are no standards or guideline values for phosgene oxime. 

28 

29 8.3. Data Adequacy and Research Needs 

30 

31 Inhalation toxicity data for phosgene oxime are extremely limited. Additional studies 

32 examining low level exposure for longer exposure durations as well as data allowing for 

33 estimation of a lethality threshold are required for a more definitive assessment. At the present 

34 time, no empirical data regarding the exposure concentration-time relationship for phosgene 

35 oxime are available. 

36 

37 
PHOSGENE OXIME Page 16 of 31 Proposed 06/2009 v.1 

1 9. REFERENCES

2 

3 Balev, P. and T. Andreev. 1957. [Clinics of the intoxication with phosgene oxime]. Nauchni Tr Vissh 

4 Med Inst Sofiia 4 (4):77-98. (Translated from Bulgarian) 

5 

6 CDC (Centers for Disease Control). 2003. Phosgene oxime. Dept. of Health and Human Services, Centers 

7 for Disease Control and Prevention. Found online at http://www.bt.cdc.gov/agent/phosgene8 oxime/index.asp. 

9 

10 Haber, F.R. 1924. Zur geschichte des gaskrieges [On the history of the gas war]. In: Fuenf Vortraege aus 

11 den Jahren 1920-23 [Five lectures from the years 1920-1923]. Berlin, Germany: Verlag von 

12 Julius Springer; pp. 76-92. 

13 

14 Malatesta, P., B. Bianchi and C. Malatesta. 1983. Contributo allo studio delle sostanze orticanti 

15 [Contributions to the study of oro-nasal irritants]: Nota 1. Boll. Chim. Farm 122: 96-103. 

16 (Translated from Italian) 

17 

18 NRC (National Research Council). 2001. Standing operating procedures for developing acute exposure 

19 guideline levels for hazardous chemicals. Committee on Toxicology, Board on Toxicology and 

20 Environmental Health Hazards, Commission on Life Sciences, National Research Council. 

21 National Academy Press, Washington, DC. 

22 Rinehart, W. E. and Hatch, T. 1964. Concentration-time product (CT) as an expression of dose in sublethal 

23 exposures to phosgene. Ind. Hyg. J. 25: 545-553. 

24 

25 Sidell, F.R., E.T. Takafuji, and D.R. Franz (editors). 1997. Medical aspects of chemical and biological 

26 warfare. Part 1. Textbook of Military Medicine. TMM Publications, Borden Institute, 

27 Washington D.C. p. 199 and 220-222. 

28 

29 ten Berge, W.F., Zwart, A., Appelman, L.M. 1986. Concentration-time mortality response relationship 

30 of irritant and systemically acting vapours and gases. J. Hazard. Materials 13: 301-309. 

31 Tschanatschev, I.S. and T.D. Dronzin. 1957. [Experimental therapy of poisoning with phosgene oxime 

32 through inhalation]. Nauchni Tr Vissh Med Inst Sofiia 4(4):111-114. (Translated from Bulgarian) 

33 

34 USACHPPM (United States Army Center for Health Promotion and Preventive Medicine). 1996. 

35 Detailed and General Facts About Chemical Agents – TG 218. USACHPPM, Aberdeen Proving 

36 ground, MD. 

37 

38 U.S. Army. 2005. Potential Military Chemical/Biological Agents and Compounds. 

39 Online at www.us.army.mil. 

40 
PHOSGENE OXIME Page 17 of 31 Proposed 06/2009 v.1 

1 

2 

3 

4 

5 

6 

7 

8 

9 APPENDIX A: Derivation of AEGL Values 
PHOSGENE OXIME Page 18 of 31 Proposed 06/2009 v.1 

1 Derivation of AEGL-1 Values for Phosgene Oxime 

2 Key Study: Malatesta, P., B. Bianchi and C. Malatesta. 1983. Contributo allo studio 

3 delle sostanze orticanti [Contributions to the study of oro-nasal irritants]: 

4 Nota 1. Boll. Chim. Farm 122: 96-103. (Translated from Italian) 

5 

6 Critical effect: Awareness of chemical by ocular, nasal, and dermal sensation following 

7 10-minute exposure of 6 informed human volunteers to 1 mg phosgene 

oxime/m3 8 

9 

Time scaling: Time scaling using Cn 10 x t = k, where n = 1 for extrapolating from the 10-

11 minute experimental exposure duration to AEGL-specific exposure 

12 durations (NRC, 2001). 

13 

14 Uncertainty factors: Total uncertainty factor 3. 

15 Interspecies: 1; informed volunteers 

16 

17 Intraspecies: 3; direct contact irritant (ocular, nasal, dermal contact) requiring no 

18 metabolism/disposition processes; initial awareness of this 

19 urticant/nettle agent is not expected to vary among individuals 

20 

21 Modifying Factor: 2; overall data set for phosgene oxime inhalation toxicity is limited; 

22 available studies lack analytical exposure terms; animal studies lack 

23 adequate post exposure follow-up, gross necropsy and histopathology 

24 findings 

25 

Calculation: 1 mg/m3 x 10 min = 10 mg·min/m3 26 

27 

10-min AEGL-1 C mg/m3 x 10 min. = 10 mg·min/m3 28 

 C = 1 mg/m3 29 

 (1 mg/m3

)/6 = 0.17 mg/m3 30 

31 

30-min AEGL-1 C mg/m3

 x 30 min. = 10 mg·min/m3 32 

 C = 0.33 mg/m3 33 

 (0.33 mg/m3)/6 = 0.056 mg/m3 34 

35 

1-hr AEGL-1 C mg/m3

 x 60 min. = 10 mg·min/m3 36 

 C = 0.167 mg/m3 37 

 (0.167 mg/m3

)/6 = 0.028 mg/m3 38 

39 

4-hr AEGL-1 C mg/m3

 x 240 min. = 10 mg·min/m3 40 

 C = 0.0416 mg/m3 41 

 (0.0416 mg/m3

)/6 = 0.0069 mg/m3 42 

43 

8-hr AEGL-1 C mg/m3

 x 480 min. = 10 mg·min/m3 44 

 C = 0.0208 mg/m3 45 

 (0.0208 mg/m3

)/6 = 0.0035 mg/m3 46 
PHOSGENE OXIME Page 19 of 31 Proposed 06/2009 v.1 

1 Derivation of AEGL-2 Values for Phosgene Oxime 

2 

3 Key Study: Malatesta, P., B. Bianchi and C. Malatesta. 1983. Contributo allo studio 

4 delle sostanze orticanti [Contributions to the study of oro-nasal irritants]: 

5 Nota 1. Boll. Chim. Farm 122: 96-103. (Translated from Italian) 

6 

7 Critical effect: Awareness of chemical by ocular, nasal, and dermal sensation following 

8 10-minute exposure of 6 informed human volunteers to 1 mg phosgene 

oxime/m3 9 . 

10 

Time scaling: Time scaling using Cn 11 x t = k, where n = 1 for extrapolating from the 

12 10-minute experimental exposure duration to AEGL-specific exposure 

13 durations (NRC, 2001). 

14 

15 Uncertainty factors: Total uncertainty factor: 1 

16 

17 Interspecies: 1; informed human volunteers 

18 

19 Intraspecies: 1; no uncertainty factor for sensitive individuals was applied with the 

implication that the 10-min. exposure to 1 mg/m3 20 would result in effects 

21 approaching AEGL-2 severity for these individuals. This approach was 

22 considered more defensible than utilizing notable irritation reported by 

Malatesta et al. (1983) for volunteers exposed to 3 mg/m3 23 for only 1 

24 minute. 

25 

26 Modifying Factor: 2; overall data set for phosgene oxime inhalation toxicity is limited; 

27 available studies lack analytical exposure terms; animal studies lack 

28 adequate post exposure follow-up, gross necropsy and histopathology 

29 findings 

30 

Calculation: 1 mg/m3 x 10 min = 10 mg·mg/m3 31 

32 

33 

10-min AEGL-2 C mg/m3

 x 10 min. = 10 mg·min/m3 34 

 C = 1 mg/m3 35 

 (1 mg/m3

)/2 = 0.50 mg/m3 36 

37 

38 

30-min AEGL-2 C mg/m3

 x 30 min. = 10 mg·min/m3 39 

 C = 0.33 mg/m3 40 

 (0.33 mg/m3

)/2 = 0.17 mg/m3 41 

42 

43 

1-hr AEGL-2 C mg/m3

 x 60 min. = 10 mg·min/m3 44 

 C = 0.167 mg/m3 45 

 (0.167 mg/m3

)/2 = 0.083 mg/m3 46 

47 

48 
PHOSGENE OXIME Page 20 of 31 Proposed 06/2009 v.1 

4-hr AEGL-2 C mg/m3 x 240 min. = 10 mg·min/m3 1 

 C = 0.0416 mg/m3 2 

 (0.0416 mg/m3)/2 = 0.021 mg/m3 3 

4 

5 

8-hr AEGL-2 C mg/m3 x 480 min. = 10 mg·min/m3 6 

 C = 0.0208 mg/m3 7 

 (0.0208 mg/m3

)/2 = 0.010 mg/m3 8 

9 
PHOSGENE OXIME Page 21 of 31 Proposed 06/2009 v.1 

1 

2 Derivation of AEGL-3 Values for Phosgene Oxime

3 

4 Key Study: Malatesta, P., B. Bianchi and C. Malatesta. 1983. Contributo allo studio 

5 delle sostanze orticanti: Nota 1. Boll. Chim. Farm 122: 96-103. 

6 (Translated from Italian) 

7 

Critical effect: 30-minute exposure to 500 mg/m3 8 was the highest nonlethal exposure for 

9 mice guinea pigs and rabbits; responses included lacrimation, agitation 

10 and respiratory difficulty which resolved by day 3 post-exposure 

11 

Time scaling: Time scaling using Cn 12 x t = k, where n = 1 for extrapolating from the 

13 10-minute experimental exposure duration to longer AEGL-specific 

14 exposure durations and n = 3 for extrapolating to the 10-min AEGL 

15 duration (NRC, 2001). 

16 

17 Uncertainty factors: Total uncertainty factor: 10 

18 

19 Interspecies: 3; all three test species exhibited the same signs of toxicity 

20 

21 Intraspecies: 3; direct contact irritant (ocular, nasal, dermal contact) requiring no 

22 metabolism/disposition processes; effects are due to interaction of parent 

23 molecule with any tissues. 

24 

25 Modifying Factor: 2; overall data set for phosgene oxime inhalation toxicity is limited; 

26 available studies lack analytical exposure terms; animal studies lack 

27 adequate post exposure follow-up, gross necropsy and histopathology 

28 findings 

29 

Calculation: 500 mg/m3

 x 0.5 hr = 250 mg·hr/m3 30 

(500 mg/m3

)

3

 x 0.5 hr min = 62,500,000 mg·hr/m3 31 

32 

33 

10-min AEGL-3 (C mg/m3

)

3

 x 0.1667 hr = 62,500,000 mg·hr/m3 34 

 C = 721 mg/m3 35 

 (721 mg/m3

)/20 = 36 mg/m3 36 

37 

38 

30-min AEGL-3 C mg/m3

 x 0.5 hr = 250 mg·hr/m3 39 

 C = 500 mg/m3 40 

 (500 mg/m3

)/20 = 25 mg/m3 41 

42 

43 

1-hr AEGL-3 C mg/m3

 x 1 hr = 250 mg·hr/m3 44 

 C = 250 mg/m3 45 

 (250 mg/m3

)/20 = 13 mg/m3 46 

47 

48 
PHOSGENE OXIME Page 22 of 31 Proposed 06/2009 v.1 

4-hr AEGL-3 C mg/m3 x 4 hrs = 250 mg·hr/m3 1 

 C = 62.5 mg/m3 2 

 (62.5 mg/m3)/20 = 3.1 mg/m3 3 

4 

5 

8-hr AEGL-3 C mg/m3 x 8 hrs = 250 mg·min/m3 6 

 C = 31.25 mg/m3 7 

 (31.25 mg/m3

)/20 = 1.6 mg/m3 8 

9 
PHOSGENE OXIME Page 23 of 31 Proposed 06/2009 v.1 

1 

2 

3 

4 

5 

6 

7 

8 

9 

10 

11 

12 

13 

14 

15 

16 

17 APPENDIX B: Time Scaling Calculations 
PHOSGENE OXIME Page 24 of 31 Proposed 06/2009 v.1 

1 

2 The relationship between dose and time for any given chemical is a function of the 

3 physical and chemical properties of the substance and the unique toxicological and 

4 pharmacological properties of the individual substance. Historically, the relationship according 

5 to Haber (1924), commonly called Haber=s Law or Haber=s Rule (C x t = k, where C = exposure 

6 concentration, t = exposure duration, and k = a constant) has been used to relate exposure 

7 concentration and duration to effect (Rinehart and Hatch, 1964). This concept states that 

8 exposure concentration and exposure duration may be reciprocally adjusted to maintain a 

9 cumulative exposure constant (k) and that this cumulative exposure constant will always reflect a 

10 specific quantitative and qualitative response. This inverse relationship of concentration and 

11 time may be valid when the toxic response to a chemical is equally dependent upon the 

12 concentration and the exposure duration. However, an assessment by ten Berge et al. (1986) of 

13 LC50 data for certain chemicals revealed chemical-specific relationships between exposure 

14 concentration and exposure duration that were often exponential. This relationship can be 

expressed by the equation C n 15 x t = k, where n represents a chemical specific, and even a toxic 

16 endpoint specific, exponent. The relationship described by this equation is basically in the form 

17 of a linear regression analysis of the log-log transformation of a plot of C vs t. ten Berge et al. 

18 (1986) examined the airborne concentration (C) and short-term exposure duration (t) relationship 

19 relative to death for approximately 20 chemicals and found that the empirically derived value of 

20 n ranged from 0.8 to 3.5 among this group of chemicals. Hence, the value of the exponent (n) in 

the equation Cn 21 x t = k quantitatively defines the relationship between exposure concentration 

22 and exposure duration for a given chemical and for a specific health effect endpoint. Haber's 

23 Rule is the special case where n = 1. As the value of n increases, the plot of concentration vs 

24 time yields a progressive decrease in the slope of the curve. 

25 

26 The available data do not allow for empirical derivation of a temporal scaling factor (n) 

27 for phosgene oxime. The concentration-exposure time relationship for many irritant and 

systemically acting vapors and gases may be described by Cn 28 x t = k, where the exponent n 

29 ranges from 0.8 to 3.5 (ten Berge et al. 1986). Data are unavailable with which to evaluate the 

30 exposure time-exposure concentration relationship and empirical derivation of the exponent, n, 

for the relationship Cn 31 x t = k is not possible. In the absence of definitive data, temporal scaling 

32 default exponents of n = 3 are typically applied when extrapolating to shorter time points and n

33 = 1 when extrapolating to longer time points (NRC 2001).

34 
PHOSGENE OXIME Page 25 of 31 Proposed 06/2009 v.1 

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2 

3 

4 

5 

6 

7 

8 

9 

10 

11 

12 

13 

14 

15 

16 APPENDIX C: Derivation Summary Tables
PHOSGENE OXIME Page 26 of 31 Proposed 06/2009 v.1 

1 

AEGL-1 VALUES FOR PHOSGENE OXIME (ppm) 

10 min 30 min 1 h 4 h 8 h 

0.17 mg/m3 0.056 mg/m3 0.028 mg/m3 0.0069 mg/m3 0.0035 mg/m3

Reference: Malatesta, P., B. Bianchi and C. Malatesta. 1983. Contributo allo studio delle sostanze orticanti 

[Contributions to the study of oro-nasal irritants]: Nota 1. Boll. Chim. Farm 122: 96-103. (Translated 

from Italian) 

Test Species/Strain/Number: Informed volunteers/ 6

Exposure Route/Concentrations/Durations : 1 mg /m3 for 10-min ; 3 mg/m3 for 1 min 

Effects: 1 mg/m3: Awareness of chemical based upon ocular, nasal, and dermal sensations following 10-min 

exposure (POD for AEGL-1 derivation) 3 mg/m3 : unpleasant irritation ; 1-min exposure duration 

Endpoint/Concentration/Rationale: Awareness of chemical based upon ocular, nasal, and dermal sensations 

following 10-min exposure to 1 mg/m3

Uncertainty Factors/Rationale: 

Interspecies: 1; Human volunteers 

Intraspecies: 3; Direct contact irritant (ocular, nasal, dermal contact) requiring no metabolism/disposition 

processes; initial awareness of this urticant/nettle agent is not expected to vary significantly among 

individuals 

Modifying Factor: 2 ; A modifying factor of 2 was applied to account for the overall limited data on this 

chemical as well as deficiencies (no analytical determination of concentrations ; limited exposure 

durations and concentrations) in the available studies 

Animal to Human Dosimetric Adjustment: not applicable 

Time Scaling: Cn x t = k, where n = 1 

Data Adequacy: Data are sufficient for derivation of AEGL-1 values for phosgene oxime. Although the overall 

data set is very limited, the AEGL-1 values are based upon controlled exposure studies with informed 

volunteers. 

2 
PHOSGENE OXIME Page 27 of 31 Proposed 06/2009 v.1 

1 

AEGL-2 VALUES FOR PHOSGENE OXIME (mg/m3)

10 min 30 min 1 h 4 h 8 h 

0.50 mg/m3 0.17 mg/m3 0.083 mg/m3 0.021 mg/m3 0.010 mg/m3

Reference: Malatesta, P., B. Bianchi and C. Malatesta. 1983. Contributo allo studio delle sostanze orticanti 

[Contributions to the study of oro-nasal irritants]: Nota 1. Boll. Chim. Farm 122: 96-103. (Translated 

from Italian) 

Test Species/Strain/Number: Informed volunteers/6 

Exposure Route/Concentrations/Durations: 1 mg /m3 for 10-min ; 3 mg/m3 for 1 min 

Effects: 1 mg/m3: Awareness of chemical based upon ocular, nasal, and dermal sensations following 10-min 

exposure to 3 mg/m3 : unpleasant irritation ; 1-min exposure duration (POD for AEGL-2 derivation) 

Endpoint/Concentration/Rationale: Awareness of chemical based upon ocular, nasal, and dermal sensations 

following 10-min exposure to 1 mg/m3

Uncertainty Factors/Rationale: 

Interspecies: 1; Human volunteers 

Intraspecies: 1; no uncertainty factor for sensitive individuals was applied with the implication that the 10-

min. exposure to 1 mg/m3

 would result in effects approaching AEGL-2 severity for these 

individuals. This approach was considered more defensible than utilizing notable irritation 

reported by Malatesta et al. (1983) for volunteers exposed to 3 mg/m3

 for only 1 minute. 

Modifying Factor: 2 ; A modifying factor of 2 was applied to account for the overall limited data on this 

chemical as well as deficiencies (no analytical determination of concentrations ; limited exposure 

durations and concentrations) in the available studies 

Animal to Human Dosimetric Adjustment: not applicable 

Time Scaling: Cn x t = k, where n = 1 

Data Adequacy: Data are marginally sufficient for derivation of AEGL-2 values for phosgene oxime. 

Although the overall data set is very limited, the AEGL-2 values are based upon controlled exposure 

studies with informed human volunteers. 

2 
PHOSGENE OXIME Page 28 of 31 Proposed 06/2009 v.1 

1 

AEGL-3 VALUES PHOSGENE OXIME (mg/m3) 

10 min 30 min 1 h 4 h 8 h 

36 mg/m3 25 mg/m3 13 mg/m3 3.1 mg/m3 1.6 mg/m3

Key Study: Malatesta, P., B. Bianchi and C. Malatesta. 1983. Contributo allo studio delle sostanze orticanti: Nota 

1. Boll. Chim. Farm 122: 96-103. (Translated from Italian)

Test Species/Strain/Sex/Number: mice, guinea pigs and rabbits (number of animals, species or gender were not 

provided) were exposed by inhalation to phosgene oxime at concentrations of 100 to 500 mg/m3

 (only the range 

was provided) 

Exposure Route/Concentrations/Durations: inhalation/ 100-500 mg/m3/30 minutes 

Effects: For all concentrations: no deaths; lacrimation, agitation and respiratory difficulty resolved by day 3 postexposure

Endpoint/Concentration/Rationale: 30-min. exposure to 500 mg/m3 was highest nonlethal exposure and 

selected as POD for AEGL-3 derivation 

Uncertainty Factors/Rationale: 10 

Interspecies: 3; all three test species exhibited the same signs of toxicity 

Intraspecies: 3; direct contact irritant (ocular, nasal, dermal contact) requiring no 

 metabolism/disposition processes; effects are due to interaction of parent 

 molecule with any tissue 

Modifying Factor: 2; deficient overall database 

Animal to Human Dosimetric Adjustment: not applicable 

Time Scaling: Cn x t = k, where n = 1 or 3 

Data Adequacy: marginal; assessment of a lethality threshold using empirical data not possible. 

2 
PHOSGENE OXIME Page 29 of 31 Proposed 06/2009 v.1 

1 

2 

3 

4 

5 

6 

7 

8 

9 

10 

11 

12 

13 

14 

15 

16 

17 

18 APPENDIX D: Category Plot
PHOSGENE OXIME Page 30 of 31 Proposed 06/2009 v.1 

1 

2 

3 

4 

5 

6 

7 

8 

9 

10 

0.0010 

0.0100 

0.1000 

1.0000 

10.0000 

100.0000 

1000.0000 

10000.0000 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 Oxime

AEGL-2

AEGL-1

AEGL-3

11 

12 

13 

14 

15 

16 

17 

18 
PHOSGENE OXIME Page 31 of 31 Proposed 06/2009 v.1 

1 

Phosgene oxime 

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 0.17 10 AEGL 

NAC/AEGL-1 0.056 30 AEGL 

NAC/AEGL-1 0.028 60 AEGL 

NAC/AEGL-1 0.0069 240 AEGL 

NAC/AEGL-1 0.0035 480 AEGL 

 

NAC/AEGL-2 0.5 0 10 AEGL 

NAC/AEGL-2 0.17 30 AEGL 

NAC/AEGL-2 0.083 60 AEGL 

NAC/AEGL-2 0.021 240 AEGL 

NAC/AEGL-2 0.010 480 AEGL 

 

NAC/AEGL-3 36 10 AEGL 

NAC/AEGL-3 25 30 AEGL 

NAC/AEGL-3 13 60 AEGL 

NAC/AEGL-3 3.1 240 AEGL 

NAC/AEGL-3 1.6 480 AEGL 

 

 human m 1 1 10 0 awareness but no irritation (Malatesta et al., 1983) 

 human m 1 3 1 1 unpleasant irritation (Malatesta et al., 1983) 

 mouse 1 100 30 2 extreme lacrimation, agitation, labored breathing (Malatesta et al., 1983) 

 guinea 

pig 

 1 100 30 2 extreme lacrimation, agitation, labored breathing (Malatesta et al., 1983) 

 rabbit 1 100 30 2 extreme lacrimation, agitation, labored breathing (Malatesta et al., 1983) 

 dog 1 1200 30 3 lethality in dogs (Tschanatschev and Dronzin, 1957) 

 dog 1 3000 30 3 lethality in dogs (Balev and Andreev , 1957) 

 500 30 2 extreme lacrimation, agiatation, labored breathing (Malatesta et al., 1983) 

 

2