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4 Perchloromethyl Mercaptan1 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 Claudia Troxel (Oak Ridge National Laboratory) and Zarena Post and Susan Ripple (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Sub- stances). 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 concluded that the AEGLs developed in this document are scientifically valid conclu- sions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 198

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199 Perchloromethyl Mercaptan 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 levels for the general public, including susceptible subpopulations, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic responses, could experience the effects described at concentrations below the correspond- ing AEGL. SUMMARY Perchloromethyl mercaptan is an oily, yellow liquid with an unbearable, acrid odor and a reported odor threshold of approximately 0.001 ppm (Ruth 1986; ACGIH 1991; NIOSH 1996). Although it was used as a chemical warfare agent by the French in the 1915 battle of Champagne, wartime use was aban- doned shortly thereafter because of the clear warning properties, the decomposi- tion in the presence of iron and steel, and the easy removal of the vapor by char- coal (Prentiss 1937). Today, perchloromethyl mercaptan is used as an inter- mediate in the synthesis of dyes and phthalimide fungicides. Data addressing human and animal toxicity following exposure to per- chloromethyl mercaptan vapor are sparse. Only secondary sources described human data; case reports described respiratory and topical exposures to unquan- tified amounts of perchloromethyl mercaptan; and sources did not provide ex- perimental details. Animal data addressing the lethal and nonlethal effects of perchloromethyl mercaptan were limited to rats, and studies addressing nonlethal effects were limited to repeat-exposure protocols. Because there were no acute animal toxicity data appropriate for deriving an AEGL-1, the AEGL-1 is based on the repeat-exposure study by Knapp et al. (1987) in which rats were exposed 6 h/day, 5 days/week, for 2 weeks, to 0.02, 0.13, or 1.15 ppm. No effects were reported at 0.02 ppm, mild nasal epithelial changes were noted at 0.13 ppm, and mild nasal epithelial changes and pulmo-

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200 Acute Exposure Guideline Levels nary irritation (labored breathing, increased lung weight, pulmonary edema, increased mucous secretion, alveolitis, interstitial fibroplasia, and perivascular edema) were noted at 1.15 ppm. The AEGL-1 point of departure is based on mild nasal epithelial changes noted at 0.13 ppm, which represents a no- observed-adverse-effect level (NOAEL) for notable irritation. This concentra- tion is also a NOAEL for pulmonary irritation. A total uncertainty factor of 10 was applied. An intraspecies uncertainty factor of 3 and an interspecies uncer- tainty factor of 3 were applied because perchloromethyl mercaptan is highly irritating and corrosive, and much of the toxicity is probably caused by a direct chemical effect on the tissues; this type of port-of-entry effect is not expected to vary greatly among individuals or among species. No modifying factor was ap- plied because the minor epithelial changes were noted in a repeat-exposure study; it is likely that the epithelial changes following a single exposure would have been less pronounced. The derived value was set equal at all AEGL time- points because the end point is a no-effect level for perchloromethyl mercaptan as a respiratory irritant. Insufficient data are available to derive values consistent with the AEGL-2 definition. Studies that reported analytic exposure concentrations failed to de- scribe adverse health effects consistent with an AEGL-2 end point. In the ab- sence of specific data that could be used to determine AEGL-2 values, one-third of the AEGL-3 values have been used to establish the AEGL-2 values when the data indicated a steep exposure-based relationship. Therefore, the AEGL-2 val- ues were derived by dividing the AEGL-3 values by 3. No deaths occurred in male and female rats exposed at 9 ppm for 1 h, while 7 of 10 rats died at 18 ppm (Stauffer Chemical Company 1971). There- fore, 9 ppm represents a no-effect-level for mortality and was selected as the most appropriate basis for the AEGL-3 derivation, given the limited database. All exposed rats developed ocular and mucosal irritation within 5 min of initial exposure; dyspnea, gasping, and “acute depression” were also observed. Ne- cropsy revealed inflamed oral and nasal mucosa. A total uncertainty factor of 10 was applied. An intraspecies uncertainty factor of 3 and an interspecies uncer- tainty factor of 3 were applied because perchloromethyl mercaptan is highly irritating and corrosive, and much of the toxicity is probably caused by a direct chemical effect on the tissues. This type of port-of-entry effect is not expected to vary greatly among individuals or among species. The intraspecies uncertainty factor of 3 is also supported by the steep dose-response curve, which may be an indication of relatively little variation within a population. The values are scaled to AEGL time frames using the concentration-time relationship given by the equation Cn × t = k, where C = concentration, t = time, k is a constant, and n generally ranges from 1 to 3.5 (ten Berge et al. 1986). Al- though the mechanism of action appears to be direct contact irritation, it is not appropriate to set the values equal across time because the irritation is no longer considered mild, but rather the AEGL-3 concentration represents a threshold for lethality. Therefore, the irritation is sufficiently severe that continued exposure would produce increased and likely irreversible damage. The value of n could

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201 Perchloromethyl Mercaptan not be empirically derived because of inadequate data. Therefore, the default values of n = 1 and 3 were used for extrapolating from shorter to longer and longer to shorter durations of exposure, respectively. The derived AEGL values are listed in Table 4-1. All values are above the estimated odor threshold of 0.001 ppm; therefore, odor will not provide informa- tion on the extent of exposure. Perchloromethyl mercaptan is corrosive to the skin, and skin absorption may provide additional exposure (Stauffer Chemical Co. 1971). I. INTRODUCTION Perchloromethyl mercaptan is an oily, yellow liquid with an unbearable, acrid odor (ACGIH 1991; NIOSH 1996). Although it was used as a chemical warfare gas by the French in the battle of the Champagne in 1915, wartime use was abandoned shortly thereafter because of the strong warning odor, decompo- sition in the presence of iron and steel, and because the vapor could easily be removed by charcoal (Prentiss 1937). Today, perchloromethyl mercaptan is used as an intermediate in the synthesis of dyes and phthalimide fungicides (ACGIH 1991; Shertzer 2001). Production data for perchloromethyl mercaptan were not available. The physicochemical data on perchloromethyl mercaptan are pre- sented in Table 4-2. 2. HUMAN TOXICITY DATA 2.1 Acute Lethality Althoff (1973) published the case of a 15-year-old male laboratory assis- tant who was exposed to perchloromethyl mercaptan liquid and vapor when a flask was broken. Approximately 200 mL of perchloromethyl mercaptan spilled onto his clothing and onto the floor. He was taken to the hospital and admitted. Thirty-six hours following exposure, the patient died from massive hemorrhag- ing pulmonary edema and simultaneous heart, circulatory, and kidney failure from the resultant hypoxia. Damage noted during autopsy included partly hem- orrhagic, necrotizing tracheobronchitis and bronchiolitis with numerous mucus obstructions, high-grade diffuse hemorrhagic lung edema, and extreme intersti- tial edema; and pleural discharge on both sides of the lungs. 2.2. Nonlethal Toxicity The odor of perchloromethyl mercaptan has been described as unbearable, acrid, and disagreeable (ACGIH 1991; NIOSH 1996). Secondary sources re- ported an odor threshold of 0.001 ppm (reported as 0.0075 mg/m3) (Ruth 1986)

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202 Acute Exposure Guideline Levels TABLE 4-1 Summary of AEGL Values for Perchloromethyl Mercaptan End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 0.013 0.013 0.013 0.013 0.013 Nasal epithelial (nondisabling) ppm ppm ppm ppm ppm changes in rats (0.099 (0.099 (0.099 (0.099 ([0.099 exposed at 0.13 ppm mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) for 6 h /d, 5 d/wk, for 2 weeks (Knapp et al. 1987) AEGL-2 0.53 0.37 0.30 0.077 0.037 One-third of the (disabling) ppm ppm ppm ppm ppm AEGL-3 values (4.0 (2.8 (2.3 (0.59 (0.28 mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 1.6 1.1 0.90 0.23 0.11 No mortality in rats (lethality) ppm ppm ppm ppm ppm exposed at 9 ppm (12 (8.4 (6.8 (1.7 (0.84 for 1 h (Stauffer mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) Chemical Co. 1971) TABLE 4-2 Chemical and Physical Data on Perchloromethyl Marcaptan Parameter Value Reference Synonyms Clarisit (war gas); methane sufenyl ACGIH 1991 chloride; PCM; perchloromethanethiol; thrichloromethylsulfenyl chloride CAS registry no. 594-42-3 ACGIH 1991 Chemical formula CCl3SCl ACGIH 1991 Molecular weight 185.87 ACGIH 1991 Physical state Liquid ACGIH 1991 Color Yellow ACGIH 1991 Boiling point 147-148°C Shertzer 2001 Density (air = 1) 6.414 Shertzer 2001 Solubility Insoluble in water; soluble in ether ACGIH 1991 Vapor pressure 65 torr at 70ºC ACGIH 1991 3 mmHg at 20ºC Shertzer 2001 Specific gravity (water = 1) 1.7 at 20ºC ACGIH 1991 1 ppm = 7.60 mg/m3 Conversion factors Farr and Kirwin 1994 1 mg/m3 = 0.132 ppm

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203 Perchloromethyl Mercaptan and an “olfactory threshold” of 0.24 ppm (reported as 1.8 mg/m3) (Izmerov et al. 1982). Flury and Zernik (1931) reported severe eye, mouth, and chest irritation in humans following exposure to low (unspecified) concentrations of per- chloromethyl mercaptan. A 19-year-old male accidentally exposed (“in the face”) to an unknown concentration of perchloromethyl mercaptan experienced irritation of the conjunctiva and respiratory tract mucosa and developed exten- sive bronchopneumonia within 20 h (Spácilová 1971). He was treated with anti- biotics, oxygen, and “cardiotonics”, and recovered within 14 days. Prentiss (1937) stated that perchloromethyl mercaptan caused lacrimation at 1.3 ppm (reported as 0.010 mg/L) was intolerable at 9.2 ppm (0.070 mg/L) and was lethal at 390 ppm (3.0 mg/L) after 10 min (no original citations or details provided). The National Institute for Occupational Safety and Health (NIOSH) con- ducted a combined environmental and medical evaluation of a chemical plant in which workers were potentially exposed to Folpet, Captan, phthalimide, tet- rahdrophthalimide, perchloromethyl mercaptan, carbon tetrachloride, carbon disulfide, mercaptan, and chlorine (Burroughs and Hora 1982). Unfortunately, NIOSH investigators were unable to measure perchloromethyl mercaptan air samples because of an inadequate analytic method. The conclusion of the inves- tigation was that the acute symptoms reported by workers were nonspecific and not necessarily related to occupational exposure, “although the most commonly reported symptoms involved eye irritation, which is typical of exposure to Cap- tan and Folpet.” 2.3. Developmental and Reproductive Effects No human developmental and reproductive toxicity data on perchloro- methyl mercaptan were found in the open literature. 2.4. Genotoxicity No human genotoxicity data on perchloromethyl mercaptan were found in the open literature. 2.5. Carcinogenicity No data were found in the available literature regarding the carcinogenic potential of perchloromethyl mercaptan. 2.6. Summary Data addressing toxicity following perchloromethyl mercaptan exposure in humans are sparse. Following exposure to an unknown concentration of per- chloromethyl mercaptan vapor and skin contact with the liquid, one fatality oc-

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204 Acute Exposure Guideline Levels curred due to massive hemorrhagic pulmonary edema, accompanied by simulta- neous heart, circulatory, and kidney collapse (Althoff 1973). 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Rats Vernot et al. (1977) determined the 1-h lethal concentration to 50% of the exposed population (LC50) for perchloromethyl mercaptan in rats. Groups of five male or five female Sprague-Dawley rats were exposed to various concentra- tions of perchloromethyl mercaptan (individual concentrations not given) for 1 h in an exposure chamber (in either bell jar or large desiccators). The 1-h LC50 values were calculated by probit analysis of the data and were 11 ppm (95% confidence interval [C.I.]: 10-13) for male rats and 16 ppm (95% C.I.: 13-22) for female rats. When averaged, the 1-h LC50 for male and female Sprague-Dawley rats (combined) is 13 ppm. Groups of 10 Sprague-Dawley rats (five males and five females) were ex- posed to perchloromethyl mercaptan vapor at concentrations of 9, 18, 124, 382, 822, or 2,342 ppm for 1 h in a 32-liter (L) positive pressure chamber (concentra- tions given in report as 0.066, 0.133, 0.940, 2.900, 6.250, and 17.800 mg/L/h) (Stauffer Chemical Co. 1971). The vapor was generated using a midget impinger. It is not clear from the text of the original report whether exposure concentrations were nominal or measured. Animals were observed for clinical signs of toxicity and mortality during the exposure and for 14-days thereafter. All animals exhibited eye and mucosa irritation within 5 min of initial exposure, and dyspnea, gasping, and “acute depression” ensued. Mortality occurred in all test groups by 24 h postexposure except for the 9-ppm group (Table 4-3). Ne- cropsy of animals that died revealed pulmonary edema, heart and liver conges- tion, and inflammation of the pericardial and peritoneal membranes and upper gastrointestinal tract. Oral and nasal mucosa were inflamed at all exposure con- centrations. Corneal opacity was present in animals exposed at 124 ppm and greater. The authors calculated a 1-h LC50 of 13 ppm (reported as 0.1 mg/L/h). A 4-h LC100 value of 34 ppm (given as 260 mg/m3) was reported for rats (Izmerov et al. 1982). No other details were provided. Gage (1970) conducted a series of experiments in which Alderley Park specific-pathogen-free rats were exposed to perchloromethyl mercaptan at 0.5, 2, 10, or 100 ppm in a glass desiccator with wire mesh separating the animals. The appropriate nominal concentration was produced by injecting perchloro- methyl mercaptan at a known rate into a metered flow of air using a controlled fluid-feed atomizer, but analytic chamber concentrations were not determined during the exposures. When nominal concentrations were less than 100 ppm, perchloromethyl mercaptan was mixed with acetone. In an acute exposure ex-

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205 Perchloromethyl Mercaptan periment, four male rats were exposed at 100 ppm for 1 h. The animals exhibited severe respiratory difficulty, and all died. Postmortem examination revealed pulmonary edema. In another experiment, four male rats were exposed to per- chloromethyl mercaptan in acetone for 6 h at 10 ppm. Animals developed leth- argy and respiratory difficulty, and three animals died. Necropsy again revealed pulmonary edema. In a series of short-term exposures, four male rats exposed to perchloromethyl mercaptan in acetone 20 times at 2 ppm for 6 h (time between exposures not stated) had initial respiratory difficulty. No animals died. Pulmo- nary congestion was noted during postmortem examination (conducted the day after the last exposure). In another experiment, four male and four female rats were exposed to perchloromethyl mercaptan in acetone at 0.5 ppm for 20 expo- sures over 6 h (time between exposures not stated). No signs of toxicity were noted, and all organs were found to be normal during necropsy conducted on the day after the last exposure. The protocol used by Gage was confounded by sev- eral factors, including the lack of information on the purity of the chemical, the mixing of the chemical with acetone for exposure purposes, and the lack of ana- lytic verification of chamber concentrations. 3.1.2. Mice A 2-h LC50 value of 38.9 ppm (reported as 296 ± 43 mg/m3) and a 3-h LC50 of 9 ppm were reported for mice following inhalation exposure to per- chloromethyl mercaptan (Althoff 1973; Izmerov et al. 1982). No further details were provided. Mice inhaling approximately 46 ppm for 15 min (reported as 0.35 mg/L) died from pulmonary edema within 1-2 days of exposure (Flury and Zernick 1931). TABLE 4-3 Mortality of Sprague-Dawley Rats Exposed to Perchloromethyl Mercaptan for 1 h Concentration Mortality After Exposure ppm mg/L/h 1h 2h 6h 12 h 24 h 48 h 9 0.066 0/10 0/10 0/10 0/10 0/10 0/10 18 0.133 0/10 0/10 2/10 6/10 7/10 7/10 124 0.940 1/10 9/10 10/10 — — — 382 2.900 10/10 7/10 10/10 — — — 822 6.250 10/10 10/10 — — — — 2,342 17.800 10/10 10/10 — — — — Source: Stauffer Chemical Co. 1971.

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206 Acute Exposure Guideline Levels 3.1.3. Cats Cats exposed to perchloromethyl mercaptan at approximately 46 ppm for 15 min (reported as 0.35 mg/L) died from pulmonary edema within 1-2 days of exposure (Flury and Zernick 1931). 3.2. Nonlethal Toxicity 3.2.1. Rats Groups of 15 male and female Sprague-Dawley rats were exposed to “cu- mulative” mean air concentrations of 0, 0.02, 0.13, or 1.15 ppm (reported as 0, 0.13, 1.0, or 8.7 mg/m3) for 6 h/day, 5 days/week, for 2 weeks (Knapp et al. 1987). At 1.15 ppm, signs consisted of haircoat stains, dyspnea, tremors, and reduced body-weight gain. Necropsy revealed increased lung weight, pulmonary edema, and increased mucous secretion, and microscopic examination of the lungs found alveolitis, interstitial fibroplasia, and perivascular edema. Mild na- sal epithelial changes (not further described) were noted in animals exposed at 0.13 and 1.15 ppm. Groups of 18 male and 18 female Sprague-Dawley CD rats were exposed to perchloromethyl mercaptan vapor in the air at measured concentrations of 0, 0.014, 0.079, or 0.580 ppm (reported as 0, 0.11, 0.60, or 4 mg/m3) for 6 h/day, 5 days/week, for a total of 70 to 72 exposure days (Knapp and Thomassen 1987). The exposures were conducted in 1.0-m3-inhalation exposure chambers. No animals died from the exposure, and no exposure-related effects were noted in hematology or clinical chemistry parameters. Exposure-related effects were ob- served in the high-concentration group. Clinical signs consisted of increased incidences of salivation in males and increased sneezing in males and females starting on test days 18 and 59, respectively. High-concentration-group females had a time-related decrease in absolute body weight starting at week 1 and con- tinuing throughout the study (−6-12% compared with controls). The controls had a total body-weight gain of 64%. Necropsy of the high-concentration groups at study termination revealed increased absolute lung weight and lung weight relative to body weight and brain weight in males (+9%, +16%, and +10%, re- spectively) and increased lung weight relative to body weight in females (+15%) compared with controls. Other effects noted in animals from the high- concentration group included gross mucus in the trachea in 4 of 18 males and in 2 of 18 females. Microscopic findings of acute inflammation and hypertrophy, and hyperplasia of respiratory nasal epithelium in males and females were re- ported. Residues of purulent or serum exudate were noted in all males and in 13 of 18 females in the 0.580-ppm group and in one male and one female exposed at 0.079 ppm. The only exposure-related pulmonary lesion was mild-to-minimal focal subacute interstitial pneumonia in five males and one female from the high-concentration group.

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207 Perchloromethyl Mercaptan As discussed in Section 3.1.1, Gage (1970) conducted a series of experi- ments in which Alderley Park specific-pathogen-free rats were exposed to per- chloromethyl mercaptan at 100, 10, 2, or 0.5 ppm for various time periods. No deaths occurred in the four male rats exposed at 2 ppm or in the four male or female rats exposed at 0.5 ppm for 20 exposures over 6 h (time between expo- sures not stated). In the 2-ppm group, initial respiratory difficulty was reported, and pulmonary congestion was noted during postmortem examination. No clini- cal signs of toxicity or remarkable necropsy findings were reported for rats in the 0.5-ppm group. It should be reemphasized that the protocol used by Gage was compromised by several factors, including the lack of information on the purity of the chemical, the mixing of the chemical with acetone for exposure purposes, and the lack of analytic verification of chamber concentrations. 3.2.2. Other Species Seven rats, seven guinea pigs, and two dogs were exposed to perchloro- methyl mercaptan at a nominal concentration of 1 ppm for 8 h/day, 5 days/week, for 3 months (Hazleton Laboratories 1952). For numerous reasons, this study can be used only to provide descriptive data. The materials and methods and the results sections of the study report were mostly illegible (poor copy quality). It appeared that the laboratory had difficulty with the instrumentation used to de- liver the perchloromethyl mercaptan to the exposure chamber. The (legible) summary section failed to discuss or mention control animals, suggesting that control animals were not assigned. At least one of the dogs had parasitic infesta- tion and findings suggestive of bronchopneumonia; the guinea pigs that died appeared to have had pneumonia with septicemia, and the surviving guinea pig had signs of a chronic infection. The study authors suggested that the irritative effects of perchloromethyl mercaptan led to increased susceptibility to secon- dary infections. However, it is not clear that these infections were not already present prior to or at the start of exposures. The data for all the animals are pre- sented together below. In summary, six of seven guinea pigs died within the first 3 weeks of ex- posure. Signs included lacrimation, rhinorrhea, lethargy, and increased respira- tion. Guinea pigs that died had pneumonia with septicemia, and the surviving guinea pig developed fibrotic lungs and liver findings consistent with a chronic infection. Neither of the dogs died as a result of their exposure. The dogs devel- oped lacrimation, rhinorrhea, nausea and retching, coughing and sneezing, diar- rhea, and occasional blood-stained stools. (Note that at least one of the dogs had a parasitic infection.) Microscopic examination of the lungs of one of the dogs revealed bronchiolitis with possible bronchopneuomonia. Clinical signs in rats were not summarized. Microscopic examination of the lungs revealed thin al- veolar walls with a hyaline-like appearance, and in some areas, the alveolar walls ruptured and formed emphysematous blebs.

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208 Acute Exposure Guideline Levels 3.3. Developmental and Reproductive Effects No developmental and reproductive toxicity data on perchloromethyl mer- captan were found in the available literature. 3.4. Genotoxicity Perchloromethyl mercaptan was mutagenic in a number of in vitro assays, including Salmonella typhimurium strains TA 1535, TA 1537, TA 1538, TA 98, and TA 100 with or without metabolic activation (Stauffer Chemical Company 1982a), the DNA-polymerase-deficient Escherichia coli (pol A1- strain) without metabolic activation (Rosenkranz and Leifer 1980), inhibition of DNA synthesis (via DNA polymerase β inhibition) in isolated bovine liver nuclei (Dillwith and Lewis 1980), induction of mutations at the thymidine kinase locus in cultured L5178Y mouse lymphoma cells with or without metabolic activation (Stauffer Chemical Company 1983a), and induction of morphologic transformations in the BALB/3T3 morphologic transformation assay (Stauffer Chemical Company 1982b). Perchloromethyl mercaptan failed to increase chromosomal aberrations or sister chromatid exchanges in cultured Chinese hamster ovary cells with or without metabolic activation, and there was no increase in micronuclei in the bone marrow of mice in a micronucleus assay (Stauffer Chemical Company 1983b, 1984). 3.5. Carcinogenicity No data were found in the literature concerning the carcinogenic potential of perchloromethyl mercaptan in animals. 3.6. Summary A summary of lethal and nonlethal data is presented in Table 4-4. Acute lethality data were available for rats: 1-h inhalation LC50 values for perchloro- methyl mercaptan vapor were 13 ppm for males and females combined (Stauffer Chemical Co. 1971) and 11 ppm for males and 16 ppm for females for an aver- age of 13.5 ppm for males and females combined (Vernot et al. 1977). Although a 3-h LC50 value of 9 ppm and a 2-h LC50 value of 39 ppm were reported in mice, these values were published in a secondary source and did not provide any original citation or experimental details (Stauffer Chemical Co. 1971, as cited in Althoff 1973; Eastman Kodak Co. 1979; Izmerov et al. 1982).

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216 Acute Exposure Guideline Levels TABLE 4-8 Summary of AEGL Values for Perchloromethyl Mercaptan Classification 10 min 30 min 1h 4h 8h AEGL-1 0.013 ppm 0.013 ppm 0.013 ppm 0.013 ppm 0.013 ppm (nondisabling) (0.099 (0.099 (0.099 (0.099 ([0.099 mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-2 0.53 ppm 0.37 ppm 0.30 ppm 0.077 ppm 0.037 ppm (disabling) (4.0 (2.8 (2.3 (0.59 (0.28 mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 1.6 ppm 1.1 ppm 0.90 ppm 0.23 ppm 0.11 ppm (lethality) (12 (8.4 (6.8 (1.7 (0.84 mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) The AEGL-1 values were based on mild nasal epithelial changes in rats from a repeat-exposure study. This end point represents a NOAEL for notable discomfort. Data were insufficient to derive AEGL-2 values; therefore, the AEGL-2 values were obtained by dividing the AEGL-3 values by 3. The AEGL- 3 values were based on a no-effect level for lethality. At the no-effect level for increased mortality, exposed animals developed eye and mucosa irritation, dyspnea, gasping, and acute depression, and necropsy revealed inflamed oral and nasal mucosa. One way to evaluate the AEGL values in context of existing empirical data is presented in Figure 4-1. For this plot, the toxicity response was placed into severity categories. The severity categories fit into definitions of the AEGL health effects: no effects; discomfort; disabling; lethal, and partially lethal (an experimental concentration at which some of the animals died and some did not). The effects that place an experimental result into a particular category vary according to the spectrum of data available on a specific chemical and the ef- fects from exposure to that chemical. The concentrations often span a number of orders of magnitude, especially when human data exist. Therefore, the concen- tration is placed on a log scale. The graph in Figure 4-1 plots the perchloro- methyl mercaptan AEGL values along with the existing acute animal toxicity data in terms of the categories assigned to them. From this plot, it is evident that the AEGL values are below any exposure concentration in animals resulting in adverse effects and, therefore, should be protective of human health. 8.2. Comparisons with Other Standards Published standards and guidance levels for perchloromethyl mercaptan are listed in Table 4-9.

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217 Perchloromethyl Mercaptan FIGURE 4-1 Category plot of animal toxicity data compared with AEGL values. TABLE 4-9 Extant Standards and Guidelines for Perchloromethyl Mercaptan Exposure Duration Guideline 10 min 30 min 1h 4h 8h AEGL-1 0.013 ppm 0.013 ppm 0.013 ppm 0.013 ppm 0.013 ppm AEGL-2 0.53 ppm 0.37 ppm 0.30 ppm 0.077 ppm 0.037 ppm AEGL-3 1.6 ppm 1.1 ppm 0.90 ppm 0.23 ppm 0.11 ppm IDLH (NIOSH)a 10 ppm TLV-TWA 0.1 ppm (ACGIH)b PEL-TWA 0.1 ppm (OSHA)c REL-TWA 0.1 ppm (NIOSH)d MAK (Germany)e Not established; insufficient data (0.01mg/m3 = MAC (The Netherlands)f 0.01 ppm) a IDLH (immediately dangerous to life or health, National Institute of Occupational Safety and Health) (NIOSH 1996; 2005) represents the maximum concentration from which one could escape within 30 min without any escape-impairing symptoms or any irreversible health effects. The IDLH for perchloromethyl mercaptan is based on the statement by Prentiss (1937) that perchloromethyl mercaptan is about one-sixth as toxic as phosgene; the phosgene IDLH is 2 ppm. b TLV-TWA (Threshold Limit Value–time-weighted average, American Conference of Governmental Industrial Hygienists) (ACGIH 1991, 2008) is the time-weighted average

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218 Acute Exposure Guideline Levels concentration for a normal 8-h workday and a 40-h workweek to which nearly all work- ers may be repeatedly exposed, day after day, without adverse effect. c PEL-TWA (permissible exposure limits–time-weighted average, Occupational Health and Safety Administration) (OSHA) (29 CFR 1910.1000 [1996]) is analogous to the ACGIH TLV-TWA but is for exposures of no more than 10 h/day, 40 h/week. d REL-TWA (recommended exposure limits–time-weighted average, National Institute for Occupational Safety and Health) (NIOSH 2005) is analogous to the ACGIH TLV-TWA. e MAK (maximale Argeitsplatzkonzentration [maximum workplace concentration]) (Deutsche Forschungsgemeinschaft [German Research Association] (DFG 2007) is analogous to the ACGIH TLV-TWA. f MAC (maximaal aanvaaarde concentratie [maximal accepted concentration]) Dutch Expert Committee for Occupational Standards, The Netherlands) (MSZW 2004) is analogous to the ACGIH TLV-TWA. 8.3. Data Quality and Research Needs Data addressing human and animal toxicity following exposure to per- chloromethyl mercaptan vapors were very limited. Human data were generally limited to case reports describing exposures to an unquantifiable amount of per- chloromethyl mercaptan, secondary sources, and/or sources in which the ex- perimental details were not provided. Further studies addressing the acute lethal and nonlethal effects of perchloromethyl mercaptan in animals would be of util- ity, since available animal data were limited to rats, and studies addressing nonlethal effects were limited to repeat-exposure protocols. No data were avail- able addressing the potential for perchloromethyl mercaptan exposure to cause developmental or reproductive effects or neoplasia. 9. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Per- chloromethyl mercaptan. Pp. 1195-1196 in Documentation of the Threshold Limit Values and Biological Exposure Indices, Vol. II, 6th Ed. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. ACGIH (American Conference of Governmental Industrial Hygienists). 2008. TLVs and BEIs: Based on Documentation of the Threshold Limit Values for Chemical Sub- stances and Physical Agents and Biological Exposure Indices: Perchloromethyl Mercaptan. American Conference of Governmental Industrial Hygienists, Cincin- nati, OH. Althoff, H. 1973. Fatal perchloromethyl mercaptan intoxication [in German]. Arch. Toxi- col. 31(2):121-135. Burroughs, G.E., and J. Hora. 1982. Health Hazard Evaluation Report: Calhio Chemical Company, Perry, OH. HETA-80-147-1076. NTIS PB 83-199463. National Insti- tute for Occupational Safety and Health, Cincinnati, OH. DFG (Deutsche Forschungsgemeinschaft). 2007. List of MAK and BAT Values 2007. Maximum Concentrations and Biological Tolerance Values at the Workplace Re- port No. 43. Weinheim, Federal Republic of Germany: Wiley VCH.

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219 Perchloromethyl Mercaptan Dillwith, J.W., and R.A. Lewis. 1980. Inhibition of DNA polymerase β activity in iso- lated bovine liver nuclei by captan and related compounds. Pestic. Biochem. Phys. 14(2):208-216. Eastman Kodak Co. 1979. Toxicity and Health Hazard Summary. Eastman Kodak Co., Rochester, NY. EPA Document No. 86-920000003. U.S. Environmental Protec- tion Agency, Washington, DC. EPA (U.S. Environmental Protection Agency). 2008. Interim Acute Exposure Guideline Levels (AEGLs) for Methyl Mercaptan (CAS Reg. No. 74-93-1). Interim 2: 10/2008 [online]. Available: http//www.epa.gov/oppt/aegl/pubs/chemlist.htm [ac- cessed Nov. 16, 2010]. Farr, C.H., and C.J. Kirwin. 1994. Organic sulfur compounds. Pp 4311-4372 in Patty’s Industrial Hygiene and Toxicology, Vol. II, Part F, Toxicology, 4th Ed., G.D. Clayton, and F.E. Clayton, eds. New York: John Wiley and Sons. Flury, F., and F. Zernik. 1931. Perchlormethylmercaptan. P. 362 in Schädliche Gase Dämpfe, Nebel, Rauch-, und Stauberten. Berlin, Germany: Verlag von Julius Springer. Gage, J.C. 1970. The subacute inhalation toxicity of 109 industrial chemicals. Br. J. Ind. Med. 27(1):1-18. Hazleton Laboratories. 1952. Chronic Inhalation Toxicity. Report No. CAP0026. Submit- ted by ICI Americas Inc., to U.S. Environmental Protection Agency, Washington, DC, August 28, 1992. EPA Document No. 88920007341. Microfiche No. OTS 0538474. Izmerov, N.F., I.V. Sanotskii, and K.K. Siderov. 1982. Toxicometric Parameters of In- dustrial Toxic Chemicals under Single Exposure. Moskow, Russia: Center of In- ternational Projects, Soviet State Committee for Science and Technology (GKNT). Knapp, H.F., and R.W. Thomassen. 1987. Subchronic Inhalation Study with Perchloro- methyl Mercaptan (PMM) in Rats. Report No. T-11848. Stauffer Chemical Com- pany, Westport, CT. Submitted by Zeneca, Inc., to U.S. Environmental Protection Agency, Washington, DC. EPA Document No. 86-960000548. Microfiche No. OTS 0558749. Knapp, H.F., S.M. MacAskill, G.M. Zwicker, and G.L. Sprague. 1987. Effects in rats of repeated inhalation exposure to perchloromethyl mercaptan. Toxicologist 7(1):191 [Abstract 762]. MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst 2004: Perchloormethyulmercaptaan. Den Haag: SDU Uitgevers [online]. Available: http://www.lasrook.net/lasrookNL/maclijst2004.htm [accessed Nov. 16, 2010]. NIOSH (National Institute for Occupational Safety and Health). 1996. Documentation for Immediately Dangerous to Life or Health Concentrations (IDLH): NIOSH Chemical Listing and Documentation of Revised IDLH Values (as of 3/1/95)- Perchloromethyl Mercaptan. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health. August 1996 [online]. Available: http://www.cdc.gov/niosh/ idlh/594423.html [accessed Nov. 16, 2010]. NIOSH (National Institute for Occupational Safety and Health). 2005. NIOSH Pocket Guide to Chemical Hazards: Perchloromethyl Mercaptan. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Na- tional Institute for Occupational Safety and Health, Cincinnati, OH. September 2005 [online]. Available: http://www.cdc.gov/niosh/npg/npgd0489.html [accessed Nov. 16, 2010].

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220 Acute Exposure Guideline Levels NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na- tional Academy Press. Prentiss, A.M. 1937. P. 154 in Chemicals in War: A Treatise on Chemical Warfare. New York: McGraw-Hill. Rosenkranz, H.S., and Z. Leifer. 1980. Determining the DNA-modifying activity of chemicals using DNA-polymerase-deficient Escherichia coli. Pp. 109-147 in Chemical Mutagens: Principles and Methods for Their Detection, Vol. 6, F.J. de Serres, and A. Hollaender, eds. New York: Plenum Press. Ruth, J.H. 1986. Odor thresholds and irritation levels of several chemical substances: A review. Am. Ind. Hyg. J. 47(3):A142-A151. Shertzer, H.G. 2001. Organic sulfur compounds. Pp. 681-765 in Patty's Toxicology, Vol. VII. Glycols and Glycol Ethers/Synthetic Polymers/Organic Sulfur Compounds/ Organic Phosphates, 5th Ed., E. Bingham, B. Cohrssen, and C.H. Powell, eds. New York: Wiley. Spácilová, M. 1971. Acute inhalation damage by perchlorine-methylmercaptan [in Czechoslovakian]. Prac. Lek. 23(8):278-279. Stauffer Chemical Company. 1971. Initial Submission: Acute Inhalation Test with Perchloromethyl Mercaptan in Rats. Report No. T-1683. Stauffer Chemical Com- pany, Westport, CT. Submitted by ICI Americas Inc., to U.S. Environmental Pro- tection Agency, Washington, DC, August 28, 1992. EPA Document No. 88- 920006928. 7pp. Stauffer Chemical Company. 1982a. Perchloromethyl Mercaptan (PMM): Mutagenicity Evaluation in Salmonella typhimurium. Report No. T-10842. Stauffer Chemical Company, Westport, CT, June 25, 1982. Submitted by Zeneca, Inc., to U.S. Envi- ronmental Protection Agency, Washington, DC. EPA Document No. 86- 960000548. Microfiche No. OTS 0558749. Stauffer Chemical Company. 1982b. Perchloromethyl Mercaptan (PMM): Morphological Transformation of BALB/3T3 Cells. Report No. T-10844. Stauffer Chemical Company, Westport, CT, September 20, 1982. Submitted by Zeneca, Inc., to U.S. Environmental Protection Agency, Washington, DC. EPA Document. No. 86- 960000548. Microfiche No. OTS 0558749. Stauffer Chemical Company. 1983a. Perchloromethyl Mercaptan (PMM): Mutagenicity Evaluation in Mouse Lymphoma Multiple End point Test Forward Mutation As- say. Report No. T-10843. Stauffer Chemical Company, Westport, CT, January 10, 1983. Submitted by Zeneca, Inc., to U.S. Environmental Protection Agency, Washington, DC. EPA Document. No. 86-960000548. Microfiche No. OTS 0558749. Stauffer Chemical Company. 1983b. Perchloromethyl Mercaptan (PMM): Mutagenicity Evaluation in Chinese Hamster Ovary Cytogenetic Assay. Report No. T-11711. Stauffer Chemical Company, Westport, CT, November 7, 1983. Submitted by Zeneca, Inc., to U.S. Environmental Protection Agency, Washington, DC. EPA Document. No. 86-960000548. Microfiche No. OTS 0558749. Stauffer Chemical Company. 1984. Perchloromethyl Mercaptan (PMM): Mutagenicity Evaluation in Bone Marrow Micronucleus. Report No. T-11857. Stauffer Chemi- cal Company, Westport, CT, July 24, 1984. Submitted by Zeneca, Inc., to U.S.

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221 Perchloromethyl Mercaptan Environmental Protection Agency, Washington, DC. EPA Document. No. 86- 960000548. Microfiche No. OTS 0558749. ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Haz- ard. Mater. 13(3): 301-309. Vernot, E.H., J.D. MacEwen, C.C. Haun, and E.R. Kinkead. 1977. Acute toxicity and skin corrosion data for some organic and inorganic compounds and aqueous solu- tions. Toxicol. Appl. Pharmacol. 42(2):417-423.

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222 Acute Exposure Guideline Levels APPENDIX A DERIVATION OF AEGL VALUES FOR PERCHLOROMETHYL MERCAPTAN Derivation of AEGL-1 Key study: Knapp et al. 1987 Toxicity end point: Mild nasal epithelial changes representing a NOAEL for notable discomfort following exposure of rats at 0.013 ppm for 6 h/day, 5 days/week, for 2 weeks. Time-scaling: Values were set equal across time because the effects are those of mild irritation. Uncertainty factors: 3 for interspecies variability 3 for intraspecies variability Combined uncertainty factor of 10 Calculations: Point of departure/uncertainty factors 0.13/10 = 0.013 10-min, 30-min, 1 h, 4 h, and 8 h AEGL-1: 0.013 ppm for all time points Derivation of AEGL-2 Key study: AEGL-3 divided by 3; see AEGL-3 derivation Toxicity end point: AEGL-3 divided by 3; see AEGL-3 derivation Time-scaling: AEGL-3 divided by 3; see AEGL-3 derivation Uncertainty factors: AEGL-3 divided by 3; see AEGL-3 derivation Calculations: AEGL-3 values divided by 3 10-min. AEGL-2: 1.6 ppm/3 = .53 ppm 30-min AEGL-2: 1.1 ppm/3 = 0.37 ppm 1-h AEGL-2: 0.90 ppm/3 = 0.30 ppm

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223 Perchloromethyl Mercaptan 4-h AEGL-2: 0.23 ppm/3 = 0.077 ppm 8-h AEGL-2: 0.11 ppm/3 = 0.037 ppm Derivation of AEGL-3 Key study: Stauffer Chemical Co. 1971 Toxicity end point: No lethality in rats exposed to 9 ppm for 1 h Cn × t = k (default of n = 1 for shorter to longer exposure Time-scaling: periods and n=3 for longer to shorter exposure periods) Uncertainty factors: 3 for interspecies variability 3 for intraspecies variability Combined uncertainty factor of 10 (C/uncertainty factors)n × t = k Calculations: [(9 ppm)/10]1 × 1 h = 0.9 ppm-h [(9 ppm)/10]3 × 1 h = 0.729 ppm-h C3 × 0.167 h = 0.729 ppm-h 10-min AEGL-3: C3 = 4.365 ppm C = 1.63 ppm = 1.6 ppm C3 × 0.5 h = 0.729 ppm-h 30-min AEGL-3: C3 = 1.458 ppm C = 1.13 ppm = 1.1 ppm C1 × 1 h = 0.729 ppm-h 1-h AEGL-3: C1 = 0.729 ppm-h C = 0.90 ppm C1 × 4 h = 0.9 ppm-h 4-h AEGL-3: C1 = 0.225 ppm C = 0.225 ppm = 0.23 ppm C1 × 8 h = 0.9 ppm-h 8-h AEGL-3: C1 = 0.1125 ppm C = 0.1125 ppm = 0.11 ppm

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224 Acute Exposure Guideline Levels APPENDIX B ACUTE EXPOSURE GUIDELINE LEVELS FOR PERCHLOROMETHYL MERCAPTAN Derivation Summary for Perchloromethyl Mercaptan AEGL-1 VALUES 10 min 30 min 1h 4h 8h 0.013 ppm 0.013 ppm 0.013 ppm 0.013 ppm 0.013 ppm Reference: Knapp, H.F., S.M. MacAskill, G.M. Zwicker, and G.L. Sprague. 1987. Effects in rats of repeated inhalation exposure to perchloromethyl mercaptan. Toxicologist 7(1):191[Abstact 762]. Test species/Strain/Number: Rat/Sprague-Dawley/15 per exposure group Exposure route/Concentrations/Durations: Inhalation at 0.02, 0.13, 1.15 ppm for 6 h/d, 5 d/wk, for 2 wk Effects: 0.02 ppm: no effects 0.13 ppm: mild nasal epithelial changes 1.15 ppm: clinical signs of haircoat stains, labored breathing, tremors, and reduced body weight gain; necropsy revealed increased lung weight, pulmonary edema, and increased mucous secretion; microscopic examination found alveolitis, interstitial fibroplasia, and perivascular edema in the lungs and mild epithelial changes in the nose End point/Concentration/Rationale: NOAEL for notable discomfort of 0.13 ppm for 6 h/day Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 was applied because perchloromethyl mercaptan is highly irritating and corrosive, and much of the toxicity is probably caused by a direct chemical effect on the tissues; this type of port-of-entry effect is not expected to vary greatly among species Intraspecies: 3 was applied because perchloromethyl mercaptan is highly irritating and corrosive, and much of the toxicity is probably caused by a direct chemical effect on the tissues; this type of port-of-entry effect is not expected to vary greatly among individuals, and the steep dose-response curve may be an indication of little variation within a population; (no deaths were observed in rats exposed at 9 ppm but 7 of 10 died at 18 ppm [Stauffer Chemical Company 1971]). Modifying factor: No modifying factor was applied because the minor epithelial changes were noted in a repeated exposure study; it is likely that the epithelial changes following a single exposure would have been less pronounced. Animal-to-human dosimetric adjustment: Not applicable (Continued)

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225 Perchloromethyl Mercaptan AEGL-1 VALUES Continued 10 min 30 min 1h 4h 8h 0.013 ppm 0.013 ppm 0.013 ppm 0.013 ppm 0.013 ppm Time scaling: The derived value was set equal at all AEGL time-points because the end point is a no-effect level for irritation. Data adequacy: No acute toxicity data were available for use in the derivation of the AEGL-1; therefore, the AEGL-1 values are based on a NOAEL from a repeat- exposure study. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 0.53 ppm 0.37 ppm 0.30 ppm 0.077 ppm 0.037 ppm Reference: See “Data adequacy” below. Test species/Strain/Sex/Number: See “Data adequacy” below. Exposure route/Concentrations/Durations: See “Data adequacy” below. Effects: See “Data adequacy” below. End point/Concentration/Rationale: See “Data adequacy” below. Uncertainty factors/Rationale: See “Data adequacy” below. Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Not applicable Time-scaling: See “Data adequacy” below. Data adequacy: No acute toxicity data were available for use in the derivation of the AEGL-2. In the absence of specific data that could be used to determine AEGL-2 values, one-third of the AEGL-3 values have been used to establish the AEGL-2 values when the data indicated a steep exposure-based relationship. Therefore, the AEGL-3 values are divided by 3 (see AEGL-3 derivation). AEGL-3 VALUES 10 min 30 min 1h 4h 8h 1.6 ppm 1.1 ppm 0.90 ppm 0.23 ppm 0.11 ppm Reference: Stauffer Chemical Company. 1971. Initial Submission: Acute Inhalation Test with Perchloromethyl Mercaptan in Rats. Report No. T-1683. Stauffer Chemical Company, Westport, CT. Submitted by ICI Americas Inc., to U.S. Environmental Protection Agency, August 28, 1992. EPA Document No. 88- 920006928. 7 pp. Test Species/Strain/Number: Rat/Sprague-Dawley/5 per exposure group Exposure route/Concentrations/Durations: Inhalation at 9, 18, 124, 382, 822, or 2,342 ppm for 1 h (Continued)

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226 Acute Exposure Guideline Levels AEGL-3 VALUES Continued 10 min 30 min 1h 4h 8h 1.6 ppm 1.1 ppm 0.90 ppm 0.23 ppm 0.11 ppm Effects: Concentration (ppm): Mortality 9 0/10 18 7/10 124 10/10 382 10/10 822 10/10 2,342 10/10 End point/Concentration/Rationale: Exposure at 9 ppm for 1 h did not result in mortality; all exposed rats exhibited clinical signs of eye and mucosa irritation, dyspnea, gasping, and acute depression; necropsy revealed that the mouth and nasal mucosa were inflamed. Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 was applied because perchloromethyl mercaptan is highly irritating and corrosive, and much of the toxicity is probably caused by a direct chemical effect on the tissues; this type of port-of-entry effect is not expected to vary greatly among species. Intraspecies: 3 was applied because perchloromethyl mercaptan is highly irritating and corrosive, and much of the toxicity is probably caused by a direct chemical effect on the tissues; this type of port-of-entry effect is not expected to vary greatly among individuals; also supported by the steep dose-response curve, which may be an indication of little variation within a population. Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Insufficient data Time-scaling: Cn × t = k, where n = 3 for extrapolation from longer to shorter durations and n = 1 for extrapolation from shorter to longer durations. Data adequacy: The AEGL-3 value was based on a concentration not causing lethality and should be protective of human health.