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Sulfur Mustard (Agent HD)1

Acute Exposure Guideline Levels

SUMMARY

Sulfur mustard (agent HD) is an alkylating chemical vesicant that affects any epithelial surface it comes in contact with; it has been developed and used as a warfare agent. The active component is bis(2-chloroethyl)sulfide (CAS Registry No. 505–60–2). Although the chemical is a liquid at ordinary ambient temperatures, its volatility results in rapid generation of vapors that have a garlic-like odor. Due to its low aqueous solubility, it is

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This document was prepared by the AEGL Development Team comprising Robert Young (Oak Ridge National Laboratory) and Kenneth Still (Chemical Manager) of the National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances. The NAC reviewed and revised the document and the AEGL values as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).



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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 2 Sulfur Mustard (Agent HD)1 Acute Exposure Guideline Levels SUMMARY Sulfur mustard (agent HD) is an alkylating chemical vesicant that affects any epithelial surface it comes in contact with; it has been developed and used as a warfare agent. The active component is bis(2-chloroethyl)sulfide (CAS Registry No. 505–60–2). Although the chemical is a liquid at ordinary ambient temperatures, its volatility results in rapid generation of vapors that have a garlic-like odor. Due to its low aqueous solubility, it is 1   This document was prepared by the AEGL Development Team comprising Robert Young (Oak Ridge National Laboratory) and Kenneth Still (Chemical Manager) of the National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances. The NAC reviewed and revised the document and the AEGL values as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 persistent in the environment. Odor thresholds of 1 mg·min/m3, 0.15 mg/m3, and 0.6 mg/m3 have been reported. Among various U.S. Army facilities, there are currently approximately 17,018.1 tons of sulfur mustard (agent HD) awaiting disposal. Exposure to sulfur mustard vapor may result in irritation and damage to the eyes, respiratory tract, and skin. The toxic effects of sulfur mustard are temperature- and humidity-dependent; for a given exposure, the effects could be greater with increasing temperature and humidity. An exposure-dependent latency period of hours to days is documented and is relevant for all routes of exposure but may be shorter for ocular and upper respiratory tract effects than for dermal and systemic responses. Both human and animal data indicate that the eyes are the most sensitive organ/tissue; deaths resulting from sulfur mustard exposure are more often the result of respiratory tract involvement. Because the toxic effects of sulfur mustard (at least for short time periods) appear to be a linear function of exposure duration and exposure concentration, most of the available exposure-response data are expressed as cumulative exposures (Ct). Minor ocular irritation (conjunctival injection in the absence of irritation) occurs in humans following exposure at 12–30 mg·min/m3. More severe effects develop at 60–75 mg·min/m3 (conjunctivitis, irritation, photophobia) and at 100 mg·min/m3 (severe ocular irritation). Vapor inhalation LCt50 estimates for humans range from 900 mg·min/m3 to 1,500 mg·min/m3. Animal lethality following acute exposure to sulfur mustard occurs at cumulative exposures ranging from approximately 600 mg·min/m3 to 1,500 mg·min/m3. Nonlethal effects were similar to those observed in humans and included effects on the eyes, respiratory tract, and skin. Long-term exposure of dogs, rats, and guinea pigs to concentrations at 0.03 mg/m3 produced only minor signs of ocular and respiratory tract irritation. One-hour (h) exposure of mice to concentrations up to 16.9 mg/m3 resulted in notable effects on respiratory parameters, and acute exposures of rabbits (20 minutes [min]) to 12 h) to concentrations ranging from 58 mg/m3 to 389 mg/m3 (Ct ≥2,300 mg·min/m3) resulted in severe respiratory tract damage. Because exposure-response data were unavailable for all of the AEGL-specific exposure durations, temporal extrapolation was used in development of values for the AEGL-specific time periods. The concentration-exposure time relationship for many irritant and systemically acting vapors and gases may be described by Cn×t=k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). Data regarding AEGL-1-type ef-

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 fects reported by Reed (1918), Reed et al. (1918), Guild et al. (1941), and Anderson (1942) indicate that, for exposure periods up to several hours, the concentration-exposure time relationship is a near-linear function (i.e., Haber’s law where n=1 for Cn×t=k) as shown by n values of 1.11 and 0.96. Therefore, the empirically derived, chemical-specific estimate of n =1 was used for derivation of the AEGL-1 and AEGL-2 values. However, in the absence of chemical-specific lethality data, time scaling for AEGL-3 values was performed using exponential extrapolation (n=3) for shorter time periods and linear extrapolation (n=1) for longer time periods. This procedure provides a somewhat more conservative (i.e., protective) estimate of the AEGL-3 values than would be obtained using the single n value based upon ocular irritation. The AEGL-1 values were based on data from Anderson (1942), who found that an exposure concentration-time product of 12 mg·min/m3 represented a threshold for conjunctival injection and minor discomfort with no functional decrement in human volunteers acutely exposed to sulfur mustard. An intraspecies uncertainty factor (UF) of 3 was applied for protection of potentially sensitive individuals. This adjustment was considered appropriate for acute exposures to chemicals whose mechanism of action primarily involves surface contact irritation of ocular tissue rather than systemic toxicity. Anderson (1942) noted that there was little variability in the ocular responses among the subjects in his study, thereby providing additional justification for the intraspecies UF of 3. The AEGL-2 values for sulfur mustard were also developed using the data from Anderson (1942). Anderson reported that a Ct value of approximately 60 mg·min/m3 represented the lowest concentration-time product for which ocular effects were sufficiently severe (visual impairment and irritation) as to be characterized as military casualties. The 60-mg·min/m3 exposure was used as the basis for developing the AEGL-2 values because it represented an acute exposure that caused an effect severe enough to impair escape and, although not irreversible, would result in the potential for additional injury. Anderson (1942) characterized the 60-mg·min/m3 Ct as representing the lower margin of the concentration-effect zone that would result in ineffective military performance (i.e., performance necessary to complete a mission) and that might require treatment for up to 1 week (wk). The ocular irritation and damage were also considered appropriate as a threshold estimate for AEGL-2 effects because the eyes are generally considered the most sensitive indicator of sulfur mustard exposure, and irritation would likely occur in the absence of vesication effects and severe

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 pulmonary effects. The fact that the AEGL-2 is based on human data precludes the use of an interspecies UF. A factor of 3 was applied for intraspecies variability (protection of sensitive populations). The factor was limited to 3 under the assumption that the primary mechanism of action of sulfur mustard involves a direct effect on the ocular surface and that the response will not vary greatly among individuals. Anderson also noted little variability in the ocular responses among the subjects in his study. A modifying factor of 3 was applied to accommodate potential onset of long-term ocular or respiratory effects. This was justified by the fact that there was no long-term follow-up reported by Anderson to confirm or deny the development of permanent ocular or respiratory tract damage. The total modifying factor adjustment was 10 (because the factors of 3 each represent a logarithmic mean [3.16] of 10, that is, 3.16×3.16=10). For development of the AEGL-3, a 1-h exposure of mice at 21.2 mg/m3 was used as an estimated lethality threshold (Kumar and Vijayaraghavan 1998). That value is also near the lower bound of the 95% confidence interval for the 1-h mouse LC50 of 42.5 mg/m3 reported by Vijayaraghavan (1997). The intraspecies variability was limited to 3 because the lethality resulting from acute inhalation exposure to sulfur mustard appears to be a function of pulmonary damage resulting from direct contact of the agent with epithelial surfaces and would not likely exhibit an order-of-magnitude variability among individuals. A UF of 3 was also applied to account for possible interspecies variability in the lethal response to sulfur mustard. The resulting total UF adjustment was 10. The modifying factor of 3 used for AEGL-2 development to account for uncertainties regarding the latency and persistence of the irritant effects of low-level exposure to sulfur mustard was not applied for AEGL-3 because lethality of mice was assessed at 14 days (d) postexposure in a previous study by Vijayaraghavan (1997). Application of any additional UFs or modifying factors was not warranted because the AEGL-3 values are equivalent to exposures in humans that are known to produce only ocular and respiratory tract irritation. The AEGL values for sulfur mustard are based on noncancer end points. Sulfur mustard is genotoxic and has induced carcinogenic responses in humans following single high-concentration exposure and following multiple exposures that were sufficient to produce adverse effects. Based on available sulfur mustard data and in the absence of clinical signs, carcinogenic responses in humans have not been observed following acute low-level or nonvesicating exposures. The human data summarizing cancer

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 TABLE 2–1 AEGL Values for Sulfur Mustard in Parts Per Million and Milligrams per Cubic Meter Classification 10 min 30 min 1 h 4 h 8 h End Point (Reference) AEGL-1a 0.06 ppm (0.40 mg/m3) 0.02 ppm (0.13 mg/m3) 0.01 ppm (0.067 mg/m3) 0.003 ppm (0.017 mg/m3) 0.001 ppm (0.008 mg/m3) Conjunctival injection and minor discomfort with no functional decrement in human volunteers (Anderson 1942) AEGL-2a 0.09 ppm (0.60 mg/m3) 0.03 ppm (0.20 mg/m3) 0.02 ppm (0.10 mg/m3) 0.004 ppm (0.025 mg/m3) 0.002 ppm (0.013 mg/m3) Well-marked, generalized conjunctivitis, edema, photophobia, and eye irritation in human volunteers (Anderson 1942) AEGL-3a 0.59 ppm (3.9 mg/m3) 0.41 ppm (2.7 mg/m3) 0.32 ppm (2.1 mg/m3) 0.08 ppm (0.53 mg/m3) 0.04 ppm (0.27 mg/m3) Lethality estimate in mice (Kumar and Vijayaraghavan 1998) aAEGL-1 and AEGL-2 values, and the 4- and 8-h AEGL-3 values are at or below the odor threshold for sulfur mustard. incidences among individuals exposed to sulfur mustard is primarily that for wartime gas-factory workers and for military personnel who sustained injury following direct contact with “battlefield concentrations” of sulfur mustard liquid and/or vapor. A cancer risk assessment based on a geometric mean of inhalation slope factors developed using various data sets and procedures indicated an excess cancer risk of 1 in 10,000 (10−4) may be associated with exposures similar to the AEGL-3 values. The use of excess-cancer-risk estimates in setting AEGL values is precluded by the uncertainties involved in assessing excess cancer risk following a single acute exposure of 8 h or less, the relatively small population exposed in an

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 emergency release situation, and the potential risks associated with evacuations. The AEGL-1 and AEGL-2 values are based on human exposure data and are considered to be defensible estimates for exposures representing thresholds for the respective AEGL effect levels. Ocular irritation, which forms the basis for AEGL-1 and AEGL-2 values, is the most sensitive response to sulfur mustard vapor. The AEGL-3 values provide Ct products (approximately 39–130 mg·min/m3) that are known to cause moderate to severe ocular irritation and possible respiratory tract irritation in human subjects but no life-threatening health effects or death. It must be noted that all of the AEGL-1 and AEGL-2 values and the 4- and 8-h AEGL-3 values are at or below the odor threshold for sulfur mustard. In consequence, there is considered to be a finite amount of time to don protective equipment and safeguard critical target tissues such as the eyes and respiratory tract. Although the overall database for acute inhalation exposure to sulfur mustard is not extensive, the AEGL values appear to be supported by the available data. Extrapolation to exposure durations of less than 10 min is not recommended in the absence of careful evaluation of existing exposure-response data and comparison of any derivative values with these data. I. INTRODUCTION Sulfur mustard (agent HD) is an alkylating chemical vesicant that affects any epithelial surface it comes in contact with. It has been developed and used as a warfare agent. The active component is bis(2-chloroethyl)sulfide (CAS Registry No. 505–60–2). Although the chemical is a liquid at ordinary ambient temperatures, its volatility results in rapid generation of vapors (see review by Watson and Griffin [1992]). Ambient temperature and humidity govern the degree of “casualty effect.” Under hot and humid conditions, much lower mustard concentrations generate debilitating effects. Sulfur mustard has a garlic-like odor and, due to its low aqueous solubility, is persistent in the environment. Watson and Griffin (1992) have summarized information on the distribution of unitary chemical weapon stockpiles in the United States. Among various U.S. Army facilities, there were approximately 17,018.1 tons of sulfur mustard (agent HD) awaiting disposal in September 2001 (DA 2001). Pertinent physicochemical data for sulfur mustard are summarized in Table 2–2.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 TABLE 2–2 Physicochemical Data for Sulfur Mustard Synonyms Agent HD; sulfur mustard; dichloroethyl sulfide; yperite; mustard gas; Bis(2-chloroethyl) sulfide; sulfide, Bis(2-chloroethyl); 1,1'-thiobis[2-chloroethane]; yellow cross; LOST DA 1996; Budavari et al. 1989; Büscher 1932 Chemical formula C4H8Cl2S Budavari et al. 1989 Molecular weight 159.08 DA 1996 CAS Registry No. 505–60–2 Budavari et al. 1989 Physical state Oily liquid DA 1996 Solubility Sparingly soluble in water; soluble in organic solvents DA 1996; Budavari et al. 1989 Vapor pressure 0.072 mm Hg at 20 °C 0.11 mm Hg at 25 °C DA 1996 Density 5.4 DA 1996 Boiling/melting point 215–217 °C/13–14 °C DA 1996; Budavari et al. 1989 Conversion factors in air 1 ppm=6.49 mg/m3 1 mg/m3=0.15 ppm   2. HUMAN TOXICITY DATA 2.1. Acute Lethality Either inhalation or percutaneous exposure to sulfur mustard vapor can result in lethality, although inhalation exposure is the more sensitive route. Estimates of human LCt50 values for agent vapor inhalation are several times lower than the estimated human percutaneous LCt50 (Robinson 1967; DA 1974). This contention is supported by animal LCt50 data (Robinson 1967; DA 1974; Watson and Griffin 1992). Human lethality data are available only as estimates attained by extrapolation from animal data. The estimated human LCt50 values in use by the U.S. Army are 1,500 mg·min/m3 and 10,000 mg·min/m3 for inhalation and percutaneous vapor exposure, respectively (DA 1974; NRC 1997).

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 Although lacking quantitative exposure terms, Warthin and Weller (1919) provided qualitative clinical information regarding two fatalities resulting from sulfur mustard exposures during manufacture of the agent. Both men were wearing gas masks, so ocular involvement was inconsequential, but the exposure concentrations were high enough to result in severe skin burns. Within hours, both victims exhibited lesions about the lips and necrotic lesions in the mouth and nasopharyngeal region. By 7 to 8 d postexposure, there was evidence of more severe respiratory involvement, as demonstrated by moist rales and physical signs indicative of bronchopneumonia. One victim died 8 d after the accident, and the other died 4 wk after the exposure. Between 1919 and 1923, site remediation and scrap metal recovery operations at a vast (25 square miles) “gas dump” at Breloh, Germany, near Munster in what is now Lower Saxony, resulted in numerous cases of occupational exposure to warfare agents either manufactured or captured by German forces during World War I (Büscher 1932). Thousands of tons of “gas” munitions as well as tank cars and storage buildings containing sulfur mustard and other chemical warfare agents were involved. Summary reports for the years 1920–1923 by the primary-care physician at the site document “two or three” fatalities among workmen who had received concentrated sulfur mustard vapor exposures to the skin, eyes, and respiratory tract in combination. In these cases, “death came very soon” (Büscher 1932). Büscher (1932) was not equipped to gather source term information for any of these fatal episodes. Estimated lowest lethal doses of 150 mg/3 (10 min) and 70 mg/m3 (30 min) have been reported (Back et al. 1972; Inada et al. 1978). However, those values are not based on definitive exposure values or controlled exposure conditions. Available hospital records from World War I and sketchy casualty reports from the Iran-Iraq conflict indicate mortality rates of 1–3% from acute sulfur mustard exposure (Blewett 1986; Dunn 1986). Actual battlefield concentrations have not been reported but may well have been in excess of 1,500 mg/m3 (Watson and Griffin 1992). Human lethalities were reported by a number of European physicians asked to provide humanitarian treatment for gas casualties arising from the Iran-Iraq conflict. Eisenmenger et al. (1991) treated sulfur-mustard exposed Iranian patients in a German hospital; one patient admitted 5 d postexposure in a semiconscious state with serious exfoliative lesions died during treatment. Other Iranian soldiers exhibiting the characteristic burns,

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 edema, and damage to the respiratory tract associated with battlefield exposures to sulfur mustard died from various combinations of respiratory insufficiency and infection between 5 and 36 d postexposure (one on day 7, three on days 12–15, one on day 36; N=5) (D’Halluin and Roels 1984; Mandl and Frielinger 1984). Sulfur mustard agent is a known immunosuppressant (IOM 1993); however, no exposure terms for any of these wartime cases were available. In an effort to establish updated toxicity estimates for humans, the U.S. Army Chemical Defense Equipment Process Action Team (Reutter and Wade 1994) developed a revised estimated LCt50 of 900 mg·min/m3 for human inhalation exposure from an average of animal LCt50 data. The National Research Council Committee on Toxicology (Subcommittee on Toxicity Values for Selected Nerve and Vesicant Agents) concluded that the 900 mg·min/m3 estimate was scientifically valid (NRC 1997) but cautioned that the estimate was developed with reference to healthy male military personnel and is not applicable to civilians. 2.2. Nonlethal Toxicity Clinical presentation in humans following acute exposure to sulfur mustard vapor may involve dermal, ocular, and respiratory tract effects, all of which are preceded by a latency period dependent on the exposure concentration and exposure duration (Eisenmenger et al. 1991). Systemic effects (nausea, vomiting, abdominal pain, headache, weight loss, hematopoietic effects) may also occur as a result of gastrointestinal involvement or deep penetration dermal involvement (Büscher 1932). The eye appears to be the most frequently affected and most sensitive organ and also has one of the shortest latency periods (Warthin and Weller 1919; Papirmeister et al. 1991). Latency periods vary with changes in exposure parameters but tend to be several hours to days for dermal effects, 2–8 h for ocular effects, and several hours for upper respiratory tract effects (up to several days for progression to full severity respiratory tract involvement). Studies involving controlled exposure of human volunteers as well as studies on war casualties and occupational exposures are available; the latter provide clinical information but lack quantitative exposure data. Controlled human clinical trials conducted by Büscher (1932) to better define treatment regimens were confined to “drop” tests of sulfur mustard on various skin sites with observations of the time course under differing

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 decontamination protocols. Inhalation exposures occurred to Breloh gas-dump workers as a consequence of munition explosions, inhalation of smoke plumes generated during primitive “bonfire” heat-cleaning of contaminated metal scrap, off-gassing of contaminated clothing in warm rooms, and the use of contaminated wood scraps as heating fuel in winter quarters. Büscher (1932) describes the clinical course of respiratory effects and their treatment but does not present dose-response data. Reed (1918) conducted preliminary experiments in which he and another volunteer participated in exposure chamber experiments at a sulfur mustard concentration of 0.0012 mg/L (1.2 mg/m3); mustard was generated as a spray in absolute ethanol for 45 min in a 10,000 L chamber. The subjects were clad in ordinary khaki uniforms, without blouses, and had no facial protection. A slight odor was initially detected but the olfactory response accommodated within 3 min for one subject and 8 min for the other. Slight irritation of the mucosa of the nose and nasopharyngeal regions occurred at 8 min and progressed in severity such that at 20 min one individual determined to be sensitive to HD on the basis of skin tests withdrew from the exposure chamber. At 25 min, the remaining subject experienced heavy eyelids and “huskiness” of the voice but no coughing or sneezing. At 3 h after the 45-min exposure and 6 h after the 20-min exposure a sudden and severe conjunctivitis developed that was accompanied by photophobia and blepharospasm. By 12 h postexposure, vision was severely impaired, and severe pain and rhinitis were experienced for 30 h. These effects were somewhat less severe in the subject originally classified as more sensitive. Conjunctival injection did not resolve for over a month. At 3 d postexposure, intense pruritus and erythema developed over the neck, shoulders, upper arms, and trunk. It began abating after 7 d. Ocular hypersensitivity and exercise-induced dermal wheals occurred for weeks after the exposure. Reed (1918) conducted additional experiments using lower sulfur mustard concentrations. In those experiments, one to six volunteers were exposed at various low concentrations of sulfur mustard (0.0001–0.0043 mg/L, nominal; equivalent to 0.1–4.3 mg/m3) for time periods of 5 to 45 min. The exposure atmospheres were generated by slowly spraying sulfur mustard in absolute alcohol and continually mixing the air with an electric fan. Subsequent investigations revealed that the actual exposure concentrations were ≤60–70% of nominal, although Reed (1918) freely admitted that “it is impossible to state what the actual concentration was” due to analytical limitations of the time. It is assumed from context that the volunteers

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 were clothed similarly to those in initial trials (e.g., khaki uniforms without blouses) and wore no facial protection during the period of exposure. Of the 22 men participating in this series (see Table 2–3), a majority had been exposed to sulfur mustard before, and 12 had sustained “one or more burns” either experimentally or accidentally (Reed 1918). The most prominent effect of the controlled atmospheric exposures was ocular irritation (conjunctival injection, conjunctivitis, photophobia), which varied among individuals depending on exposure concentration and duration. The results of these experiments are summarized in Table 2–3. Reed et al. (1918) also conducted experiments that utilized improved methods (e.g., hydrogen ion method) for measurement of exposure concentrations. To minimize hydrolysis, the HD was delivered in absolute alcohol. Walker et al. (1928) reported that of seven men exposed to sulfur mustard at 0.001 mg/L (1 mg/m3) for 5–45 min, four showed conjunctivitis and two exhibited skin burns. It was also reported that of 17 men exposed at 0.0005 mg/L (0.5 mg/m3) for 10–45 min, six exhibited conjunctivitis, one had a skin burn, and that three of 13 men exposed for 10–30 min at 0.0001 mg/L (0.1 mg/m3) showed slight but distinct conjunctivitis. Guild et al. (1941) conducted experiments using human volunteers exposed to sulfur mustard at varying acute exposure regimens. The sulfur mustard vapor was generated by heat volatilization in a 100-m3 exposure chamber. The subjects were male soldiers and officers and one civilian who had not had previous exposure to sulfur mustard. All subjects wore paint or “dope” spray respirators “to protect the lungs” (Guild et al. 1941). For each of the tests, two to six individuals were exposed. Guild et al. concluded that Ct is constant for ocular effects for exposure periods of 2 min to 20 h and for sulfur mustard concentrations of 0.07–65 mg/m3. Based on the results of the experiments, it was reported that exposure at Ct values <70 mg·min/m3 would result in mild conjunctival responses that would not be indicative of a casualty (defined by the authors as temporary loss of vision); Ct values at 70–100 mg·min/m3 would produce some casualties; and Ct values at >100 mg·min/m3 would be expected to produce disabling ocular effects for several days. In the military context of this study, Guild et al. (1941) defined “disablement” as “injury sufficient to prevent troops from taking an active part in operations for 1–2 weeks.” Because the subjects wore respiratory protection, effects on the respiratory tract could not be determined and were not reported.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 APPENDIX B Determination of Temporal Scaling Factor (n) for AEGL Derivations Derivation of n for Cn×t=k; data points indicative of a 100% response for mild ocular irritation following exposure to sulfur mustard (agent HD) at various concentrations and times (Reed 1918; Reed et al. 1918; Guild et al. 1941; Anderson 1942) Time Concentration Log Time Log Concentration 1 72 0.0000 1.8573 30 1.4 1.4771 0.1461 30 0.06 1.4771 −1.2218 45 1.4 1.6532 0.1461 210 0.24 2.3222 −0.6198 480 0.1 2.6812 −1.0000 600 0.1 2.7782 −1.0000 1,440 0.06 3.1584 −1.2218 Regression output: Intercept 1.3852 Slope −0.9002 R squared 0.7434 Correlation −0.8622 Degrees of freedom 6 Observations 8 n=1.11 k=34.58  

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 Derivation of n for Cn×t=k; data points indicative of a 75–100% response for mild ocular irritation following exposure to sulfur mustard (agent HD) at various concentrations and times (Reed 1918; Reed et al. 1918; Guild et al. 1941; Anderson 1942) Time Concentration Log Time Log Concentration 1 72 0.0000 1.8573 30 1.4 1.4771 0.1461 30 0.06 1.4771 −1.2218 45 1.4 1.6532 0.1461 210 0.24 2.3222 −0.6198 480 0.1 2.6812 −1.0000 600 0.1 2.7782 −1.0000 1,440 0.06 3.1584 −1.2218 33 1.7 1.5185 0.2304 3 12.7 0.4771 1.1038 3 30 0.4771 1.4771 2.5 30 0.3979 1.4771 2 30 0.3010 1.4771 0.25 320 −0.6021 2.5051 Regression output: Intercept 1.7240 Slope −1.0356 R squared 0.8891 Correlation −0.9429 Degrees of freedom 12 Observations 14 n=0.96 k=46.05  

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 APPENDIX C Carcinogenicity Assessment for Acute Exposure to Sulfur Mustard (Agent HD) The cancer assessment for acute inhalation exposure to sulfur mustard was conducted following the NRC methodology for EEGLs, SPEGLs, and CEGLs (NRC 1986). The virtually safe dose (VSD) was determined from an inhalation slope factor of 14 (mg/kg/d)−1 for the general population (USACHPPM 2000). The slope factor was a geometric mean of slope factors developed using various data sets and procedures and was considered the most tenable quantitative assessment for potential cancer risk from inhalation exposure to sulfur mustard. The corresponding Inhalation Unit Risk was 0.0041 (µg/m3)−1 or 4.1 (mg/m3)−1 (USACHPPM 2000). The VSD was calculated as follows: VSD=Risk Level/Unit Risk Assuming the carcinogenic effect to be a linear function of cumulative dose (d), a single-day exposure is equivalent to d×25,600 d (average lifetime). 24-h exposure=VSD×25,600 =(2.5×10−5 mg/m3)×25,600 =0.64 mg/m3 Adjustment to allow for uncertainties in assessing potential cancer risks under short term exposures under the multistage model (Crump and Howe 1984).

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 If the exposure is limited to a fraction (f) of a 24-h period, the fractional exposure becomes 1/f×24 h (NRC 1985). For a 1×10−4, 1× 10−5, and 1×10−6 risk, the fractional exposures are shown below. Exposure Duration 10−4 10−5 10−6 24-h 0.1 mg/m3 (0.02 ppm) 0.01 mg/m3 (0.002 ppm) 0.001 mg/m3 (0.002 ppm) 8-h 0.3 mg/m3 (0.05 ppm) 0.03 mg/m3 (0.005 ppm) 0.003 mg/m3 (0.0005 ppm) 4-h 0.6 mg/m3 (0.09 ppm) 0.06 mg/m3 (0.009 ppm) 0.006 mg/m3 (0.0009 ppm) 1-h 2.4 mg/m3 (0.36 ppm) 0.24 mg/m3 (0.036 ppm) 0.024 mg/m3 (0.0036 ppm) 30-min 4.8 mg/m3 (0.72 ppm) 0.48 mg/m3 (0.072 ppm) 0.048 mg/m3 (0.0072 ppm) 10-min 14.1 mg/m3 (2.16 ppm) 1.41 mg/m3 (0.22 ppm) 0.141 mg/m3 (0.022 ppm) Because the derivation of the cancer slope factor requires conversion of animal doses to human equivalent doses, no reduction of exposure levels is applied to account for interspecies variability. With the exception of the 10-min, 30-min, and 1-h values for 10−4 risk and the 10-min 10−5 risk, these exposures are at or below the odor threshold for sulfur mustard. A cancer risk assessment based on a geometric mean of inhalation slope factors developed using various data sets and procedures indicated an excess cancer risk of 1 in 10,000 (10−4) may be associated with exposures similar to the AEGL-3 values. The use of excess cancer risk estimates in setting AEGL values is precluded by the uncertainties involved in assessing excess cancer risk following a single acute exposure of 8-h or less duration, by the relatively small population exposed in an emergency release situation, and by the potential risks associated with evacuations.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 APPENDIX D DERIVATION SUMMARY FOR ACUTE EXPOSURE GUIDELINES LEVELS Sulfur Mustard (CAS NO. 505–60–2) AEGL-1 10 min 30 min 1 h 4 h 8 h 0.40 mg/m3 (0.06 ppm) 0.13 mg/m3 (0.02 ppm) 0.067 mg/m3 (0.01 ppm) 0.017 mg/m3 (0.003 ppm) 0.008 mg/m3 (0.001 ppm) Key reference: Anderson, J.S. 1942. The effect of mustard gas vapour on eyes under Indian hot weather conditions. CDRE Report No. 241. Chemical Defense Research Establishment (India) Test species/strain/gender/number: 3–4 human volunteers Exposure route/concentrations/durations: Vapor exposure to varying concentrations (1.7–15.6 mg/m3) for varying durations (2–33 min) Effects: Mild ocular effects (mild injection to notable conjunctivitis) End point/concentration/rationale: Concentration-time threshold of 12 mg·min/m3 for ocular effects (conjunctival injection with minor discomfort and no functional decrement) Uncertainty factors/rationale: Interspecies: 1 (human subjects) Intraspecies: A factor of 3 was applied for intraspecies variability (protection of sensitive populations). This factor was limited to 3 under the assumption that the primary mechanism of action of agent HD involves a direct effect on the ocular surface and that the response will not vary greatly among individuals. Furthermore, little variability was observed in the tested subjects regarding ocular responses. Modifying factor: None applied Animal to human dosimetric adjustment: Not applicable Time Scaling: Cn×t=k, where n=1 based on analysis of available human exposure data for ocular effects. Data adequacy: The key study was conducted using human volunteers thus avoiding uncertainties associated with animal studies. Ocular irritation is considered the most sensitive end point for assessing the effects of acute exposure

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 to sulfur mustard and the available data were sufficient for developing AEGL-1 values.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 AEGL-2 10 min 30 min 1 h 4 h 8 h 0.60 mg/m3 (0.09 ppm) 0.20 mg/m3 (0.03 ppm) 0.10 mg/m3 (0.02 ppm) 0.025 mg/m3 (0.004 ppm) 0.013 mg/m3 (0.002 ppm) Key reference: Anderson, J.S. 1942. The effect of mustard gas vapour on eyes under Indian hot weather conditions. CDRE Report No. 241. Chemical Defense Research Establishment (India). Test species/strain/gender/number: 3–4 human volunteers Exposure route/concentrations/durations: Vapor exposure to varying concentrations (1.7–15.6 mg/m3) for varying durations (2–33 min) Effects: Ocular effects ranging from mild injection to notable conjunctivitis, photophobia, lacrimation, blepharospasm End point/concentration/rationale: Exposure-concentration time product of 60 mg·min/m3 representing exposure at which ocular irritation (well-marked, generalized conjunctivitis, edema, photophobia, and irritation) will occur resulting in performance decrement and necessitating medical treatment Uncertainty factors/rationale: Interspecies: 1 (human subjects) Intraspecies: A factor of 3 was applied for intraspecies variability (protection of sensitive populations). This factor was limited to 3 under the assumption that the primary mechanism of action of agent HD involves a direct effect on the ocular surface and that this response will not vary greatly among individuals. Furthermore, little variability was observed in the tested subjects regarding ocular responses. Modifying factor: A modifying factor of 3 was applied to accommodate uncertainties regarding the onset of potential long-term ocular effects or respiratory effects Animal to human dosimetric adjustment: Not applicable Time scaling: Cn×t=k, where n=1 based on analysis of available human exposure data for ocular effects Data adequacy: The key study was conducted using human volunteers, thus avoiding uncertainties associated with animal studies. The AEGL-2 values are based on ocular effects that may be considered severe enough to impair vision. The data were considered sufficient for developing AEGL-2 values.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 AEGL-3 10 min 30 min 1 h 4 h 8 h 3.9 mg/m3 (0.59 ppm) 2.7 mg/m3 (0.41 ppm) 2.1 mg/m3 (0.32 ppm) 0.53 mg/m3 (0.08 ppm) 0.27 mg/m3 (0.04 ppm) Key reference: Kumar, O., and R.Vijayaraghavan. 1998. Effect of sulphur mustard inhalation exposure on some urinary variables in mice. J. Appl. Toxicol. 18:257–259. Test species/strain/gender/number: Swiss mice/female/4 per exposure group Exposure route/concentrations/durations: Head-only inhalation exposure for 1 h to sulfur mustard (>99% purity) at 21.2, 42.3, or 84.6 mg/m3 (equivalent to 0.5, 1.0, and 2.0 LC50). Subjects were sacrificed at 6, 24, or 48 h or 7 d after exposure. Three groups of 10 mice were exposed at each concentration and observed for up to 14 d. Effects: Lethality assessed up to 14 d postexposure End point/concentration/rationale: No mortality in mice at 14 d following 1-h exposure at 21.2 mg/m3. The exposure was considered an estimate of the lethality threshold in mice. Uncertainty factors/rationale: Total uncertainty factor: 10 Interspecies: An uncertainty factor of 3 was applied to account for possible interspecies variability in the lethal response to sulfur mustard. Application of any additional uncertainty factors or modifying factors was not warranted because the AEGL-3 values are equivalent to exposures in humans that are known to produce only ocular and respiratory tract irritation. Intraspecies: Intraspecies variability was limited to 3 because lethality appears to be a function of extreme pulmonary damage resulting from direct contact of the agent with epithelial surfaces. Modifying factor: No modifying factor was applied because the basis of lethality estimate was from a study utilizing a 14-d observation period to assess the lethal response from a 1-h exposure Animal to human dosimetric adjustment: Insufficient data Time scaling: Cn×t=k, where n=1 or 3. The concentration-time relationship for many irritant and systemically acting vapors and gases can be described by Cn×t=k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the absence of chemical-specific lethality data, time scaling was performed using exponential extrapolation (n=3) for shorter time periods and linear extrapolation (n=1) for longer time periods, thereby providing a somewhat more conservative (i.e., protective) estimate of the

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 AEGL-3 values than would be obtained using an n value of 1 based on ocular irritation. Data adequacy: Uncertainties exist regarding a definitive lethality threshold for single acute exposures to sulfur mustard. However, the key study appeared to be well-designed and properly conducted and is considered sufficient for developing AEGL-3 values.