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1

2

3 

## ACUTE EXPOSURE GUIDELINE LEVELS 4 

## (AEGLs) 5

6 

## PROPOSED 7

8

9 

## PHOSGENE OXIME 10 

## (CAS Reg. No. 1794-86-1) 11
12

13 14
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1
PREFACE 2
3 Under the authority of the Federal Adviso ry 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 es tablished 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

CAEGL-1, 11
AEGL-2 and AEGL-3

Care developed for each of five exposure periods (10 and 30 minutes, 1 12 hour, 4 hours, and 8 hours) and are distinguished by va rying 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/m 3 ]) of a substance above which it is predicted that the general 17 population, including susceptible individuals, could experience notable discomfort, irritation, or 18 certain asymptomatic, non-sensory effects. Ho wever, the effects are not disabling and are 19 transient and reversible upon cessation of exposure. 20

21 AEGL-2 is the airborne concentration (expressed as ppm or mg/m 3 ) of a substance above 22 which it is predicted that the general population, including susceptible individuals, could 23 experience irreversible or other serious, long-lasting adverse health effects or an impaired ability 24
to escape. 25
26 AEGL-3 is the airborne concentration (expressed as ppm or mg/m 3 ) of a substance above 27 which it is predicted that the general population, including susceptible individuals, could 28 experience life-threatening health effects or death. 29
30 Airborne concentrations below the AEGL-1 represent exposure levels that could produce 31 mild and progressively increasing but transi ent and nondisabling odor, taste, and sensory 32 irritation or certain asymptomatic, non-sensory eff ects. With increasing airborne concentrations 33 above each AEGL, there is a progressive increase in the likelihood of occurrence and the 34 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 recognized 37 that individuals, subject to unique or idiosyncratic responses, could experience the effects 38 described at concentrations below the corresponding AEGL. 39
40
41PHOSGENE OXIME Page 3 of 31 Proposed 06/2009 v.1

TABLE OF CONTENTS 1

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

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

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

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

2. HUMAN TOXI CITY DATA......................................................................................................... ......9 6

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

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

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

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

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

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

3. ANIMAL TOXI CITY DATA........................................................................................................ ....10 13

3.1. Acute Lethality ........................................................................................................... ...............10 14 3.1.1 Dogs ..................................................................................................................... .................10 15

3.2. Nonlethal Toxicity........................................................................................................ .............11 16 3.2.1. Mice, Guinea Pigs, Rabbits.............................................................................................. .....11 17

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

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

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

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

4. SPECIAL CONS IDERATIONS ...................................................................................................... ..12 22

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

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

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

4.4. Other Relevant Information................................................................................................ .......13 26 4.4.1. Species Variability ..................................................................................................... ...........13 27 4.4.2. Susceptible Populations ................................................................................................. .......13 28 4.4.3. Concurrent Exposure Issues.............................................................................................. ....13 29PHOSGENE OXIME Page 4 of 31 Proposed 06/2009 v.1

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

8.3. Data Adequacy and Research Needs .........................................................................................1 6 16

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

APPENDIX A: Derivati on of AEGL Values.......................................................................................... ....18 18

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

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

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

LIST OF TABLES 1 2 S- 1. AEGL Values for phosgene oxime (mg/m 3 ) .............................................................................7 3

TABLE 1. Chemical and Physical Data for Phosgene 4

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

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

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

TABLE 4. AEGL-2 values for phosgene oxime (mg/m 3 ).........................................................................15 8

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

TABLE 6. AEGL values for phosgene oxime (mg/m 3 ) ............................................................................16 10

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1
EXECUTIVE SUMMARY 2
3 Phosgene oxime (CX) is an urticant or nettle agent causing instant intolerable pain, 4 erythema, wheals and urticaria. It is very corrosive, capable of causing extensive tissue damage. 5 Phosgene oxime was first produced by the Germans in 1929 as a possible warfare agent. The 6 mechanism of action is not fully understood but the lesions produced in the skin are similar to 7 those caused by a strong acid. Phosgene oxime w ill penetrate ordinary clothing and surgical 8

gear. 9
10 Data regarding inhalation exposure of humans to phosgene oxime are limited to a 11 controlled study with informed volunteers exposed for 1 minute (3 mg/m 3 ) or 10 minutes (1 12 mg/m 3 ); the former resulting in unpleasant irritation of the nose, eyes and skin during exposure, 13 and the latter resulting in immediate detection of compound but no notable effects (Malatesta et 14 al., 1983). 15
16 Inhalation toxicity data in animals are also limited. Results of experiments in dogs 17 showed high mortality rates following 30-minute exposures to phosgene oxime concentrations of 18 1500-3000 mg/m 3 . These studies also reported a latency period of up to three days between 19 cessation of exposure and death. Exposure of mice, rabbits and guinea pigs for 30 minutes to 20 100-500 mg phosgene oxime/m 3 resulted in agitation, respiratory difficulty, and extreme 21 lacrimation but no lethality. All of these reports lacked detail and provided no long-term follow22 up, gross pathology, or histopathology findings. 23

24 No information is available regarding metabolism and disposition, mechanism of action, 25 reproductive/developmental toxicity, mutagenicity or carcinogenicity of phosgene oxime. 26

27 AEGL-1 values for phosgene oxime were based upon awareness of the chemical as 28 determined by ocular, nasal and dermal sensations by volunteers exposed for 10 minutes to 1 29 mg/m 3 (Malatesta et al., 1983). This sensory percep tion was not considered to be disabling. The 30 use of data obtained from exposures of informed human volunteers eliminates the animal-to31 human extrapolation concerns allowing an interspecies uncertainty factor of 1. Because the 32 initial effects of phosgene oxime appear to be the result of direct-contact with exposed tissue 33 (eyes, nasal mucosae, skin), an uncertainty factor of 3 was considered sufficient to account for 34 possible individual variability. Metabolism and di sposition processes would not be critical in 35 such immediate responses. Rigorous empirical data regarding exposure concentration-duration 36 relationship are not available for phosgene oxime, and more severe effects appear to occur with 37 increasing concentration. Therefore, time scaling where n =1 in the relationship C n x t = k was 38 applied to obtain AEGL values for time points great er that 10 minutes. A modifying factor of 2 39 was applied in derivation of the AEGL-1 values to account for limited information on the 40 inhalation toxicity of phosgene oxime as well as the lack of methodologic detail in the Malatesta 41 et al. (1983) report. 42
43 AEGL-2 values were based upon the same point-of-departure (POD) used for deriving 44 AEGL-1 values; irritation (ocular, dermal, nasal) in volunteers exposed to phosgene oxime at a 45 concentration of 1 mg/m 3 for 10 minute (Malatesta et al., 1983). No uncertainty factor for 46 sensitive individuals was applied with the implication that the exposure may result in effects 47 approaching AEGL-2 severity for these individuals. This approach was considered more 48PHOSGENE OXIME Page 7 of 31 Proposed 06/2009 v.1

defensible than utilizing notable irritation re ported by Malatesta et al. (1983) for volunteers 1 exposed to 3 mg/m 3 for only 1 minute. Data from volunteers precluded the need for an 2 interspecies uncertainty factor greater than 1. As for AEGL-1 derivation, a modifying factor of 2 3 was applied for overall data deficiencies as well as study deficiencies. Time scaling was applied 4 as described for AEGL-1; C n x t = k , where n =1. 5

6 Lethality data for phosgene oxime were limited to animal studies reporting 100% 7 lethality and were inappropriate for estimating a lethality threshold and derivation of AEGL-3 8 values. In lieu of lethality data, the highest nonlethal exposure (500 mg/m 3 for 30 minutes) 9 reported by Malatesta et al. (1983) for mice, guinea pigs and rabbits was considered the POD for 10 AEGL-3 derivation. Malatesta et al. (1983) observed agitation, respiratory difficulty, and 11 intense lacrimation in these animals during the 30-minute exposure to phosgene oxime at 12 concentrations of 100-500 mg/m 3 . Total uncertainty factor application was 10. The uncertainty 13 factor for interspecies extrapolation was limited to 3 because all of the species tested by 14 Malatesta et al. (1983) exhibited a similar response. The uncertainty factor of 3 for individual 15 variability was considered sufficient for direct-contact damage attributed to the actions of the 16 parent molecule. A modifying factor of 2 was applied for data deficiencies (NRC, 2001). 17 In the absence of an empirically derived exponent ( n ), temporal scaling from the 30-minute 18 experimental duration to AEGL-speci fic durations was performed using n = 3 when 19 extrapolating to shorter time points and n = 1 when extrapolating to longer time points using the 20

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

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

24

S- 1. AEGL Values for phosgene oxime expressed as mg/m 3 [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/m 3 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/m 3 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/m 3 for 30 min.; UF= 3 x 3; MF=2; n =1 or 3 (Malatesta et al., 1983)
25
26
References 27
28 Malatesta, P., B. Bianchi and C. Malatesta. 1983. C ontributo allo studio delle sostanze orticanti: Nota 1. 29 Boll. Chim. Farm 122: 96-103. (Translated from Italian) 30PHOSGENE OXIME Page 8 of 31 Proposed 06/2009 v.1

1. INTRODUCTION 1

2 Phosgene oxime (CX) is an urticant or nettle agent causing instant intolerable pain, 3 erythema, wheals and urticaria (USACHPPM, 1996). Due to its corrosive properties, damage to 4 tissue is extensive. Phosgene oxime was first produced by the Germans in 1929 as a possible 5 warfare agent. The precise mechanism of action is not fully understood but the lesions produced 6 in the skin are similar to those made by a strong acid. Phosgene oxime penetrates ordinary 7 clothing and surgical gear. The physical/chemi cal properties of phosgene oxime are summarized 8
in Table 1. 9
10 11

TABLE 1. Chemical and Physical Data for Phosgene Oxime

Parameter Value Reference
Synonyms CX; dichloroformoxime Sidell et al., 1997

Chemical formula CHCl 2 NOH 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/m 3
1 mg/m 3 = 0.21 ppm

12
13
2. HUMAN TOXICITY DATA 14 2.1. Acute Lethality 15
16
An estimated LCt 50 of 3200 mg•min/m 3 (based upon a 10-minute exposure) for phosgene 17 oxime vapor has been reported by the U.S. Army (2005). 18
19 2.2 Nonlethal Toxicity 20

21 Phosgene oxime has been described as having a disagreeable, intensely irritating odor 22 (Sidell et al., 1997). The U.S. Armed Forces (U.S. Army, 2005) report a provisional odor 23
detection ECt 50 of 1 mg•min/m 3 (10 minutes). A provisional inhalation exposure value of 3 24 mg•min/m 3 for 1 minute was considered an incapacitating/intolerable exposure (U.S. Army, 25 2005). 26

27 Malatesta et al. (1983) conducted a study in which six informed adults, including the 28 investigators, were exposed to phosgene oxime. The exposure chamber was described as a 29 hermetically sealed room (with precisely calculated capacity) that was equipped with a fan to 30 enhance homogeneity of the test atmosphere. Phosgene oxime was introduced by high-pressure 31 (200 atm) nebulization using gas cylinders a nd stainless steel cylinders. Methods for 32 determination of exposure concentrations were not specified. A “threshold of physiologic 33 sensitivity” of 1 mg/m 3 (0.21 ppm) was reported which was also the minimal concentration 34PHOSGENE OXIME Page 9 of 31 Proposed 06/2009 v.1

achieved in the closed environment over a 10-minute period. The physiological response 1 apparently referred to awareness of the chemical by ocular sensitivity, taste, and odor. The 2 author also reported a “threshold of pathologic sensitivity ” of ~3 mg/m 3 (0.63 ppm). This value 3 was defined as the minimal concentration causing an unpleasant or irritating sensation on the 4 conjunctiva, nose (assumed to refer to nasal passage surfaces), or intact skin after one minute of 5

exposure. 6

7 2.3. Developmental/Reproductive Effects 8
9 Data on potential developmental/reproductive toxicity of phosgene oxime in humans 10
were not available. 11

12 2.4. Genotoxicity 13

14 No information regarding potential genotoxicity of phosgene oxime in humans was 15
available. 16

17 2.5. Carcinogenicity 18
19 No information regarding the carcinogenic potential of phosgene oxime in humans was 20
available. 21

22 2.6. Summary 23

24 No information regarding inhalation toxicity of phosgene oxime in humans was 25
available. 26

27
3. ANIMAL TOXICITY DATA 28 3.1. Acute Lethality 29 3.1.1 Dogs 30
31 In a Bulgarian study, dogs (breed, number, and sex not provided) were exposed to 1.5-3 32 mg phosgene oxime/L air (1500-3000 mg/m 3 ) for 30 minutes (Balev and Andreev, 1957). 33 Cage-side observations included: general behavi or, weight, body temperature, blood (no further 34 details), pulse (rhythm, frequency and “fullness”), respiration (frequency, rhythm and 35 “deepness”), and urination. Assessments were performed at pre-exposure, every 10-15 minutes 36 during the 3-4 hours following exposure, and once daily until the animals died. Dogs in the 37 study held their breath upon entering the chamber after which respiration became rapid and 38 shallow. Animals appeared distressed and exhib ited frequent movement. Increased lacrimation, 39 salivation and coughing were observed. The oral mucosae and the skin turned red and, later 40 during the exposure, became violet. Upon removal from the chamber, the dogs remained 41 agitated and continuously rubbed their eyes. At a later (unspecified) time, the dogs became 42 calmer, exhibited more normal coloration of the oral mucosae, and resumed normal breathing 43 for 30 minutes to 24 hours (rarely), after which their condition deteriorated. This second phase 44 was characterized by increased pulse, increased respiration, foaming of the mouth, cyanosis, and 45 death 2-3 days post-exposure. Based upon these findings, the investigators defined three main 46 stages of phosgene oxime toxicity: reflective, latent and manifest. These same stages were 47 observed after phosgene oxime was administered intravenously at 10 mg/kg bw. 48PHOSGENE OXIME Page 10 of 31 Proposed 06/2009 v.1

1 Two dogs/treatment group (breed, age, and gender not specified) were exposed to 1.5-2.0 2 mg phosgene oxime/L of air for 30 minutes in four treatment groups (Tschanatschev and 3 Dronzin, 1957). In each of the four groups, one dog was administered a pre-exposure treatment 4 to assess the effects on phosgene oxime-induced toxicity, while an untreated dog was exposed to 5 phosgene oxime (designated as “control” in th e study report). The treatment protocols included 6 using a combination of Novacain neck blocks, calcium, glucose, Vitamin K and oxygen. 7 Animals were placed in a dynamic flow chamber. No further detail was provided. Prior to and 8 during the exposure, the dogs were monitored for body temperature, pulse, respiratory 9 rate/pattern, blood chemistry and general behavior. Once exposures started, all dogs 10 demonstrated anxiety, lacrimation, salivation, moving or shaking the head, coughing and 11 increased respiration. Out of all four groups, only 1 of 8 dogs survived. The dog was treated 12 with a vagosympathetic neck block using novacaine, a 2% sodium bicarbonate solution rinse in 13 the eyes, oxygen, Cardiazol/Lobelin, calcium chloratum, Vitamin K, glucose supplementation 14 and a tannic acid enema after exposure. The “control dog” exposed in this scenario died 10 15 hours post-exposure. The study demonstrated that aggressive supportive care post-exposure to 16 phosgene oxime, possibly in combination with the pre-exposure treatment, could prevent 17 mortality at this concentration. 18
19
3.2. Nonlethal Toxicity 20
3.2.1. Mice, Guinea Pigs, Rabbits 21

22 In a study by Malatesta et al. (1983), mice, guinea pigs and rabbits (number of animals, 23 species and gender were not provided) were exposed by inhalation to phosgene oxime at 24 concentrations of 100 to 500 mg/m 3 (only the range was provided). The experiments were 25 conducted with an aqueous solution of phosgene oxime which was nebulized at 200 atm. using 26 gas cylinders and stainless steel sprayers. The experiments were carried out in a tightly closed 27 room with a precisely calculated capacity. Homogeneity of the test atmosphere was attempted 28 using fans, although actual concentration and homogeneity of the vapor within the chamber were 29 not confirmed analytically. No further details were provided. No deaths occurred at any 30 concentration. Agitation, respiratory difficulty, and intense lacrimation during exposure were 31 reported. No signs of phosgene oxime toxicity we re observed in any animals at 3 days following 32

exposure. 33
34 3.3 Summary of Toxicity in Animals 35
36 The limited inhalation toxicity data for phosgene oxime in animals is summarized in 37
Table 2. 38
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1
TABLE 2. Summary of inhalation toxi city of phosgene oxime in animals

Concentration Exposure Duration Species Effect Reference 100-500 mg/m 3 30 min. Mice, guinea pigs, rabbits All concentrations: no deaths; lacrimation, agitation and respiratorydifficulty resolved by day 3 postexposure Malatesta et al., 1983

1.5- 2.0 mg/L (1,500-2,000 mg/m 3 ) 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/m 3 ) 30 min. Dogs 100% lethality Balev and Andreev,
1957
2
3 3.4. Developmental/Reproductive Effects 4
5 No information is available in the open literature regarding potential developmental and 6 reproductive toxicity of phosgene oxime following inhalation exposure. 7
8 3.5. Genotoxicity 9
10 Information regarding the potential genotoxicity of phosgene oxime following inhalation 11 exposure is not available. 12
13 3.6. Carcinogenicity 14
15 Information regarding the potential carcinogenicity of phosgene oxime following 16 inhalation exposure is not available. 17
18
4. SPECIAL CONSIDERATIONS 19 4.1. Metabolism and Disposition 20

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

23 4.2. Mechanism of Toxicity 24
25 The mechanism of phosgene oxime toxicity is unknown. Damage is often instantaneous 26 and may be the result of the necrotizing effects of the chlorine, direct effect of the oxime, or 27 associated with the carbonyl group (Sidell et al., 1997). The tissue damage is very similar to that 28 caused by a concentrated mineral acid. Within 5-30 minutes of exposure, edema develops at the 29 initial site of contact and the tissues become necrotic. Over the course of 24 hours, the edema 30 regresses and the blanched area becomes pigmented with an eschar forming over the next 7 days. 31 In some cases, healing may require more than 6 months. Ocular exposure results in pain, 32 conjunctivitis, and keratitis. Phosgene oxime appears to affect the first capillary bed 33 encountered. With the exception of supportive care, there is no antidote or recommended 34 therapeutic regimen once exposure has occurred. 35
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4.3. Structure-Activity Relationships 1

2 There are no data with which to assess structure-activity relationships with respect to 3 development of AEGL values. There is no evidence that phosgene is involved in the toxicity of 4 phosgene oxime. 5

6
4.4. Other Relevant Information 7
4.4.1. Species Variability 8

9 Because the most significant and immediate e ffects of acute exposure to phosgene oxime 10 are the result of direct-contact with ocular and respiratory tract tissue, variability across species 11 is expected to be limited. These tissues represent the most sensitive targets for phosgene oxime 12

vapor exposure. 13

14 4.4.2. Susceptible Populations 15

16 Phosgene oxime toxicity occurs after direct contact with the skin, eyes or respiratory 17 tract, which would not vary between healthy individuals. However, those with compromised 18 respiratory function such as asthma or COPD experience more severe responses to phosgene 19 oxime exposure than otherwise healthy people. As the vapor is heavier than air, phosgene oxime 20 can accumulate in low-lying areas and enclosed spaces. 21

22 4.4.3. Concurrent Exposure Issues 23

24 Concurrent exposure to other irritant chemical s affecting the eyes or respiratory tract may 25 be of concern regarding exposure to phosgene oxime. No data are available with which to 26 quantify such exposure with respect to development of AEGL values for phosgene oxime. 27

28
5. DATA ANALYSIS FOR AEGL-1 29
5.1. Human Data Relevant to AEGL-1 30
31 Data regarding AEGL-1 tier effects in humans following vapor exposure to phosgene 32
oxime are limited. 33
34 Malatesta et al. (1983) conducted a study in which six informed volunteers, including the 35 investigator, were exposed to phosgene oxime. A concentration of 1 mg/m 3 (0.21 ppm) was 36 considered the “threshold of physiologic sensitivity”; this was also the minimal concentration 37 achieved in the closed environment over a 10-minute period. Higher concentrations resulted in 38 the identification/characterization of a “threshold of pathologic sensitivity ” of ~3 mg/m 3 (0.63 39 ppm). This was defined as the minimal concentration causing an unpleasant or irritating 40 sensation on the conjunctiva, nose, or skin after one minute of exposure. 41

42
5.2. Animal Data Relevant to AEGL-1 43

44 The responses of mice, guinea pigs, and rabbits described by Malatesta et al. (1983) 45 included agitation, respiratory difficulty, and inte nse lacrimation, all of which are of greater 46 severity than that consistent with the AEGL-1 definition. 47
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5.3. Derivation of AEGL-1 Values 1

2 The most appropriate data for derivation of AEGL-1 values for phosgene oxime are the 3 responses of the human volunteers exposed for 10 minutes to phosgene oxime at a concentration 4 of 1 mg/m 3 (Malatesta et al., 1983). The physiological responses (awareness based upon ocular, 5 nasal and dermal responses) over a 10-minute exposure to 1 mg/m 3 were considered an 6 appropriate point-of-departure (POD) and the critical endpoint for AEGL-1 development. 7 Although deficient in details regarding the analysis of the test atmosphere these findings provide 8 the only information regarding exposure-response data for AEGL-1 tier effects following acute 9 inhalation exposure to phosgene oxime. Further, the information comes from humans, thereby 10 eliminating the need for animal-to-human extrapolation. Because the initial effects of phosgene 11 oxime result from direct-contact with exposed tissues (eyes, nasal mucosae, skin), an uncertainty 12 factor of 3 to account for possible individual variability is appropriate. Metabolism and 13 disposition processes would not be critical in such responses. 14
15 Because rigorous empirical data regarding exposure concentration-duration relationship 16 were not available for phosgene oxime, and because more severe effects appear to occur with 17 increasing concentration, time scaling (where n =1 in the relationship C n x t = k ) was applied to 18 obtain AEGL values for time points greater than 10 minutes (NRC, 2001). A modifying factor 19 of 2 has also been applied in the derivation of the AEGL-1 values to account for limited 20 information on the inhalation toxicity of phosgene oxime as well as the recognized deficiencies 21 in the Malatesta et al. (1983) report. The AEGL-1 values for phosgene oxime are presented in 22 Table 3 and the derivation summarized in Appendices A and C. 23 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/m 3
0.036 ppm 0.056 mg/m 3
0.012 ppm 0.028 mg/m 3
0.0059 ppm 0.0069 mg/m 3
0.0014 ppm 0.0035 mg/m 3
0.00074 ppm

25

26
6. DATA ANALYSIS FOR AEGL-2 27
6.1. Human Data Relevant to AEGL-2 28
29 In a study using six informed volunteers, Mala testa et al. (1983) reported that a 1-minute 30 exposure to phosgene oxime at 3 mg/m 3 resulted in unpleasant or irritating sensations in the eyes 31 (conjunctiva), nose (assumedly nasal epithelium), and skin (termed threshold of pathologic 32 sensitivity by the investigators). The U.S. Army (2005) reported a provisional inhalation 33 exposure value of 3 mg•min/m 3 (derived based upon 1-minute exposure duration) which was 34 considered incapacitating/intolerable, but the U.S. Army assessment appears to have been based 35 upon the Malatesta et al. (1983) study. 36
37
6.2. Animal Data Relevant to AEGL-2 38
39 Mice guinea pigs and rabbits exposed to phosgene oxime at concentrations of 100 to 500 40 mg/m 3 (21 to 105 ppm) for 30 minutes displayed agitation, respiratory difficulty, and intense 41 lacrimation during exposure (Malatesta et al ., 1983). Although these changes occurred during 42 exposure and resolved within 3 days following cessation of exposure, no gross pathology or 43 histopathology findings were reported. 44PHOSGENE OXIME Page 14 of 31 Proposed 06/2009 v.1

1
6.3. Derivation of AEGL-2 Values 2
3 AEGL-2 values were based upon the same point-of-departure (POD) used for deriving 4 AEGL-1 values; irritation (ocular, dermal, nasal) in volunteers exposed to phosgene oxime at a 5 concentration of 1 mg/m 3 for 10 minutes (Malatesta et al., 1983). No uncertainty factor for 6 sensitive individuals was applied with the implication that the exposure may result in effects 7 approaching AEGL-2 severity for these individuals. This approach was considered more 8 defensible than utilizing notable irritation re ported by Malatesta et al. (1983) for volunteers 9 exposed to 3 mg/m 3 for only 1 minute. Data from human volunteers precluded the need for an 10 interspecies uncertainty factor greater than 1. As for AEGL-1 derivation, a modifying factor of 2 11 was applied for overall data deficiencies as well as study deficiencies. Time scaling was applied 12 as described for AEGL-1; C n x t = k , where n =1. 13

14 The AEGL-2 values for phosgene oxime are presented in Table 4 and the derivation 15 summarized in Appendices A and C. 16

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/m 3
0.011 ppm 0.17 mg/m 3
0.036 ppm 0.083 mg/m 3
0.017 ppm 0.021 mg/m 3
0.0044 ppm 0.010 mg/m 3
0.0021 ppm

18
19
7. DATA ANALYSIS FOR AEGL-3 20
7.1. Human Data Relevant to AEGL-3 21

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

24
7.2. Animal Data Relevant to AEGL-3 25
26 Animal lethality data were limited to two studies in dogs (Balev and Andreev, 1957; 27 Tschanatschev and Dronzin, 1957) that used very high exposure concentrations (1500-300 28 mg/m 3 ) for exposure durations of 30 minutes. These exposures caused death. The study reports 29 provided no data with which to empirically determine a lethality threshold 30
31
32
7.3. Derivation of AEGL-3 Values 33
34 Lethality data for phosgene oxime were limited to animal studies reporting 100% 35 lethality. In lieu of lethality data, the highest nonlethal exposure (500 mg/m 3 for 30 minutes) 36 reported by Malatesta et al. (1983) for mice, guinea pigs and rabbits was considered the POD for 37 AEGL-3 derivation. Malatesta et al. (1983) observed agitation, respiratory difficulty, and 38 intense lacrimation in these animals during the 30-minute exposure to phosgene oxime at 39 concentrations of 100-500 mg/m 3 . In the absence of an empirically derived exponent ( n ), 40 temporal scaling from the 30-minute experiment al duration to AEGL-specific durations was 41 performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to 42 longer time points using the C n x t = k equation (NRC, 2001). Total uncertainty factor 43 application was 10. The uncertainty factor for interspecies extrapolation was limited to 3 44PHOSGENE OXIME Page 15 of 31 Proposed 06/2009 v.1

because all of the species tested by Malatesta et al. (1983) exhibited a similar response. The 1 uncertainty factor of 3 for individual variability was considered sufficient for direct-contact 2 damage attributed to the actions of the parent mo lecule. A modifying factor of 2 was applied for 3 data deficiencies (NRC, 2001). 4
5 The AEGL-3 values for phosgene oxime are presented in Table 5 and the derivation 6 summarized in Appendices A and C. 7
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/m 3
7.6 ppm 25 mg/m 3
5.3 ppm 13 mg/m 3
2.7 ppm 3.1 mg/m 3
0.65 ppm 1.6 mg/m 3
0.34 ppm

10

11
8. SUMMARY OF AEGLs 12 8.1. AEGL Values and Toxicity Endpoints 13

14 Information regarding the toxicity of phosgene oxime following inhalation exposure is 15 limited. A single study using informed volunteers provided data for very short exposure 16 durations. These data were sufficient for deriving AEGL-1 and AEGL-2 values based upon the 17 potent irritant effects of phosgene oxime. No data were available for empirical determination of 18 a lethality threshold. AEGL-3 values were developed based upon the highest nonlethal 19 concentration in several laboratory species. The AEGL values for phosgene oxime are 20
summarized in Table 6. 21 22

TABLE 6. AEGL values for phosgene oxime expressed as mg/m 3 [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
8.2. Comparisons with Other Standards and Guidelines 25 26 There are no standards or guideline values for phosgene oxime. 27
28 8.3. Data Adequacy and Research Needs 29
30 Inhalation toxicity data for phosgene oxime are extremely limited. Additional studies 31 examining low level exposure for longer exposure durations as well as data allowing for 32 estimation of a lethality threshold are required for a more definitive assessment. At the present 33 time, no empirical data regarding the exposure concentration-time relationship for phosgene 34
oxime are available. 35
36
37PHOSGENE OXIME Page 16 of 31 Proposed 06/2009 v.1

9. REFERENCES 1
2 Balev, P. and T. Andreev. 1957. [Clinics of the in toxication with phosgene oxime]. Nauchni Tr Vissh 3 Med Inst Sofiia 4 (4):77-98. (Translated from Bulgarian) 4
5 CDC (Centers for Disease Control). 2003. Phosgene oxime . Dept. of Health and Human Services, Centers 6

for Disease Control and Prevention. Found online at http://www.bt.cdc.gov/agent/phosgene7 oxime/index.asp

. 8
9 Haber, F.R. 1924. Zur geschichte des gaskrieges [On th e history of the gas war]. In: Fuenf Vortraege aus 10 den Jahren 1920-23 [Five lectures from the years 1920-1923]. Berlin, Germany: Verlag von 11 Julius Springer; pp. 76-92. 12
13 Malatesta, P., B. Bianchi and C. Malatesta. 1983. Contributo allo studio delle sostanze orticanti 14 [Contributions to the study of oro-nasal irritants]: Nota 1. Boll. Chim. Farm 122: 96-103. 15 (Translated from Italian) 16
17 NRC (National Research Council). 2001. Standing ope rating procedures for developing acute exposure 18 guideline levels for hazardous chemicals. Committee on Toxicology, Board on Toxicology and 19 Environmental Health Hazards, Commission on Life Sciences, National Research Council. 20 National Academy Press, Washington, DC. 21

Rinehart, W. E. and Hatch, T. 1964. Concentration- time product (CT) as an expression of dose in sublethal 22 exposures to phosgene. Ind. Hyg. J. 25: 545-553. 23
24 Sidell, F.R., E.T. Takafuji, and D.R. Franz (editors). 1997. Medical aspects of chemical and biological 25 warfare. Part 1. Textbook of Military Medici ne. TMM Publications, Borden Institute, 26 Washington D.C. p. 199 and 220-222. 27
28 ten Berge, W.F., Zwart, A., Appelman, L.M. 1986. Concentration-time mortality response relationship 29 of irritant and systemically acting vapours a nd gases. J. Hazard. Materials 13: 301-309. 30

Tschanatschev, I.S. and T.D. Dronzin. 1957. [Experi mental therapy of poisoning with phosgene oxime 31 through inhalation]. Nauchni Tr Vissh Med Inst So fiia 4(4):111-114. (Translated from Bulgarian) 32
33 USACHPPM (United States Army Center for Hea lth Promotion and Preventive Medicine). 1996. 34 Detailed and General Facts About Chemical Ag ents – TG 218. USACHPPM, Aberdeen Proving 35 ground, MD. 36
37 U.S. Army. 2005. Potential Military Chemical/Biological Agents and Compounds. 38

Online at www.us.army.mil

. 39
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APPENDIX A: Derivation of AEGL Values 9PHOSGENE OXIME Page 18 of 31 Proposed 06/2009 v.1

Derivation of AEGL-1 Values for Phosgene Oxime 1

Key Study: Malatesta, P., B. Bianchi and C. Malatesta. 1983. Contributo allo studio 2
delle sostanze orticanti [ Contributions to the study of oro-nasal irritants]: 3 Nota 1. Boll. Chim. Farm 122: 96-103. (Translated from Italian) 4
5
Critical effect: Awareness of chemical by ocular, nasal, and dermal sensation following 6 10-minute exposure of 6 informed human volunteers to 1 mg phosgene 7
oxime/m 3 8

9 Time scaling: Time scaling using C n x t = k , where n = 1 for extrapolating from the 10- 10 minute experimental exposure duration to AEGL-specific exposure 11 durations (NRC, 2001). 12
13 Uncertainty factors: Total uncertainty factor 3. 14 Interspecies : 1; informed volunteers 15
16 Intraspecies : 3; direct contact irritant (ocular, nasal, dermal contact) requiring no 17 metabolism/disposition processes; initial awareness of this 18 urticant/nettle agent is not expected to vary among individuals 19
20 Modifying Factor: 2; overall data set for phosgene oxime inhalation toxicity is limited; 21 available studies lack analytical exposure terms; animal studies lack 22 adequate post exposure follow-up, gross necropsy and histopathology 23 findings 24
25
Calculation: 1 mg/m 3 x 10 min = 10 mg·min/m 3 26

27
10-min AEGL-1 C mg/m 3 x 10 min. = 10 mg·min/m 3 28 C = 1 mg/m 3 29 (1 mg/m 3 )/6 = 0.17 mg/m 3 30
31
30-min AEGL-1 C mg/m 3 x 30 min. = 10 mg·min/m 3 32 C = 0.33 mg/m 3 33 (0.33 mg/m 3 )/6 = 0.056 mg/m 3 34
35
1-hr AEGL-1 C mg/m 3 x 60 min. = 10 mg·min/m 3 36 C = 0.167 mg/m 3 37 (0.167 mg/m 3 )/6 = 0.028 mg/m 3 38
39
4-hr AEGL-1 C mg/m 3 x 240 min. = 10 mg·min/m 3 40 C = 0.0416 mg/m 3 41 (0.0416 mg/m 3 )/6 = 0.0069 mg/m 3 42
43
8-hr AEGL-1 C mg/m 3 x 480 min. = 10 mg·min/m 3 44 C = 0.0208 mg/m 3 45 (0.0208 mg/m 3 )/6 = 0.0035 mg/m 3 46PHOSGENE OXIME Page 19 of 31 Proposed 06/2009 v.1

Derivation of AEGL-2 Values for Phosgene Oxime 1

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 8
oxime/m 3

. 9
10 Time scaling: Time scaling using C n x t = k , where n = 1 for extrapolating from the 11 10-minute experimental exposure duration to AEGL-specific exposure 12 durations (NRC, 2001). 13

14 Uncertainty factors: Total uncertainty factor: 1 15

16 Interspecies : 1; informed human volunteers 17
18 Intraspecies : 1; no uncertainty factor for sensitive individuals was applied with the 19 implication that the 10-min. exposure to 1 mg/m 3 would result in effects 20 approaching AEGL-2 severity for these individuals. This approach was 21 considered more defensible than utilizing notable irritation reported by 22 Malatesta et al. (1983) for volunteers exposed to 3 mg/m 3 for only 1 23
minute. 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
30
Calculation: 1 mg/m 3 x 10 min = 10 mg·mg/m 3 31
32
33
10-min AEGL-2 C mg/m 3 x 10 min. = 10 mg·min/m 3 34 C = 1 mg/m 3 35 (1 mg/m 3 )/2 = 0.50 mg/m 3 36
37
38
30-min AEGL-2 C mg/m 3 x 30 min. = 10 mg·min/m 3 39 C = 0.33 mg/m 3 40 (0.33 mg/m 3 )/2 = 0.17 mg/m 3 41

42
43
1-hr AEGL-2 C mg/m 3 x 60 min. = 10 mg·min/m 3 44 C = 0.167 mg/m 3 45 (0.167 mg/m 3 )/2 = 0.083 mg/m 3 46

47

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

4-hr AEGL-2 C mg/m 3 x 240 min. = 10 mg·min/m 3 1 C = 0.0416 mg/m 3 2 (0.0416 mg/m 3 )/2 = 0.021 mg/m 3 3

4
5
8-hr AEGL-2 C mg/m 3 x 480 min. = 10 mg·min/m 3 6 C = 0.0208 mg/m 3 7 (0.0208 mg/m 3 )/2 = 0.010 mg/m 3 8

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

1 Derivation of AEGL-3 Values for Phosgene Oxime 2
3 Key Study: Malatesta, P., B. Bianchi and C. Malatesta. 1983. Contributo allo studio 4
delle sostanze orticanti: Nota 1. Boll. Chim. Farm 122: 96-103. 5 (Translated from Italian) 6

7
Critical effect: 30-minute exposure to 500 mg/m 3 was the highest nonlethal exposure for 8 mice guinea pigs and rabbits; responses included lacrimation, agitation 9 and respiratory difficulty which resolved by day 3 post-exposure 10

11 Time scaling: Time scaling using C n x t = k , where n = 1 for extrapolating from the 12 10-minute experimental exposure duration to longer AEGL-specific 13 exposure durations and n = 3 for extrapolating to the 10-min AEGL 14 duration (NRC, 2001). 15
16 Uncertainty factors: Total uncertainty factor: 10 17

18 Interspecies : 3; all three test species exhibited the same signs of toxicity 19
20 Intraspecies : 3; direct contact irritant (ocular, nasal, dermal contact) requiring no 21 metabolism/disposition processes; effects are due to interaction of parent 22 molecule with any tissues. 23

24 Modifying Factor: 2; overall data set for phosgene oxime inhalation toxicity is limited; 25 available studies lack analytical exposure terms; animal studies lack 26 adequate post exposure follow-up, gross necropsy and histopathology 27 findings 28
29
Calculation: 500 mg/m 3 x 0.5 hr = 250 mg·hr/m 3 30 (500 mg/m 3 ) 3 x 0.5 hr min = 62,500,000 mg·hr/m 3 31
32
33
10-min AEGL-3 (C mg/m 3 ) 3 x 0.1667 hr = 62,500,000 mg·hr/m 3 34 C = 721 mg/m 3 35 (721 mg/m 3 )/20 = 36 mg/m 3 36
37
38
30-min AEGL-3 C mg/m 3 x 0.5 hr = 250 mg·hr/m 3 39 C = 500 mg/m 3 40 (500 mg/m 3 )/20 = 25 mg/m 3 41

42
43
1-hr AEGL-3 C mg/m 3 x 1 hr = 250 mg·hr/m 3 44 C = 250 mg/m 3 45 (250 mg/m 3 )/20 = 13 mg/m 3 46

47
48PHOSGENE OXIME Page 22 of 31 Proposed 06/2009 v.1

4-hr AEGL-3 C mg/m 3 x 4 hrs = 250 mg·hr/m 3 1 C = 62.5 mg/m 3 2 (62.5 mg/m 3 )/20 = 3.1 mg/m 3 3

4
5
8-hr AEGL-3 C mg/m 3 x 8 hrs = 250 mg·min/m 3 6 C = 31.25 mg/m 3 7 (31.25 mg/m 3 )/20 = 1.6 mg/m 3 8

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

1 The relationship between dose and time for any given chemical is a function of the 2 physical and chemical properties of the substance and the unique toxicological and 3 pharmacological properties of the individual substa nce. Historically, the relationship according 4 to Haber (1924), commonly called Haber = s Law or Haber = s Rule ( C x t = k , where C = exposure 5 concentration, t = exposure duration, and k = a constant) has been used to relate exposure 6 concentration and duration to effect (Rinehart and Hatch, 1964). This concept states that 7 exposure concentration and exposure duration may be reciprocally adjusted to maintain a 8 cumulative exposure constant ( k ) and that this cumulative exposure constant will always reflect a 9 specific quantitative and qualitative response. This inverse relationship of concentration and 10 time may be valid when the toxic response to a chemical is equally dependent upon the 11 concentration and the exposure duration. However, an assessment by ten Berge et al. (1986) of 12
LC 50 data for certain chemicals revealed chemical-specific relationships between exposure 13 concentration and exposure duration that were often exponential. This relationship can be 14 expressed by the equation C n x t = k , where n represents a chemical specific, and even a toxic 15 endpoint specific, exponent. The relationship described by this equation is basically in the form 16 of a linear regression analysis of the log-log transf ormation of a plot of C vs t. ten Berge et al. 17 (1986) examined the airborne concentration (C) and short-term exposure duration (t) relationship 18 relative to death for approximately 20 chemicals and found that the empirically derived value of 19

n ranged from 0.8 to 3.5 among this group of chemicals. Hence, the value of the exponent ( n ) in 20 the equation C n x t = k quantitatively defines the relationship between exposure concentration 21 and exposure duration for a given chemical and fo r a specific health effect endpoint. Haber's 22 Rule is the special case where n = 1. As the value of n increases, the plot of concentration vs 23 time yields a progressive decrease in the slope of the curve. 24
25 The available data do not allow for empirical derivation of a temporal scaling factor ( n ) 26 for phosgene oxime. The concentration-exposure time relationship for many irritant and 27 systemically acting vapors and gases may be described by C n x t = k , where the exponent n 28 ranges from 0.8 to 3.5 (ten Berge et al. 1986). Data are unavailable with which to evaluate the 29 exposure time-exposure concentration relationship and empirical derivation of the exponent, n , 30 for the relationship C n x t = k is not possible. In the absence of definitive data, temporal scaling 31 default exponents of n = 3 are typically applied when extrapolating to shorter time points and n 32 = 1 when extrapolating to longer time points (NRC 2001). 33

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

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AEGL-1 VALUES FOR PHOSGENE OXIME (ppm)

10 min 30 min 1 h 4 h 8 h 0.17 mg/m 3 0.056 mg/m 3 0.028 mg/m 3 0.0069 mg/m 3 0.0035 mg/m 3

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 /m 3 for 10-min ; 3 mg/m 3 for 1 min

Effects : 1 mg/m 3 : Awareness of chemical based upon ocular, na sal, and dermal sensations following 10-min exposure (POD for AEGL-1 derivation) 3 mg/m 3 : 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/m 3
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: C n 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.
2PHOSGENE OXIME Page 27 of 31 Proposed 06/2009 v.1

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AEGL-2 VALUES FOR PHOSGENE OXIME (mg/m 3 )

10 min 30 min 1 h 4 h 8 h
0.50 mg/m 3 0.17 mg/m 3 0.083 mg/m 3 0.021 mg/m 3 0.010 mg/m 3

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 /m 3 for 10-min ; 3 mg/m 3 for 1 min

Effects: 1 mg/m 3 : Awareness of chemical based upon ocular, na sal, and dermal sensations following 10-min exposure to 3 mg/m 3 : 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/m 3
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/m 3 would result in effects approaching AEGL-2 severity for these individuals. This approach was considered mo re defensible than utilizing notable irritation reported by Malatesta et al. (1983) for volunteers exposed to 3 mg/m 3 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 : C n 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.

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

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AEGL-3 VALUES PHOSGENE OXIME (mg/m 3 )

10 min 30 min 1 h 4 h 8 h
36 mg/m 3 25 mg/m 3 13 mg/m 3 3.1 mg/m 3 1.6 mg/m 3

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/m 3 (only the range was provided) Exposure Route/Concentrations/Durations : inhalation/ 100-500 mg/m 3 /30 minutes

Effects: For all concentrations: no deaths; lacrimation, agita tion and respiratory difficulty resolved by day 3 postexposure Endpoint/Concentration/Rationale: 30-min. exposure to 500 mg/m 3 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/dispos ition 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: C n x t = k , where n = 1 or 3 Data Adequacy : marginal; assessment of a lethality threshold using empirical data not possible.

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

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0.0010 0.0100 0.1000 1.0000 10.0000 100.0000 1000.0000 10000.0000ppm

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
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18PHOSGENE 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, ag itation, labored breathing (Malatesta et al., 1983)

guinea pig 1 100 30 2 extreme lacrimation, agitati on, labored breathing (Malatesta et al., 1983)

rabbit 1 100 30 2 extreme lacrimation, ag itation, 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, agiata tion, labored breathing (Malatesta et al., 1983)

2