5

Lewisite
1

Acute Exposure Guideline Levels

PREFACE

Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals.

AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows:

AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory

____________________

1This document was prepared by the AEGL Development Team composed of Cheryl Bast (Oak Ridge National Laboratory), Julie Klotzbach (SRC, Inc.), Chemical Manager Warren Jederberg (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).



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5 Lewisite1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin- guished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory 1 This document was prepared by the AEGL Development Team composed of Cher- yl Bast (Oak Ridge National Laboratory), Julie Klotzbach (SRC, Inc.), Chemical Manag- er Warren Jederberg (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed neces- sary. Both the document and the AEGL values were then reviewed by the National Re- search Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC com- mittee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 130

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Lewisite 131 effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopula- tions, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic respons- es, could experience the effects described at concentrations below the corre- sponding AEGL. SUMMARY Because lewisite compounds were developed as chemical warfare agents, military literature is a major source of relevant toxicity data. Consequently, many of the study reports have “limited distribution", which is a separate issue from “classification”. For various reasons, sources may have a restricted distri- bution because of treaty restrictions on data access with allies, concerns regard- ing distribution of engineering information characterizing agent dissemination or generation in other sections of the same document, and related issues. To ensure public access to pertinent toxicity data originating from limited-distribution ma- terials, pertinent data from those sources have been incorporated into this chap- ter.2 Lewisite-1 (L-1) is an organic arsenical with vesicant properties. It can ex- ist as a trans-isomer or a cis-isomer; in aqueous solutions, the cis-isomer under- goes photoconversion to the trans-isomer. Lewisite causes local corrosive dam- age and may cause systemic poisoning after absorption through skin or mucous membranes. Exposure to lewisite causes almost immediate irritation and burning sensation in the eyes, skin, upper respiratory tract, and lungs. Death may result from direct pulmonary damage or from circulatory failure due to fluid loss and 2 The NRC committee that reviewed this document was not provided with the lim- ited-distribution materials, so it relied on the information as presented in the text.

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132 Acute Exposure Guideline Levels arrhythmia. Death that occurs within 24 h of exposure is likely due to pulmonary damage (Lindberg et al. 1997). Lewisite-2 (L-2) and lewisite-3 (L-3) are co- products concurrently formed with L-1(Trammel 1992). L-1 yield is greater than 65%, and approximate yields of L-2 and L-3 are 7-10% and 4-12%, respectively (Lindberg et al. 1997). L-2 and L-3 are present in smaller quantities and have comparatively low volatility, so those compounds will be less toxicologically significant than L-1. Furthermore, the toxicity of L-2 and L-3 is comparable to L-1 (Lindberg et al. 1997). Therefore, AEGL values were derived for “lewisite”, rather than for the individual lewisite compounds, and are considered protective for L-1, L-2, and L-3 compounds. Appropriate data were not available for deriving AEGL-1 values for lewis- ite. Odor cannot be used as a warning for potential exposure. For L-1, the odor threshold is reported to be between 14-23 mg/m3 (1.7-2.7 ppm), concentrations greater than those that are highly irritating and higher than the AEGL-2 and AEGL-3 values. Therefore, AEGL-1 values are not recommended. No inhalation studies with both concentration and duration parameters and with effects consistent with the definition of AEGL-2 end points were available. Therefore, the AEGL-2 values for lewisite, were determined by taking a three- fold reduction in the AEGL-3 values; the resulting values are considered to be estimated thresholds for irreversible effects (NRC 2001). The reduction ap- proach is considered appropriate because of the steep concentration-response curve for mortality from lewisite. In studies with mice, the 10-min LC50 (lethal concentration, 50% lethality) was 200 mg/m3 [24 ppm], and the 10-min LC100 (lethal concentration, 100% lethality) was 240 mg/m3 [28 ppm]. In dogs, no deaths occurred after a 7.5-min exposure to lewisite at 126 mg/m3 [15 ppm], and the LC50 was 176 mg/m3 [21 ppm]). AEGL-3 values for lewisite were based on lethality data for L-1 in dogs (Armstrong 1923). Points of departure were the calculated LC01 values: 38.7 mg/m3 (4.6 ppm) for the 10-min value, 14.0 mg/m3 (1.7 ppm) for the 30-min value, 7.4 mg/m3 (0.87 ppm) for the 1-h value, 2.1 mg/m3 (0.25 ppm) for the 4-h value, and 1.1 mg/m3 (0.13 ppm) for the 8-h value. The LC01 values are consid- ered estimated lethality thresholds. Interspecies and intraspecies uncertainty factors of 3 each were applied. The interspecies uncertainty factor of 3 is sup- ported by data suggesting little species variability with regard to lethality from inhalation exposure to lewisite; C × T values are relatively constant across spe- cies, except for the guinea pig, and the interspecies uncertainty factor of 3 en- compasses the two- to three-fold difference in sensitivity between guinea pigs and rats, mice, rabbits, dogs, and goats. The intraspecies uncertainty factor of 3 is supported by the steep concentration-response curve with regard to lethality, which implies limited intraspecies variation. Thus, the total uncertainty factor was 10. The AEGL values for lewisite are presented in Table 5-1.

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Lewisite 133 TABLE 5-1 AEGL Values for Lewisite End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1a NR NR NR NR NR Insufficient (nondisabling) data AEGL-2 1.3 mg/m3 0.47 mg/m3 0.25 mg/m3 0.070 mg/m3 0.037 mg/m3 One-third (disabling) (0.15 (0.055 (0.030 (0.0083 (0.0044 of AEGL-3 ppm) ppm) ppm) ppm) ppm) values AEGL-3 3.9 mg/m3 1.4 mg/m3 0.74 mg/m3 0.21 mg/m3 0.11 mg/m3 Dog LC01 (lethal) (0.46 (0.16 (0.087 (0.025 (0.013 values ppm) ppm) ppm) ppm) ppm) (Armstrong 1923). Abbreviations: LC01, lethal concentration, 1% lethality; NR, not recommended. a Absence of AEGL-1 values does not imply that exposure below the AEGL-2 values is without adverse effects. 1. INTRODUCTION Lewisite is an organic arsenical with vesicant properties. It can exist as a trans- or cis-isomer; in aqueous solutions, the cis-isomer undergoes photocon- version to the trans-isomer. Pure lewisite is a colorless, odorless oily liquid; however, synthesized agent is an amber to dark brown liquid with a geranium- like odor (Munro et al. 1999). Lewisite causes local corrosive damage and may cause systemic poisoning after absorption through skin or mucous membranes. Exposure to lewisite causes almost immediate irritation and burning sensation of the eyes, skin, upper respiratory tract, and lungs. Death may result from direct pulmonary damage or circulatory failure from fluid loss and arrhythmia. Death that occurs within 24 h of exposure is likely due to pulmonary damage (Lind- berg et al. 1997). Lewisite was developed as a chemical warfare blister agent during the lat- ter part of World War I and was named after its inventor Captain W. Lee Lewis. When the first ship loaded with lewisite reached Europe in 1918, the war ended, and the cargo was dumped into the sea. During the period between World War I and World War II, few studies on lewisite were conducted; however, when World War II began, the research efforts intensified. Results of those studies suggested that lewisite had limited utility as a war gas because of hydrolysis to a nonvolatile and water insoluble oxide, poor penetration of protective clothing, and difficulty in attaining lethal concentrations on the battle field (Lindberg et al. 1997). Also, lewisite is so immediately irritating at low concentrations (about 6-8 mg/m3) that troops would be warned of its presence, even before detecting the geranium-like odor at 14-23 mg/m3, and take protective action by deploying gas masks or retreating from the toxic atmosphere (Gates et al. 1946). Lewisite-1 (L-1) is formed by the reaction of acetylene with arsenic trichlo- ride using aluminum trichloride as a catalyst. Arsenic trichloride, lewisite-2 (L-2),

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134 Acute Exposure Guideline Levels and lewisite-3 (L-3) are co-products concurrently formed with L-1 (Trammel 1992). L-1 yield is greater than 65%, and approximate yields of arsenic trichloride, L-2, and L-3 are 16-21%, 7-10%, and 4-12%, respectively (Lindberg et al. 1997). Therefore, an accidental release from storage tanks of L-1 will likely be the release of a mixture of L-1, L-2, L-3, and arsenic trichloride. Exposure will be to these compounds and to potential hydrolysis products, sodium arsenite (NaAsO2) and arsenic acid (H3AsO4). Toxicologic data on arsenic trichloride are limited; howev- er, effects are similar to those of L-1 (corrosiveness, damage to skin, eyes, and mucous membranes). With regard to lethality, arsenic trichloride appears to be approximately 2-3 times less toxic than L-1; the LCt50 (lethal concentration [prod- uct of concentration and time] that will cause death in 50% of the exposed popula- tion) for arsenic trichloride is 4,000-5,000 mg-min/m3 whereas the LCt50 for L-1 is 1,200-1,500 mg-min/m3 (Flury 1921). L-2 and L-3 will be less significant toxico- logically because of their smaller quantities and comparatively low volatility. However, the toxicity of L-2 and L-3 is reportedly comparable to L-1 (Lindberg et al. 1997). Therefore, AEGL values were derived for “lewisite” rather than for the individual lewisite compounds, and are considered protective for L-1, L-2, and L- 3. In addition, in the review of literature, L-1, L-2, and L-3 are discussed only if the primary literature makes a distinction. A summary of the nomenclature for the lewisite compounds is presented in Table 5-2, and chemical and physical data are summarized in Table 5-3. 2.1. Acute Lethality Gates et al. (1946) estimated (based on animal data presented later in this chapter) that the inhalation LC50 for lewisite vapor in humans was 120 mg/m3 for 10 min and 50 mg/m3 for 30 min. An LC50 of 3,300 mg/m3 for 30 min for lewisite vapor absorption through the bare skin was also estimated. This estimate is based on animal data and assumes that absorption of lewisite through skin is a function of the ratio of surface exposed to body volume. A dermal LD50 of more than 40 mg/kg was also estimated by Gates et al. (1946) based on ani- mal data presented later in this chapter. TABLE 5-2 Nomenclature for Lewisite Agents Military Common Name Designator Chemical Names and Synonyms CAS Registry No. Lewisite-1 L or L-1 2-Chlorovinyldichloroarsine; 541-25-3 (2-chlorovinyl)arsenous dichloride; beta-chlorovinyldichloroarsine; dichloro(2-chlorovinyl) arsine; chlorovinylarsine dichloride; EA 1034 Lewisite-2 L-2 bis-(2-chlorovinyl)chloroarsine 40334-69-8 Lewisite-3 L-3 tris-(2-chlorovinyl)arsine 40334-70-1 Sources: Gates et al. 1946; Cookson and Nottingham 1969; USACHPPM 1996.

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Lewisite 135 TABLE 5-3 Chemical and Physical Data for Lewisite Compounds Parameter Value Reference Chemical formula Lewisite-1 (L or L-1) ClCH=CHAsCl2 Gates et al. 1946 Lewisite-2 (L-2) (ClCH=CH)2 AsCl Gates et al. 1946 Lewisite-3 (L-3) (ClCH=CH)3As Gates et al. 1946 Molecular weight Lewisite-1 (L or L-1) 207.32 HSDB 2008; Lewisite-2 (L-2) 233.32 Lindberg et al. 1997 Lewisite-3 (L-3) 259.35 Physical state Lewisite-1 (L or L-1) Oily liquid for all forms Lindberg et al. 1997 Lewisite-2 (L-2) Lewisite-3 (L-3) Color Lewisite-1 (L or L-1) Mixture: amber to brown Munro et al. 1999 Lewisite-2 (L-2) Colorless (pure) Munro et al. 1999 Lewisite-3 (L-3) – Melting point Lewisite-1 (L or L-1) 0.1°C HSDB 2008 Lewisite-2 (L-2) – Lewisite-3 (L-3) – Boiling point Lewisite-1 (L or L-1) 190°C Trammel 1992 Lewisite-2 (L-2) – Lewisite-3 (L-3) – Specific gravity (water = 1) Lewisite-1 (L or L-1) 1.888 at 20°C HSDB 2008 Lewisite-2 (L-2) – Lewisite-3 (L-3) – Density (air = 1) Lewisite-1 (L or L-1) 7.1 Trammel 1992 Lewisite-2 (L-2) – Lewisite-3 (L-3) – Solubility Lewisite-1 (L or L-1) Insoluble in water; soluble in most USACHHPM 1996 Lewisite-2 (L-2) organic solvents USACHHPM 1996 Lewisite-3 (L-3) Insoluble in water; soluble in most USACHHPM 1996 organic solvents Insoluble in water; soluble in most organic solvents Vapor pressure Lewisite-1 (L or L-1) 0.34 mm Hg at 25°C; 0.22 mm Hg at 20°C USACHHPM 1996 Lewisite-2 (L-2) – Lewisite-3 (L-3) – Conversion factors Lewisite-1 (L or L-1) 1 mg/m3 = 0.118 ppm Lewisite-2 (L-2) 1 ppm = 8.48 mg/m3 Lewisite-3 (L-3)

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136 Acute Exposure Guideline Levels 2. HUMAN TOXICITY DATA 2.2. Nonlethal Toxicity 2.2.1. Individual Studies Lewisite is immediately and highly irritating at concentrations of about 6- 8 mg/m3. The geranium-like odor is reportedly detectable at 14-23 mg/m3 (Gates et al. 1946). Inhalation of lewisite at10 mg/m3 for 30 min reportedly resulted in severe intoxication and incapacitation that lasted for several weeks, and exposure at 10 mg/m3 for 15 min caused inflammation of the eyes and swelling of the eyelids (Franke 1968, as cited in Ottinger et al. 1973). Ottinger et al. (1973) is a review article, and did not provide experimental details or information regarding the severity of effects. No further details were available. A dermal vapor study was conducted by Eldridge (1923). To select “men of average resistance” for the study, pin-point drops of 0.1 or 2% solutions of liquid lewisite in alcohol were applied to the forearms of 52 male volunteers at Edge- wood Arsenal. If a subject showed no reaction to the 2% solution, he was classi- fied as “resistant” and not used in the dermal vapor study. If a subject showed a marked reaction to the 0.1% solution, he was classified as “sensitive” and not used in the dermal vapor study. Of the 52 men, 14 were resistant and 3 were sensitive. Further dermal tests with liquid lewisite were done on the sensitive and resistant subjects; the tests showed that the sensitive subjects had no effects when treated with a 0.01% lewisite solution, and the resistant subjects developed blistering with a 5% solution. Dermal effects included blanching or graying of the skin, followed by severe erythema within 15-30 min. Vesication, accompanied by some edema, occurred within 12 h. Within less than 24 h, a raised area of redness measuring 2 × 2.5 inches in diameter appeared, accompanied by a 1.5-inch diameter blister sur- rounded by hundreds of minute vesicles. Forty-eight hours later, the raised area of redness had increased to 6 × 3.5 inches in diameter, and fluid seeped from the blis- ter. The smaller vesicles also ruptured as the severity of the burns continued to increase up to the fourth day. No change was noted from days 4 to 7, and from day 7 onward improvement was observed until the burns were completely healed by the end of week 4. The men described a stinging sensation that lasted for 2 min and occurred within 2.5 min of exposure. No further sensation was noted until approximately 20 min later, when the stinging sensation was again reported and lasted for approximately 2 h. Five hours later, a “continuous feeling of discomfort” was described; burning lasted until the blister ruptured 22.5 h after lewisite was administered. Intermittent stinging and burning followed and the area became sore to the touch. By the end of day 6, the pain was more severe and occurred at shorter time intervals. By day 9, all pain had resolved. Groups of 1-7 men (from the 35 male volunteers of average sensitivity de- scribed above) were exposed on their arms to varying concentrations of lewisite vapor for periods ranging from 10 min to 3 h to determine the concentration nec-

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Lewisite 137 essary to produce blistering (Eldridge 1923). The exposure apparatus allowed for a constant stream of air-lewisite mixture to pass over a square centimeter area of the subject’s forearm under atmospheric pressure. Lewisite concentrations were de- termined by dividing the loss in weight of the gas container by the total volume of air passing through the apparatus during the test. Skin burns ranged in severity from reddish discoloration to a clear watery blister over the entire burned area, accompanied by reddening, swelling, and hardening of the surrounding skin. The burns reached maximum severity in 36-48 h, and healing was complete in 6 days to 2 weeks. The men reported that the healed skin remained sensitive for several weeks after the healing was complete. Data from this study are summarized in Table 5-4. Lewisite liquid at doses of 3.5, 7, and 14 μg produced erythema and vesica- tion of human skin, and doses of 22, 32, and 40 μg produced vesication (NDRC 1944). Davis (1943) analyzed fluid from human lewisite blisters and found arse- nic at 0.8-1.3 mg/mL, equivalent to 2.5-4.0 mg of lewisite. 2.2.2. Case Report A male worker at Pine Bluff Arsenal experienced lewisite burns over 20% of his body surface, with the majority of burns on his legs. He hadan anemia 10- 15 days after the burn, but had no signs of systemic arsenic poisoning (Gates et al. 1946). No further information was available on this incident. 2.3. Developmental and Reproductive Effects Human developmental and reproductive toxicity data concerning lewisite were not found. 2.4. Genotoxicity Human genotoxicity toxicity data concerning lewisite were not found. TABLE 5-4 Average Lewisite Concentration Causing Blistering on Human Forearm Skin Duration of Exposure (min) Average Blistering Concentration (mg/m3) 5 2,090 10 1,040 30 340 60 150 120 62 180 26.2 Source: Eldridge 1923.

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138 Acute Exposure Guideline Levels 2.5. Carcinogenicity In 1940, a World War II German soldier was accidentally exposed to lew- isite on his lower right leg. The blistered lesion never healed, and was diagnosed as malignant in 1948. Bowen’s disease (intraepidermal squamous cell carcino- ma) was diagnosed 38 years later (Krause and Grussendorf 1978). Wada et al. (1962) reported increased incidences of cancer mortality (14% respiratory tract; 9.6% digestive tract) in workers from the Okuno-Jima poison gas factory. When cancer rates were correlated with job classification, the fre- quency of respiratory and gastrointestinal tract neoplasms were highest in work- ers involved in the production of mustard gas or lewisite, followed by those who worked indirectly with mustard gas or lewisite, and the lowest frequency was found in those that had no direct contact with mustard or lewisite (Yamakido et al. 1985). However, this information is confounded by the fact that workers were also exposed to mustard gas in addition to lewisite, and the factory also produced hydrocyanic acid, diphenylcyanarsine, chloroacetophenone, and phos- gene. 2.6. Summary Exposure to lewisite in air and by contact to liquid causes immediate irri- tation, burning, and corrosive damage to the eyes and exposed skin; inhalation exposure may also affect the upper airway and lungs. Human exposure data are dated and studies are, in many cases, not well described. No information con- cerning developmental or reproductive toxicity or genotoxicity with regard to lewisite exposure in humans was identified. Information suggesting an increased cancer incidence in workers from a Japanese poison gas factory is confounded because workers were exposed to several chemicals. Selected data on humans exposed to lewisite by inhalation are summarized in Table 5-5, and selected data on human exposed to liquid lewisite are presented in Table 5-6. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality Several inhalation LC50 values were identified in the literature. In some cases no detailed methods were presented; however, only data from studies where concentrations were reported to be analytically determined are presented in this chapter. Oral, dermal, subcutaneous, and intravenous LD50 values were also identified in a variety of species. A 9-min LC50 of 166 mg/m3 was reported for rats (Gates et al. 1946). An oral LD50 of 50 mg/kg (U.S. Army 1974), dermal LD50 of 24 mg/kg (Cameron et al. 1946), and subcutaneous LD50 of 1 mg/kg (Cameron et al. 1946) were report- ed for rats.

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Lewisite 139 TABLE 5-5 Data on Humans Exposed to Lewisite in Air Exposure Concentration C × T Effect Duration (min) (mg/m3) (mg-min/m3) Reference Odor perception Threshold 14-23 – Gates et al. 1946 Nasal irritation, mild Threshold 0.8 – Prentis 1937 Irritation, pronounced Threshold 2.0 – Cherkes et al. 1965 Irritation, highly irritating Threshold 6-8 – Gates et al. 1946 Irritation, severe Threshold 10-30 – Cherkes et al. 1965 Ocular inflammation/ 15 10 150 Ottinger et al. 1973 swelling Incapacitation 30 10 300 Ottinger et al. 1973 Skin lesions 5 2,090 10,450 Eldridge 1923 (skin exposure) 10 1,040 10,400 30 340 10,200 60 150 9,000 120 62 7,440 180 26.2 4,716 Estimated inhalation LC50 10 120 1,200 Gates et al. 1946 Estimated inhalation LC50 30 50 1,500 Gates et al. 1946 Estimated percutaneous LC50 30 3,300 100,000 Gates et al. 1946 TABLE 5-6 Skin Effects in Humans Exposed to Liquid Lewisite Dose (µg) Effect Incidence Reference 3.5 Erythema 24/29 NRDC 1944 Vesication 21/29 7 Erythema 30/30 NRDC 1944 Vesication 30/30 14 Erythema 26/26 NRDC 1944 Vesication 26/26 22 Vesication 10/10 CWS 1944 32 Vesication 7/9 CWS 1944 40 Vesication 100% CWS 1944 3.1.1. Rats Olajos et al. (1998) exposed groups of six male and six female Sprague- Dawley rats (head-only) to product solution (waste stream) from the chemical neutralization of Chemical Agent Identification Sets (CAIS). The CAIS waste stream contained chloroform (vehicle), t-butanol (vehicle), and lewisite. Expo- sures to the CAIS waste stream were at 6,000, 12,000, 18,000, or 24,000 ppm and to the chloroform-butanol solvent were at 24,000 ppm for 1 h. The concen-

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140 Acute Exposure Guideline Levels tration of lewisite in the test atmospheres was 0, 0.17, 0.67, 0.96, and 0.31 mg/m3 for the vehicle controls and the 6,000, 12,000, 18,000, and 24,000 ppm groups, respectively. Toxic signs were consistent with those of chloroform and butanol, and were noted in the control (vehicle) and waste-stream exposed ani- mals. Ocular effects (corneal opacity and erosion) and pulmonary function ef- fects (decreased minute volume) were similar in control and waste-stream ex- posed groups. The authors concluded that effects were due to chloroform and butanol, not lewisite. 3.1.2. Mice Silver and McGrath (1943) exposed groups of 20 male CF-1 mice to vary- ing concentrations of cis- or trans-lewisite for 10 min. Animals were exposed in a 386-L continuous flow chamber. Lewisite was vaporized by passing 20-30 L of air per minute (L/min) through lewisite in a bubbler at room temperature. Chamber airflow was maintained at 250 L/min. Lewisite concentrations in the chamber were measured analytically using a wet test meter. No animals were placed in the chamber until the chamber atmosphere reached equilibrium (ap- proximately 10 min). Ten-min mouse LC50 values of 190 and 200 mg/m3 were determined for the cis- and trans-isomers, respectively. All mice exposed to lewisite for 10 min at 240 mg/m3 died. 3.1.3. Dogs In an acute inhalation toxicity study, Armstrong (1923) exposed groups of dogs (sex not reported) to varying concentrations of L-1(purity 99%) for 7.5, 15, 30, 60, 120, or 240 min. The number of dogs per group varied from 1 to 17 (see Table 5-7); no explanation for the variation was provided. The dogs were ex- posed in an air-tight glass chamber (74.9 × 69.6 × 71.2 cm) with a sliding front and entrance and exit ports for the air-lewisite mixture. Affluent air was sup- plied by an air pump and was passed through a series of drying bottles. Dried air was then passed through a flowmeter to regulate the amount entering the expo- sure chamber. This metered stream then entered a bubbler containing the lewis- ite; the bubbler was immersed in a water bath so that it could be heated or cooled. The temperature of the bath and flow rate was then adjusted to prede- termined points (from blank runs) to obtain the desired chamber concentrations. Lewisite concentrations in the exposure chamber were determined analytically from samples aspirated from the chamber during exposures. Clinical signs in dogs exposed for 7.5 or 15 min included detection of lew- isite within 30 seconds, as evidenced by continual eye blinking, followed by excessive nasal secretion, lacrimation, and sneezing (Armstrong 1923). Vomit- ing occurred and ocular irritation was observed in some dogs before exposure ended. In dogs exposed for 30-min or longer, frequent retching, vomiting, ex- treme salivation, and labored breathing were observed, in addition to signs noted

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Lewisite 155 Young, R.A. 1999. Appendix F. Health risk assessment for lewisite. Pp. 277-294 in Re- view of the U.S. Army’s Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents. Washington, DC: National Academy Press.

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156 Acute Exposure Guideline Levels APPENDIX A DERIVATION OF AEGL VALUES FOR LEWISITE Derivation of AEGL-1 Values The available data were insufficient to derive AEGL-1 values for lewisite. Derivation of AEGL-2 Values In the absence of relevant data to derive AEGL-2 values, a one-third re- duction of the AEGL-3 values was used to derive AEGL-2 values (NRC 2001). 10-min AEGL-2: 3.9 mg/m3 ÷ 3 = 1.3 mg/m3 30-min AEGL-2: 1.4 mg/m3 ÷ 3 = 0.47 mg/m3 1-h AEGL-2: 0.74 mg/m3 ÷ 3 = 0.25 mg/m3 4-h AEGL-2: 0.21 mg/m3 ÷ 3 = 0.070 mg/m3 8-h AEGL-2: 0.11 mg/m3 ÷ 3 = 0.037 mg/m3 Derivation of AEGL-3 Values Key study: Armstrong, G.C. 1923. The toxicity of M-1 by inhalation for dogs. Chapter II in The Toxicity, Pathology, Chemistry, Mode of Action, Penetration, and Treatment for M-1 and its Mixtures with Arsenic Trichloride, Part 1. ADB954935. Edgewood Arsenal, Aberdeen Proving Ground, MD. August 13, 1923. (unclassified report/limited distribution). Toxicity end point: Calculated LC01 values (estimated 1% lethality thresholds) 10-min 38.7 mg/m3 30-min 14.0 mg/m3 1-h 7.4 mg/m3 4-h 2.1 mg/m3 8-h 1.1 mg/m3 Uncertainty factors: 3 for interspecies differences 3 for intraspecies variability

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Lewisite 157 Appropriate chemical-specific data were not available to derive AEGL-3 values for L-2 or L-3. However, L-2 and L-3 exist as a small fraction of total lewisite (7-10% for L-2 and 4-12% for L-3) and have comparatively low volatilities. Because of these chemical characteristics, AEGL-3 values for L-1 were adopted as AEGL-3 values for the mixture of L-1, L-2, and L-3. Calculations: 10-min AEGL-3: 38.7 mg/m3 ÷ 10 = 3.9 mg/m3 30-min AEGL-3: 14.0 mg/m3 ÷ 10 = 1.4 mg/m3 1-h AEGL-3: 7.4 mg/m3 ÷ 10 = 0.74 mg/m3 4-h AEGL-3: 2.1 mg/m3 ÷ 10 = 0.21 mg/m3 8-h AEGL-3: 1.1 mg/m3 ÷ 10 = 0.11 mg/m3

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158 Acute Exposure Guideline Levels APPENDIX B ACUTE EXPOSURE GUIDELINE LEVELS FOR LEWISITE Derivation Summary AEGL-1 VALUES The available data on lewisite were inadequate to derive AEGL-1 values. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 3 3 3 3 1.3 mg/m 0.47 mg/m 0.25 mg/m 0.070 mg/m 0.037 mg/m3 (0.15 ppm) (0.055 ppm) (0.030 ppm) (0.0083 ppm) (0.0044 ppm) Data adequacy: The available data on lewisite were inadequate to derive AEGL-2 values. When data are lacking and the concentration-response curve is steep, AEGL-2 values may be derived by dividing the AEGL-3 values by 3 (NRC 2001). A steep concentration- response curve has been demonstrated for lewisite. In studies with mice, the 10-min LC50 was 200 mg/m3 and the 10-min LC100 was 240 mg/m3. In dogs, no deaths occurred after a 7.5-min exposure to lewisite at 126 mg/m3, and the LC50 was 176 mg/m3. AEGL-3 VALUES 10 min 30 min 1h 4h 8h 3.9 mg/m3 1.4 mg/m3 0.74 mg/m3 0.21 mg/m3 0.11 mg/m3 (0.46 ppm) (0.16 ppm) (0.087 ppm) (0.025 ppm) (0.013 ppm) Key reference: Armstrong, G.C. 1923. The toxicity of M-1 by inhalation for dogs. Chapter II in The Toxicity, Pathology, Chemistry, Mode of Action, Penetration, and Treatment for M-1 and its Mixtures with Arsenic Trichloride. Part 1. ADB954935. Edgewood Arsenal, Aberdeen Proving Ground, MD. August 13, 1923. (unclassified report/limited distribution). Test species/Strain/Number: Dog; breed not specified; 1-17 per group. Exposure route/Concentrations/Durations: Inhalation; 126, 176, 231, 274, and 330 mg/m3 for 7.5 min Inhalation; 68.7, 87.7, 96, 102, 125, and 233 mg/m3 for 15 min Inhalation; 11.5, 24.5, 30.6, 41.5, 48, and 58.6 mg/m3 for 30 min Inhalation; 5.8, 8, 25, 35, 43, and 53 mg/m3 for 1 h Inhalation; 4.8, 12.5, 17.9, 24.5, and 34.5 mg/m3 for 2 h Inhalation; 2.1, 6.2, 10, and 16.9 mg/m3 for 4 h Effects: Concentration (mg/m3) 176 7.5-min LC50 100 15-min LC50

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Lewisite 159 48 30-min LC50 25.7 1-h LC50 11.8 2-h LC50 6.6 4-h LC50 38.7 10-min LC01 14.0 30-min LC01 7.4 1-h LC01 2.1 4-h LC01 1.1 8-h LC01 End point/Concentration/Rationale: Calculated LC01 values, considered thresholds for lethality. Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3, data suggest little species variability with regard to lethality from inhalation exposure to L-1; C × T values are relatively constant across species, except for the guinea pig, and the interspecies uncertainty factor of 3 encompasses the 2- to 3-fold difference in sensitivity between guinea pigs and rats, mice, rabbits, dogs, and goats. Intraspecies: 3, steep concentration-response curve with regard to lethality implies limited intraspecies variation. In studies with mice, the 10-min LC50 was 200 mg/m3 and the 10-min LC100 was 240 mg/m3. In dogs, no deaths occurred after a 7.5-min exposure to lewisite at 126 mg/m3, and the LC50 was 176 mg/m3. Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Not applicable Time scaling: Points of departure were time-specific LC01 values. Data adequacy: Data are adequate to derive AEGL-3 values for lewisite.

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160 Acute Exposure Guideline Levels APPENDIX C CALCULATION OF LC01 VALUE FOR DOGS Data source: Armstrong (1923) Filename: ten Berge Spreadsheet Data for Log Probit Model Date: 15 October 2010 Time: 09:03:51 Sequence No. Concentration (mg/m3) Minutes Exposed Responded 1 126 7.5 2 0 2 176 7.5 12 7 3 231 7.5 17 10 4 274 7.5 4 4 5 330 7.5 1 1 6 68.7 15 4 1 7 87.7 15 5 2 8 96 15 5 3 9 102 15 3 2 10 125 15 12 6 11 233 15 3 3 12 11.5 30 1 0 13 24.5 30 4 0 14 30.6 30 2 0 15 41.5 30 2 0 16 48 30 3 2 17 58.6 30 4 4 18 5.8 60 2 0 19 8 60 5 0 20 25 60 9 5 21 35 60 9 5 22 43 60 7 5 23 53 60 1 1 24 4.8 120 4 0 25 12.5 120 3 2 26 17.9 120 6 4 27 24.5 120 5 4 28 34.5 120 3 3 29 2.1 240 3 0 30 6.2 240 9 5 31 10 240 17 10 32 16.9 240 2 2

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Lewisite 161 Used Probit Equation Y = B0 + B1*X1 + B2*X2 X1 = concentration mg/m3, ln-transformed X2 = minutes, ln-transformed Chi-Square = 15.93 Degrees of freedom = 29 Probability Model = 9.76E-01 Ln(Likelihood) = -29.24 B 0 = -7.7323E+00 Student t = -3.1898 B 1 = 1.7999E+00 Student t = 5.3334 B 2 = 1.6615E+00 Student t = 5.2230 Variance B 0 0 = 5.8761E+00 Covariance B 0 1 = -8.1104E-01 Covariance B 0 2 = -7.6250E-01 Variance B 1 1 = 1.1390E-01 Covariance B 1 2 = 1.0355E-01 Variance B 2 2 = 1.0120E-01 Estimation ratio between regression coefficients of ln(conc) and ln(minutes) Point estimate = 1.083 Lower limit (95% CL) = 0.976 Upper limit (95% CL) = 1.191 Estimation of concentration mg/m3 at response of 1% Minutes = 10 Point estimate concentration mg/m3 = 3.869E+01 for response of 1% Lower limit (95% CL) concentration mg/m3 = 1.699E+01 for response of 1% Upper limit (95% CL) concentration mg/m3 = 5.741E+01 for response of 1% Estimation of concentration mg/m3 at response of 1% Minutes = 30 Point estimate concentration mg/m3 = 1.403E+01 for response of 1% Lower limit (95% CL) concentration mg/m3 = 6.185E+00 for response of 1% Upper limit (95% CL) concentration mg/m3 = 2.064E+01 for response of 1% Estimation of concentration mg/m3 at response of 1% Minutes = 60 Point estimate concentration mg/m3 = 7.400E+00 for response of 1% Lower limit (95% CL) concentration mg/m3 = 3.237E+00 for response of 1% Upper limit (95% CL) concentration mg/m3 = 1.094E+01 for response of 1%

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162 Acute Exposure Guideline Levels Estimation of concentration mg/m3 at response of 1% Minutes = 120 Point estimate concentration mg/m3 = 3.903E+00 for response of 1% Lower limit (95% CL) concentration mg/m3 = 1.682E+00 for response of 1% Upper limit (95% CL) concentration mg/m3 = 5.838E+00 for response of 1% Estimation of concentration mg/m3 at response of 1% Minutes = 240 Point estimate concentration mg/m3 = 2.058E+00 for response of 1% Lower limit (95% CL) concentration mg/m3 = 8.675E-01 for response of 1% Upper limit (95% CL) concentration mg/m3 = 3.138E+00 for response of 1% Estimation of concentration mg/m3 at response of 1% Minutes = 480 Point estimate concentration mg/m3 = 1.085E+00 for response of 1% Lower limit (95% CL) concentration mg/m3 = 4.447E-01 for response of 1% Upper limit (95% CL) concentration mg/m3 = 1.697E+00 for response of 1%

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Lewisit te 1 163 AP PPENDIX D CATEGORY PLOT FOR L C P LEWISITE FIGUR D-1 Category plot of anima and human to RE y al oxicity data and AEGL values for d lewisite e.

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164 TABLE D-1 Data Used in the Category Plot for Lewisite Source Species Sex No. of Exposures mg/m3 Minutes Category Comments AEGL-1 NR 10 AEGL AEGL-1 NR 30 AEGL AEGL-1 NR 60 AEGL AEGL-1 NR 240 AEGL AEGL-1 NR 480 AEGL AEGL-2 1.3 10 AEGL AEGL-2 0.47 30 AEGL AEGL-2 0.25 60 AEGL AEGL-2 0.070 240 AEGL AEGL-2 0.037 480 AEGL AEGL-3 3.9 10 AEGL AEGL-3 1.4 30 AEGL AEGL-3 0.74 60 AEGL AEGL-3 0.21 240 AEGL AEGL-3 0.11 480 AEGL Franke 1968 Human 1 10 30 2 Severe intoxication, incapacitation Silver and McGrath 1943 Mouse Male 1 240 10 3 Mortality (10/10) Armstrong 1923 Dog 1 126 7.5 2 Mortality (0/2) Dog 1 176 7.5 SL Mortality (7/12) Dog 1 274 7.5 3 Mortality (4/4) Dog 1 68.7 15 SL Mortality (1/4) Dog 1 102 15 SL Mortality (2/3) Dog 1 233 15 3 Mortality (3/3)

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Dog 1 41.5 30 2 Mortality (0/2) Dog 1 58.6 30 3 Mortality (4/4) Dog 1 8 60 2 Mortality (0/5) Dog 1 25 60 SL Mortality (5/7) Dog 1 53 60 3 Mortality (1/1) Dog 1 4.8 120 2 Mortality (0/4) Dog 1 12.5 120 SL Mortality (2/3) Dog 1 34.5 120 3 Mortality (3/3) Dog 1 2.1 240 2 Mortality (0/3) Dog 1 6.2 240 SL Mortality (5/9) Dog 1 16.9 240 3 Mortality (2/2) Harrison et al. 1946 Dog 1 50 30 SL Dog 1 121 10 SL Gates et al. 1946 Dog 1 20 30 2 Ocular lesions Silver and McGrath 1943 Mouse 1 240 10 3 100% mortality (10/10) Gates et al. 1946 Rat 1 166 9 SL LC50 Silver and McGrath 1943 Mouse 1 190 10 SL LC50 Silver and McGrath 1943 Mouse 1 200 10 SL LC50 Silver and McGrath 1943 Mouse 1 240 10 3 100% mortality (10/10) Gates et al. 1946 Guinea pig 1 8 60 SL LC50 Gates et al. 1946 Rabbit 1 160 7.5 SL LC50 Gates et al. 1946 Rabbit 1 25 60 SL LC50 Gates et al. 1946 Goat 1 12.5 100 SL LC50 For category: 0 = no effect, 1 = discomfort, 2 = disabling, 3 = lethal; SL = some lethality. 165