2

Methyl Mercaptan
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 effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure.

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1This document was prepared by the AEGL Development Team composed of Cheryl Bast (Oak Ridge National Laboratory), Gary Diamond (SRC, Inc.), and Chemical Manager Ernest V. Falke (U.S. Environmental Protection Agency and National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). 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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2 Methyl 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 effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. 1 This document was prepared by the AEGL Development Team composed of Cheryl Bast (Oak Ridge National Laboratory), Gary Diamond (SRC, Inc.), and Chemical Man- ager Ernest V. Falke (U.S. Environmental Protection Agency and National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). 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 con- cluded 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 re- ports (NRC 1993, 2001). 44

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Methyl Mercaptan 45 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 non- disabling odor, taste, and sensory irritation or certain asymptomatic, nonsensory effects. With increasing airborne concentrations above each AEGL, there is a pro- gressive increase in the likelihood of occurrence and the severity of effects de- scribed 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 responses, could experience the effects described at concentrations below the corresponding AEGL. SUMMARY Methyl mercaptan is a colorless gas with a strong odor. It is used in me- thionine synthesis and as an intermediate in the manufacture of pesticides, jet fuels, and plastics. It is found in a wide variety of vegetables (such as garlic and onions), in “sour” gas in oil fields, and in coal tar and petroleum distillates. Me- thyl mercaptan occurs in the human body as a metabolite of the degradation of methionine and other compounds. Methyl mercaptan depresses the central nervous system and affects the respiratory center, similar to hydrogen sulfide, producing death by respiratory paralysis. Clinical signs of exposure are ocular and mucous membrane irritation, headache, dizziness, staggering gait, nausea, and vomiting. Paralysis of the lo- comotor muscles and pulmonary edema have also been observed. Its primary mechanism of action appears to be interference with cytochrome oxidase. Data on methyl mercaptan were not sufficient to derive AEGL-1 values, so no values are recommended. The level of distinct odor awareness (LOA) for methyl mercaptan is 0.0019 ppm (see Appendix C for LOA derivation). The LOA represents the concentration above which it is predicted that more than half of the exposed population will experience at least a distinct odor intensity, and about 10% of the population will experience a strong smell. The LOA should help chemical emergency responders in assessing the public awareness of the exposure on the basis of odor perception. No robust data on methyl mercaptan consistent with the definition of AEGL-2 were available. Therefore, AEGL-2 values were based on a 3-fold re- duction in the AEGL-3 values. These calculations are considered estimated

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46 Acute Exposure Guideline Levels thresholds for inability to escape and are appropriate because of the steep con- centration-response relationship for lethality. AEGL-3 values for methyl mercaptan were based on the calculated 4-h LC01 (lethal concentration, 1% lethality) of 430 ppm for rats (Tansy et al. 1981). An intraspecies uncertainty factor of 3 was applied, and is considered sufficient because of the steepness of the lethality concentration-response relationship, which implies limited individual variability. An interspecies uncertainty factor of 3 was also applied. Although an interspecies uncertainty factor of 10 might normally be applied because of limited data, AEGL-3 values calculated with that larger factor would be inconsistent with the total database. AEGL-3 values would range from 7.3 to 40 ppm if a total uncertainty factor of 30 was used; however, no effects were noted in rats repeatedly exposed to methyl mercaptan at 17 ppm for 3 months. It is unlikely that people exposed to methyl mercaptan in this range for 10 min to 8 h would experience lethal effects. Furthermore, use of a total uncertainty factor of 30 would yield AEGL-3 values 2- to 4-fold lower than the AEGL-3 values for hydrogen sulfide. Because hydrogen sulfide has a robust database and because data suggest that methyl mercaptan is less toxic than hydrogen sulfide, it would be inconsistent with the total data set to derive AEGL-3 values for methyl mercaptan that are below the AEGL-3 values for hydrogen sulfide. Thus, a total uncertainty factor of 10 was used. The concentration-exposure time relationship for many irritant and sys- temically-acting vapors and gases may be described by the equation Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). To obtain conservative and protective AEGL values in the absence of a chemical-specific exponent, temporal scaling was performed using default values of n = 3 for ex- trapolating from longer to shorter durations (10 min, 30 min, and 1 h) and n = 1 when extrapolating from shorter to longer durations (8 h). AEGL values for methyl mercaptan are presented in Table 2-1. 1. INTRODUCTION Methyl mercaptan is used in methionine synthesis, as an intermediate in the manufacture of pesticides, jet fuels, and plastics, and as a gas odorant to serve as a warning property for odorless but hazardous gases (Farr and Kirwin 1994; Pohanish 2002). Methyl mercaptan is also released from pulp manufactur- ing plants and in kraft and sulfite mills (Kangas et al. 1984). Concentrations of methyl mercaptan in kraft and sulfite mills may be as high as 15 ppm (Kangas et al. 1984). Methyl mercaptan is an odorous, colorless gas. The disagreeable odor has been described as garlic-like (Pohanish 2002) or as similar to rotten cabbage (HSDB 2013). It is found in a wide variety of vegetables (such as garlic and onions), in “sour” gas in West Texas oil fields, and in coal tar and petroleum distillates (Farr and Kirwin 1994). Methyl mercaptan occurs in the human body

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Methyl Mercaptan 47 as a metabolite of the degradation of methionine and other compounds (Binkley 1950; Canellakis 1952). Methyl mercaptan is a major contributor to bad breath in human (NIOSH 1978). Methyl mercaptan is produced commercially by the reaction of hydrogen sulfide with methanol; production volumes were not found (ATSDR 1992). The physical and chemical properties of methyl mercaptan are presented in Table 2-2. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality Methyl mercaptan depresses the central nervous system and affects the respiratory center, similar to hydrogen sulfide, producing death by respiratory paralysis (Farr and Kirwin 1994). Clinical signs of exposure are ocular and mu- cous membrane irritation, headache, dizziness, staggering gait, nausea, and vom- iting (Deichmann and Gerarde 1973). Paralysis of the locomotor muscles and pulmonary edema have also been observed (NIOSH 1978; Matheson 1982). Acute hemolytic anemia and methemoglobinemia were found in one male laborer (53-years old) who developed a coma after handling tanks of methyl mercaptan. Transfusions alleviated these hematologic findings. When he arrived at the hospital, his blood pressure ranged from 188/90 to 230/130 mm Hg and his pulse was 120 beats/min. Later, the man was found to have a deficiency of glucose-6-phosphate dehydrogenase. Seizure activity consisted of random myo- clonic tremors. On the 28th day in the hospital the man died as the result of em- boli in both pulmonary arteries (Shults et al. 1970). TABLE 2-1 AEGL Values for Methyl Mercaptan End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1a NR NR NR NR NR Insufficient data (nondisabling) AEGL-2 40 ppm 29 ppm 23 ppm 14 ppm 7.3 ppm One-third reduction (disabling) (80 (57 (43 (28 (14 of AEGL-3 values mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 120 ppm 86 ppm 68 ppm 43 ppm 22 ppm LC01 in rats (lethal) (240 (170 (130 (85 (43 (Tansy et al. 1981) mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) Abbreviations: LC01, lethal concentration, 1% lethality; NR, not recommended. a The absence of AEGL-1 values does not imply that concentrations below AEGL-2 will be without effect.

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48 Acute Exposure Guideline Levels TABLE 2-2 Physical and Chemical Data on Methyl Mercaptan Parameter Value Reference Synonyms Methanethiol; mercaptomethane; HSDB 2013 methyl sulfhydrate; thiomethyl alcohol CAS registry no. 74-93-1 HSDB 2013 Chemical formula CH3SH HSDB 2013 Molecular weight 48.11 HSDB 2013 Physical state Water-white liquid or colorless gas HSDB 2013 Odor Like garlic or rotten cabbage Pohanish 2002; HSDB 2013 Melting point -123°C HSDB 2013 Boiling point 5.95°C HSDB 2013 Flash point < - 17.78°C (open cup) HSDB 2013 Density/Specific gravity 0.9600 at 25°C HSDB 2013 Solubility Soluble in water (23.3 g/L at 20°C); HSDB 2013 very soluble in alcohol and ether Saturated vapor 5.0 × 105 ppm Calculated concentration (neat) 9.9 × 105 mg/m3 at 25°C Vapor pressure 1,510 mm Hg at 25°C HSDB 2013 Incompatibility Strong oxidizers, bleaches, copper, NIOSH 2011 aluminum, nickel-copper alloys Conversion factors in air 1 mg/m3 = 0.51 ppm NIOSH 2011 1 ppm = 1.97 mg/m3 A 24-year-old male working in a sodium methyl sulfhydrate factory was found dead. Large quantities of methyl mercaptan were detected in his liver, kidneys, lungs, blood, urine, and in the washout solution of his trachea (Shertzer 2001). In another incident, a 19-year-old was exposed to methyl mercaptan at concentrations greater than 10,000 ppm for a few minutes. Death ensued after 45 min as a result of respiratory arrest and “heart failure”. The blood concentration of methyl mercaptan was greater than 2.5 nmol/mL (Syntex Corporation 1979). 2.2. Nonlethal Toxicity Kangas et al. (1984) collected air samples from kraft and sulfite mills (pulp industry) and reported methyl mercaptan concentrations ranging from 0 to 15 ppm. Thirteen to 15 mill workers reported headache and trouble concentrat- ing; however, they were also simultaneously exposed to hydrogen sulfide, dime- thyl sulfide, and dimethyl disulfide. Therefore, symptoms cannot be attributed to any one chemical at any concentration.

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Methyl Mercaptan 49 2.3. Odor Katz and Talbert (1930) exposed six human subjects to methyl mercaptan at a range of concentrations via a nosepiece. The subjects rated the odor intensi- ty (see Table 2-3). Wilby (1969) exposed 34 individuals to methyl mercaptan at 12 concentra- tions representing a 100-fold range. For each subject an odor recognition threshold was determined on the basis of three trials. The mean odor threshold concentration was 9.9 × 10-4 ppm with a standard deviation of 7.2 × 10-4 ppm and a coefficient of variation of 0.72. No other effects were noted. Selyuzhitskii (1972) derived an MPC (maximum permissible concentration) of 5 × 10-4 mg/m3 (2.5 × 10-4 ppm) for methyl mercaptan. MPC was defined as being above the odor threshold concentration but below the “irritating concentra- tion” in man. Williams et al. (1977) used a dynamic triangle olfactometer, an instrument that measures odor thresholds by dilution and steady state flow, to determine the odor threshold at which 50% of subjects can detect the odor. Using an unspeci- fied number of subjects, the odor threshold for methyl mercaptan was deter- mined to be 1.5 × 10-5 ppm. No other health effects were noted. Nishida et al. (1979) exposed 8-11 subjects (18-40 years old) to a series of chemicals, including methyl mercaptan. Subjects rated odors on a scale of 0 to 8, where 0 indicated no smell and 8 an extremely strong smell. A PPT50 (percep- tive threshold to 50% of population) was determined for methyl mercaptan and used to obtain an odor detection level of 0.019 ppm (range 0.010-0.430 ppm). No other health effects were noted. 2.4. Developmental and Reproductive Toxicity Developmental and reproductive studies regarding human exposure to me- thyl mercaptan were not available. 2.5. Genotoxicity Genotoxicity studies regarding human exposure to methyl mercaptan were not available. TABLE 2-3 Odor Intensity of Methyl Mercaptan Intensity Description Concentration (ppm) 0 No odor 0.0030 1 Threshold 0.041 2 Faint 0.57 3 Median, easily noticeable 7.9 4 Strong 110 5 Most intense 1,500 Source: Adapted from Katz and Talbert 1930.

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50 Acute Exposure Guideline Levels 2.6. Carcinogenicity Carcinogenicity studies regarding human exposure to methyl mercaptan were not available. 2.7. Summary Data concerning human exposure to methyl mercaptan are limited. Case reports of deaths from accidental exposure to methyl mercaptan were available; however, definitive exposure durations and concentrations were not reported. Nonlethal toxicity data are limited to odor detection or identification studies that had no accompanying health effects information. Data on developmental and reproductive toxicity, genotoxicity, and carcinogenicity in humans were not available. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Mice A 4-h LC50 (lethal concentration, 50% lethality) value of 1,664 ppm was reported for an unspecified strain and sex of mice (Horiguchi 1960). Experi- mental concentrations of 1,300, 1,500, 1,600, 1,800, 1,900, 2,000, and 2,200 ppm appeared to be determined by the nominal concentration of methyl mercap- tan used during the exposure period. Animals were observed for 24-h post- exposure. No other experimental details were reported. A 6-h nose-only expo- sure of Swiss-Webster mice to methyl mercaptan at 512 ppm resulted in 17% lethality (5/30). Three female and two male mice were found dead on day 2 (SRI International1996; see Section 3.2.1 for a more detailed description of the study). 3.1.2. Rats Groups of five male and five female Charles River Sprague-Dawley rats were exposed methyl mercaptan for 4 h at 0, 400, 600, 650, 680, 690, 700(two groups), or 800 ppm, followed by a 14-day observation period (Tansy et al. 1981). Animals were exposed in a 75-L glass chamber that allowed for continu- ous observation during exposure. Methyl mercaptan was fed through a two-stage corrosion-resistant regulator which was maintained at delivery pressure of 15 psi to a metering flowmeter. The gas was then mixed with air and drawn through the exposure chamber by a vacuum pump. For this 4-h exposure, the LC50 value

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Methyl Mercaptan 51 was 675 ppm and the LC01 was 430 ppm. Any animal alive 24 h after the expo- sure survived until the end of the 14-day observation period. Mortality data from this study are summarized in Table 2-4, where the strength of the concentration- response relationship can be readily seen. Groups of two male albino rats were exposed to methyl mercaptan at 250, 500, 750, 1,000, or 2,000 ppm for up to 4 h (DuPont 1992). Methyl mercaptan was mixed with air in a carboy and the mixture passed into a bell jar containing the rats; the “nominal” concentrations were calculated from the respective flow rates of the methyl mercaptan and air. Data from this study are summarized in Table 2-5. Groups of six male WBS/W rats were exposed to methyl mercaptan at 1,000, 1,400, 2,000, or 2,800 ppm for up to 1 h and were observed for up to 7 days (Latven 1977). Two rats were placed in 20-L static exposure chambers. A small volume of air was withdrawn from each chamber and replaced with the required volume of sample (20 mL for 1,000 ppm, 28 mL for 1,400 ppm, 40 mL for 2,000 ppm, or 56 mL for 2,800 ppm). Clinical signs included dyspnea, atax- ia, loss of righting reflex, progressive respiratory depression, and cyanosis. Sur- viving rats showed only dyspnea. Mortality was 0/6 at 1,000 ppm, 1/6 at 1,400 ppm, 5/6 at 2,000 ppm, and 6/6 at 2,800 ppm. A 1-h LC50 value of 1,680 ppm (95% CI: 1,428, 1,980 ppm) was calculated. No other experimental details were available. White female rats were exposed one at a time to methyl mercaptan at con- centrations of approximately 500, 700, 1,500, or 10,000 ppm for 30 min (Ljung- gren and Norberg 1943). The report implied that only one rat was used for each exposure. At 500 ppm, no effects were observed. Fatigue was noted at 700, with instantaneous recovery after removal from exposure. After 15 min at 1,500 ppm, the rat had difficulty maintaining an upright posture, and by the end of the expo- sure period exhibited whole-body tremors and was only able to acquire an up- right position for a very brief period. Recovery occurred after 5 min. This ani- mal had thickened alveolar walls and exudate containing blood cells in the alveoli. The 10,000-ppm exposure produced convulsions after 1 min and fast superficial respiration after 2 min. The animal was on its side after 6 min, respi- ration was irregular after 8 min, and death occurred after 14 min. Necropsy find- ings included “small bleedings in the lungs”, alveoli filled with erythrocytes, and moderate amounts of serous fluid in the alveoli. Male Holtzman or Sprague-Dawley rats (weighing 285 to 325 g) were in- dividually exposed in a 27-L glass chamber to methyl mercaptan at concentra- tions ranging from 0.08 to 0.2% until they became comatose or for 15 min (Zieve et al. 1974). The mercaptan concentration in the chamber atmosphere was not analyzed, rather concentrations were calculated from the dose injected. A CD50 (coma induction in 50% of subjects) value of 0.16% (1,600 ppm) was determined from these exposure concentrations. Blood concentrations of methyl mercaptan found in comatose animals were greater than 0.5 nmoles/mL.

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52 Acute Exposure Guideline Levels TABLE 2-4 Mortality in Rats Exposed to Methyl Mercaptan for 4 Hours Concentration (ppm) Mortality 0 0/10 400 0/10 600 2/10 650 5/10 680 4/10 690 4/10 700a 10/10, 10/10 800 10/10 a There were two 700 ppm exposure groups. Source: Adapted from Tansy et al. 1981. TABLE 2-5 Acute Inhalation Toxicity in Rats Exposed to Methyl Mercaptan Concentration Duration (ppm) (hours) Mortality Clinical Signs Necropsy Findings 250 4 0/2 Ocular and nasal irritation. Pneumonitis in half of the rats; considered coincidental. 500 4 0/2 Ocular and nasal irritation, Focal atelectasis (9 days after shallow respiration. treatment in half of the rats). 750 3-3.5 2/2 Comatose a few minutes None before death 1,000 3.17 2/2 Shallow respiration, None cyanosis, comatose in 3 h 2,000 0.33 2/2 Comatose in 15 min None Source: DuPont 1992. 3.2. Nonlethal Toxicity 3.2.1. Mice As part of a bone marrow erythrocyte micronucleus assay, 15 Swiss- Webster mice/sex were exposed nose-only to methyl mercaptan at 0, 114, 258, or 512 ppm for 6 h, and animals were killed 24, 48, or 72 h after exposure (SRI In- ternational1996). Methyl mercaptan concentrations were analyzed by gas chroma- tography hourly during the exposure period, and temperature, relative humidity, and pressure differential were measured at 10-min intervals. Shallow breathing and hypoactivity were observed in all mice in the 258-ppm group during the fourth and fifth hour of exposure and appeared normal by day 2. Shallow breathing at the third and fourth hour of exposure and hypoactivity during the fifth hour were ob- served in all mice exposed at 512 ppm. Three female and two male mice from the 512-ppm exposure group were found dead on day 2; all surviving mice from the 512-ppm group appeared normal by day 2. No clinical signs were noted in control animals or mice exposed to methyl mercaptan at 114 ppm.

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Methyl Mercaptan 53 3.3. Subchronic Exposure Groups of two or four male albino rats were exposed to methyl mercaptan at 100 or 200 ppm for 6 h/day for 6 or 10 days (DuPont 1992). Methyl mercap- tan was mixed with air in a carboy and the mixture passed into a bell jar contain- ing the rats; the “nominal” concentrations were calculated from the respective flow rates of the methyl mercaptan and air. Data from this study are summarized in Table 2-6. Groups of 31 male Charles River Sprague-Dawley rats were exposed me- thyl mercaptan at 0, 2, 17, or 57 ppm for 7 h/day, 5 days/week for 3 months (Tansy et al. 1981). Animals were exposed in 11.4-ft3 stainless steel chambers that allowed for continuous observation during exposure. Flow rates were calcu- lated to yield the desired gas concentrations, and were verified by spectropho- tometric analysis of gas samples. No animals died during the study, and no treatment-related effects were noted in animals exposed at 0, 2, or 17 ppm. Body weights were decreased by 15% in the 57-ppm group compared with controls. Blood chemistry analysis showed increased total protein and decreased serum albumin at 57 ppm. The observed increased protein might have been due to de- hydration, and the decreased albumin may be indicative of liver involvement, although no treatment-related liver histopathology was observed. 3.4. Developmental and Reproductive Toxicity Developmental and reproductive studies regarding animal exposure to me- thyl mercaptan were not available. TABLE 2-6 Subchronic Inhalation Toxicity in Rats Exposed to Methyl Mercaptan Concentration (ppm) Duration Mortality Clinical Signs Necropsy Findings 100 6 h/d for 10 d 0/2 Occasional Bronchopneumonia (2 rats) restlessness. 200 6 h/d for 6 d 1/4 Occasional No effects (2 rats); pneumonia restlessness, red ears. (2 rats, including decedent). 200 6 h/d for 10 d 1/4 Slight dyspnea and Decedent: bronchopneumonia; chromodacryorrhea Rat No. 2: coincidental after 6th exposure, atelectasis; Rat No. 3: slight slight cyanosis, moist pulmonary congestion and rales (decedent). emphysema; Rat No. 4: slight bronchitis and emphysema, coincidental atelectasis. Source: DuPont 1992.

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54 Acute Exposure Guideline Levels 3.5. Genotoxicity In a bone marrow erythrocyte micronucleus assay in mice (SRI Interna- tional 1996), a statistically significant increase in micronucleated polychromatic erythrocytes was observed in male mice only at the 24-h sacrifice after exposure to methyl mercaptan at 512 ppm for 6 h. (The protocol and clinical signs ob- served in this study are described in Section 3.2.1.) However, the increase is of questionable biologic significance because the control group had a micronucleus frequency lower than the historical control mean for the laboratory (0.05% vs. 0.21% historical frequency). In another study, Garrett and Fuerst (1974) report that methyl mercaptan was mutagenic in a sex-linked recessive lethal test in Drosophila melanogaster; however, no data were presented. 3.6. Carcinogenicity Carcinogenicity studies in animals exposed to methyl mercaptan were not available. 3.7. Summary Animal toxicity data for methyl mercaptan are limited. Lethality studies are available for rats and mice, and suggest a steep concentration-response rela- tionship for methyl mercaptan. In studies of rats, 4-h exposures to methyl mer- captan at 600 and 700 ppm caused 20 and 100% lethality, respectively; the 4-h LC50 value was 675 ppm; and the 4-h LC01 value was 430 ppm (Tansy et al. 1981). In another rat study, a 4-h exposure at 500 ppm caused no lethality (0/2), and a 3.5-h exposure at 750 ppm caused death in both rats (DuPont 1992). Non- lethal effects included dyspnea, cyanosis, and breathing difficulties. Genotoxici- ty data are limited and equivocal, and no reproductive and developmental toxici- ty data or carcinogenicity studies on methyl mercaptan were located. 4. SPECIAL CONSIDERATIONS 4.1. Metabolism and Disposition Rats injected intraperitoneally with methyl mercaptan excreted CO2 and volatile sulfur-containing compounds in the expired breath (Canellakis and Tarver 1953). After rats were injected with 35S-methyl mercaptan, approximate- ly 94% of the sulfur was found in the urine as 35SO42- (Derr and Draves 1983, 1984). Methyl mercaptan and dimethyl sulfide were found in the expired breath of one mouse injected with methyl mercaptan (Susman et al. 1978). Erythro- cytes were found to oxidize methyl mercaptan, producing formic acid, sulfite ion, and sulfate ion (Blom and Tangerman 1988).

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64 Acute Exposure Guideline Levels Deichmann, W.B., and H.W. Gerarde. 1973. P. 371 in Toxicology of Drugs and Chemi- cals. New York: Academic Press. Derr, R.F., and K. Draves. 1983. Methanethiol metabolism in the rat. Res. Commun. Chem. Pathol. Pharmacol. 39(3):503-506. Derr, R.F., and K. Draves. 1984. The time course of methanethiol in the rat. Res. Com- mun. Chem. Pathol. Pharmacol. 46(3):363-369. DFG (Deutsche Forschungsgemeinschaft). 2012. List of MAK and BAT Values: Maxi- mum Concentrations and Biological Tolerance Values at Workplace. Report No. 48. Wiley-VCH [online]. Available: http://onlinelibrary.wiley.com/doi/10.1002/ 9783527666034.oth01/pdf [accessed June 21, 2013]. DuPont. 1992. Toxicity of Methyl Mercaptan. Medical Research Project No. MR-287. Haskell Laboratory for Toxicology and Industrial Medicine. June 24, 1992. Fairchild, E.J., and H.E. Stokinger. 1958. Toxicologic studies on organic sulfur com- pounds. I. Acute toxicity of some aliphatic and aromatic thiols (mercaptans). Am. Ind. Hyg. Assoc. J. 19(3):171-189. Farr, C.H., and C.J. Kirwin. 1994. Organic sulfur compounds. Pp. 4311-4314 in Patty’s Industrial Hygiene and Toxicology, 4th Ed., Vol. IIF. Toxicology, G.D. Clayton, and F.E. Clayton, eds. New York: John Wiley & Sons. Garrett, S., and R. Fuerst. 1974. Sex linked mutations in Drosophila after exposure to various mixtures of gas atmospheres. Environ Res. 7(3):286-293. Horiguchi, M. 1960. An experimental study on the toxicity of methyl mercaptan in com- parison with hydrosulfide [in Japanese]. J. Osaka City Med. Cent. 9:5257-5293. HSDB (Hazardous Substances Data Bank). 2013. Methyl mercaptan (CAS Reg. No. 74-93- 1). TOXNET, Specialized Information Services, U.S. National Library of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen? HSDB [accessed June 24, 2013]. Kangas, J., P. Jappinen, and H. Savolainen. 1984. Exposure to hydrogen sulfide, mercap- tans and sulfur dioxide in pulp industry. Am. Ind. Hyg. Assoc. J. 45(12):787-790. Katz, S.H., and E.J. Talbert. 1930. Intensities of Odors and Irritating Effects of Warning Agents for Inflammable and Poisonous Gases. Technical Report No. 480. Wash- ington DC: U.S. Government Printing Office. Latven, A.R. 1977. Methyl Mercaptan. One-Hour Inhalation Toxicity in Rats. Toxicology Report for Pennwalt Corporation by Pharmacology Research, Inc. Protocol Ref: PR No. 76-5317; RL34, 67. April 25, 1977. Ljunggren, G., and B. Norberg. 1943. On the effect and toxicity of dimethyl sulfide, di- methyl disulfide and methyl mercaptan. Acta Physiol. Scand. 5(2-3):248-255. Matheson. 1982. Methyl mercaptan. P. 16 in Guide to Safe Handling of Compressed Gases (GSHCG), 2nd Ed. Matheson Gas Products, Inc., East Rutherford, NJ. MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst 2004: Methaanthiol. Den Haag: SDU Uitgevers [online]. Available: http://www. lasrook.net/lasrookNL/maclijst2004.htm [accessed Mar.1, 2013]. NIOSH (National Institute for Occupational Safety and Health). 1978. Criteria for a Rec- ommended Standard. Occupational Exposure to n-Alkane Monothiols, Cyclohex- anethiol, and Benzenethiol. DHEW(NIOSH) No. 78-213. U.S. Department of Health and Human Services, National Institute for Occupational Safety and Health, Atlanta, GA [online]. Available: http://www.cdc.gov/niosh/pdfs/78-213a.pdf [accessed June 21, 2013]. NIOSH (National Institute for Occupational Safety and Health). 1994. Documentation for Immediately Dangerous to Life or Health Concentrations (IDLHs): Methyl mer- captan. U.S. Department of Health and Human Services, Centers for Disease Con-

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Methyl Mercaptan 65 trol and Prevention, National Institute for Occupational Safety and Health, Atlanta, GA [online]. Available: http://www.cdc.gov/niosh/idlh/74931.html [accessed June 21, 2013]. NIOSH (National Institute for Occupational Safety and Health). 2011. NIOSH Pocket Guide to Chemical Hazards (NPG): Methyl mercaptan. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Insti- tute for Occupational Safety and Health, Atlanta, GA [online]. Available: http:// www.cdc.gov/niosh/npg/npgd0425.html [accessed June 21, 2013]. Nishida, K., M. Yamakawa, and T. Honda. 1979. Experimental investigations on combined actions of components mixed in odorous gas. Mem. Fac. Eng. Kyoto Univ. 41(4): 552-565. 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. Pohanish, R.P. 2002. Methyl mercaptan. In Sittig’s Handbook of Toxic and Hazardous Chemicals and Carcinogens, 4th Ed. Norwich, NY: William Andrew Publishing Noyes. Selyuzhitskii, G.V. 1972. Test data, substantiating maximum permissible concentrations of methyl mercaptan of dimethyl sulfide and dimethyl disulfide [in Russian]. Gig. Tr. Prof. Zabol. 16(6):46-47. Shertzer, H.G. 2001. Organic sulfur compounds. Pp. 681-765 in Patty’s Toxicology, Vol. 7. Glycols and Glycol Ethers/Synthetic Polymers/Organic Sulfur Com- pounds/Organic Phosphates, 5th Ed., E. Bingham, B. Cohrssen, and C.H. Powell, eds. New York: John Wiley & Sons. Shults, W.T., E.N. Fountain, and E.C. Lynch. 1970. Methanethiol poisoning.Irreversible coma and hemolytic anemia following inhalation. J. Am. Med. Assoc. 211(13):2153- 2154. Smith, R.P. 1991. Toxic responses of the blood. Pp. 276-278 in Casarett and Doull's Tox- icology: The Basic Science of Poisons, 4th Ed., M.O. Amdur, J. Doull, and C.D. Klaassen, eds. New York: Pergamon Press. SRI International. 1996. Bone Marrow Micronucleus Assay in Male and Female Swiss- Webster Mice Following Acute Nose-Only Inhalation Exposure to Methyl Mer- captan. Final Report. SRI Study No. MMO- 95. Prepared for Elf Atochem North America, Inc, by SRI International, Menb Park, CA. July 9, 1996. Susman, J.L., J.F. Hornig, S.C. Thomae, and R.P. Smith. 1978. Pulmonary excretion of hydrogen sulfide, methanethiol, dimethyl sulfide and dimethyl disulfide in mice. Drug Chem. Toxicol. 1(4):327-338. Syntex Corporation. 1979. Acute Toxicity Human Exposure, Accident Report. TSCA Section 8e submission ID No. FYI-059-0000032A. May 15, 1979 Tansy, M.F., F.M. Kendall, J. Fantasia, W.E. Landin, and R. Oberly. 1981. Acute and subchronic toxicity studies of rats exposed to vapors of methyl mercaptan and oth- er reduced-sulfur compounds. J. Toxicol. Environ. Health 8(1-2):71-88. 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.

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66 Acute Exposure Guideline Levels van Doorn, R., M. Ruijten, and T. van Harreveld. 2002. Guidance for the Application of Odor in Chemical Emergency Response. Version 2.1, August 29, 2002. Presented at the NAC/AEGL Meeting September 2002, Washington, DC. Waller, R.L. 1977. Methanethiol inhibition of mitochondrial respiration. Toxicol. Appl. Pharmacol. 42(1): 111-117. Wilby, F.V. 1969. Variation in recognition odor threshold of a panel. J. Air Pollut. Con- trol Assoc. 19(2):96-100. Williams, F.D., J.F. Emele, and M.C. Alford. 1977. The application of the dynamic trian- gle olfactometer to the evaluation of oral odor. Chem. Senses 2(4):497-502. Zieve, L., W.M. Doizaki, and F.J. Zieve. 1974. Synergism between mercaptans and am- monia or fatty acids in the production of coma: A possible role for mercaptans in the pathogenesis of hepatic coma. J. Lab. Clin. Med. 83(1):16-28. Zieve, L., W.M. Doiaki, and C. Lyftogt. 1984. Brain methanethiol and ammonia concen- trations in experimental hepatic coma and coma induced by injections of various combinations of these substances. J. Lab. Clin. Med. 104(5):655-664.

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Methyl Mercaptan 67 APPENDIX A DERIVATION OF AEGL VALUES METHYL MERCAPTAN Derivation of AEGL-1 Values Data on methyl mercaptan were inadequate to derive AEGL-1 values. Ab- sence of AEGL-1 values does not imply that exposure below the AEGL-2 values are without adverse effect. Derivation of AEGL-2 Values In the absence of relevant data to derive AEGL-2 values and because me- thyl mercaptan has a steep concentration-response curve, AEGL-3 values were divided by 3 to estimate thresholds for inability to escape. 10-min AEGL-2: 120 ppm ÷ 3 = 40 ppm 30-min AEGL-2: 86 ppm ÷ 3 = 29 ppm 1-h AEGL-2: 68 ppm ÷ 3 = 23 ppm 4-h AEGL-2: 43 ppm ÷ 3 = 14 ppm 8-h AEGL-2: 22 ppm ÷ 3 = 7.3 ppm Derivation of AEGL-3 Values Key study: Tansy, M.F., F.M. Kendall, J. Fantasia, W.E. Landin, and R. Oberly. 1981. Acute and subchronic toxicity studies of rats exposed to vapors of methyl mercaptan and other reduced-sulfur compounds. J. Toxicol. Environ. Health 8(1-2):71-88. Toxicity end point: Estimated lethality threshold in rats, 4-h LC01 of 430 ppm Time scaling: Cn × t = k (default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations) (430 ppm)3 × 4 h = 318,028,000 ppm-h (430 ppm)1 × 4 h = 1,720 ppm-h

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68 Acute Exposure Guideline Levels Uncertainty factors: 3 for interspecies differences 3 for intraspecies variability 10-min AEGL-3: C3 × 0.167 h = 318,028,000 ppm3-h C3 = 1,904,359,281 ppm C = 1,240 ppm 1,240 ppm ÷ 10 = 120 ppm 30-min AEGL-3: C3 × 0.5 h = 318,028,000 ppm-h C3 = 636,056,000 ppm C = 860 ppm 860 ppm ÷ 10 = 86 ppm 1-h AEGL-3: C3 × 1 h = 318,028,000 ppm-h C3 = 318,028,000 ppm C = 682.7 ppm 682.7 ppm ÷ 10 = 68 ppm 4-h AEGL-3: 430.0 ppm ÷ 10 = 43 ppm 8-h AEGL-3: C1 × 8 h = 1,720 ppm-h C1 = 215 ppm C = 215 ppm 215 ppm ÷ 10 = 22 ppm

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Methyl Mercaptan 69 APPENDIX B ACUTE EXPOSURE GUIDELINE LEVELS FOR METHYL MERCAPTAN Derivation Summary AEGL-1 VALUES Data on methyl mercaptan were insufficient to derive AEGL-1 values. Absence of AEGL-1 values does not imply that exposure below the AEGL-2 values are without adverse effect. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 40 ppm 29 ppm 23 ppm 14 ppm 7.3 ppm (80 mg/m3) (57 mg/m3) (43 mg/m3) (28 mg/m3) (14 mg/m3) Data adequacy: Data inadequate to derive AEGL-2 values. AEGL-3 values were divided by 3 to estimate thresholds for the inability to escape. This calculation is supported by the steep concentration-response relationship for methyl mercaptan (lethality in rats exposed for 4 h was 20% at 600 ppm and 100% at 700 ppm; the 4-h LC50 value was 675 ppm and the 4-h LC01 value was 430 ppm in rats [Tansy et al. 1981]). AEGL-3 VALUES 10 min 30 min 1h 4h 8h 120 ppm 86 ppm 68 ppm 43 ppm 22 ppm (240 mg/m3) (170 mg/m3) (130 mg/m3) (85 mg/m3) (43 mg/m3) Reference: Tansy, M.F., F.M. Kendall, J. Fantasia, W.E. Landin, and R. Oberly. 1981. Acute and subchronic toxicity of rats exposed to vapors of methyl mercaptan and other reduced-sulfur compounds. J. Toxicol. Environ. Health 8(1-2):71-88. Test species/Strain/Sex/Number: Rats, Sprague-Dawley, 5 males and 5 females per group Exposure route/Concentrations/Durations: Inhalation; 0, 400, 600, 650, 680, 690, 700 (two groups), or 800 ppm for 4 h Effects: Concentration (ppm) Mortality 0 0/10 400 0/10 600 2/10 650 5/10 680 4/10 690 4/10 (Continued)

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70 Acute Exposure Guideline Levels AEGL-3 VALUES Continued 700 10/10 700 10/10 800 10/10 LC50 675 ppm LC01 430 ppm End point/Concentration/Rationale: Estimated lethality threshold in rats, 4-h LC01 of 430 ppm Uncertainty factors/Rationale: Intraspecies: 3, considered sufficient because of steep lethality concentration-response relationship (20% mortality at 600 ppm, 100% mortality at 700 ppm), which implies limited individual variability. Interspecies: 3, although an interspecies uncertainty factor of 10 might normally be applied because of limited data, AEGL-3 values calculated using a total uncertainty factor of 30 would be inconsistent with the total database. AEGL-3 values would range from 7.3 to 40 ppm if the larger factor is used; however, occupational exposures of up to 15 ppm (along with hydrogen sulfide, ≤20 ppm; dimethyl sulfide, ≤15 ppm; and dimethyl disulfide, ≤1.5 ppm) resulted in headache and trouble concentrating (Kangas et al. 1984). Furthermore, no effects were found in rats exposed at 17 ppm for 7 h/d, 5 d/wk for 3 mos. It is unreasonable to expect that people exposed to methyl mercaptan in the range of 7.3 to 40 ppm for 10 min to 8 h would experience lethal effects. Furthermore, those values are 2- to 4-fold below the AEGL-3 values for hydrogen sulfide. Because a robust database exists for hydrogen sulfide and because data suggest that methyl mercaptan is less toxic than hydrogen sulfide (4-h LC50 is 675 ppm for methyl mercaptan and 444 ppm for hydrogen sulfide [Tansy et al. 1981]), it would be inconsistent with the total data set to have AEGL-3 values for methyl mercaptan that are in the range of the AEGL-3 values for hydrogen sulfide. Total uncertainty factor: 10 Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Insufficient data Time scaling: Cn × t = k; default value of n = 3 was used for extrapolation to the shorter durations (10 min, 30 min, and 1 h) and n = 1 for extrapolation to the longer duration (8 h). Extrapolation from 4 h to 10 min is supported by the fact that no deaths were observed in rats exposed to methyl mercaptan at 1,000 ppm for 1 h (Latven 1977). Using this end point, an exponent n = 3, and total uncertainty factor of 10, would yield a 10-min AEGL-3 value of 182 ppm. This suggests that the 10-min AEGL-3 value of 120 ppm is protective and that time scaling is appropriate. Data adequacy: The study was well conducted and used a sufficient number of animals of both sexes. The point of departure is an estimated threshold for lethality; the 4-h LC01 in rats is consistent with observations in mice, which suggest that the 6-h lethality threshold is at or above 258 ppm and below 612 ppm (SRI International 1996). When the 4-h LC01 in rats is scaled to 6 h (n = 1), the 6-h LC01 is estimated to be 287 ppm. AEGL-3 values are considered protective because rats exposed to methyl mercaptan at 57 ppm for 7 h/d, 5 d/wk for 3 mos experienced only decreased body weight and decreased serum albumin (Tansy et al. 1981), and rats exposed at 100 ppm for 6 h/d for 10 d experienced occasional restlessness and had bronchopneumonia at necropsy (DuPont 1992).

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Methyl Mercaptan 71 APPENDIX C DERIVATION OF THE LEVEL OF DISTINCT ODOR AWARENESS FOR METHYL MERCAPTAN Even though methyl mercaptan has an extremely unpleasant odor, olfacto- ry desensitization or fatigue occurs at high concentrations. Therefore, odor and symptoms of irritation may not adequately provide warning of high concentra- tions of methyl mercaptan (Shertzer 2001). The level of distinct odor awareness (LOA) represents the concentration above which it is predicted that more than half of the exposed population will experience at least a distinct odor intensity, and about 10% of the population will experience a strong odor intensity. The LOA should help chemical emer- gency responders in assessing the public awareness of the exposure on the basis of odor perception. The LOA derivation follows the guidance of van Doorn et al. (2002). The odor detection threshold (OT50) for methyl mercaptan was calculated to be 0.00012 ppm (van Doorn et al. 2002). The concentration (C) leading to an odor intensity (I) of distinct odor de- tection (I = 3) is derived using the Fechner function: I = kw × log (C ÷ OT50) + 0.5 For the Fechner coefficient, the default of kw = 2.33 was used due to the lack of chemical-specific data: 3 = 2.33 × log (C ÷ 0.00012) + 0.5 log (C ÷ 0.00012) = (3 - 0.5) ÷ 2.33 log (C ÷ 0.00012) = 1.07 C = (101.07) × 0.00012 C = 0.00141 ppm The resulting concentration is multiplied by an empirical field correction factor. It takes into account that factors in everyday life, such as sex, age, sleep, smoking, upper airway infections, and allergy, as well as distractions, increase the odor detection threshold by a factor of 4. In addition, it takes into account that odor perception is very fast (about 5 seconds) which leads to the perception of concentration peaks. On the basis of current knowledge, a factor of 1/3 is applied to adjust for peak exposure. Adjustment for distraction and peak expo- sure lead to a correction factor of 4 ÷ 3 = 1.33. LOA = C × 1.33 LOA = 0.00141 ppm × 1.33 LOA = 0.001875 ppm

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72 Ac cute Exposure Guideline Levels AP PPENDIX D CATEGORY PLOT FOR METHY MERCAPT F YL TAN FIGUR D-1 Categor plot of toxicit data and AE GL values for m RE ry ty methyl mercaptan. The dec cimal point is lo on this log-sc plot. ost cale

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TABLE D-1 Data Used in the Category Plot for Methyl Mercaptan Source Species Sex No. Exposures ppm Minutes Category Effect 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 40 10 AEGL AEGL-2 29 30 AEGL AEGL-2 23 60 AEGL AEGL-2 14 240 AEGL AEGL-2 7.3 480 AEGL AEGL-3 120 10 AEGL AEGL-3 86 30 AEGL AEGL-3 68 60 AEGL AEGL-3 43 240 AEGL AEGL-3 22 480 AEGL Horiguchi 1960 Mouse 1 1,664 240 LC50 SRI International 1996 Mouse Both 1 114 360 0 Mouse Both 1 258 360 1 Shallow breathing, hypoactivity Mouse Both 1 512 360 SL Mortality (5/15); shallow breathing; hypoactivity Tansy et al. 1981 Rat Both 1 400 240 2 (Continued) 73

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74 TABLE D-1 Continued Source Species Sex No. Exposures ppm Minutes Category Effect Rat Both 1 600 240 SL Mortality (2/10) Rat Both 1 650 240 SL Mortality (5/10) Rat Both 1 680 240 SL Mortality (4/10) Rat Both 1 700 240 3 Mortality (10/10) Rat Both 1 700 240 3 Mortality (10/10) Rat Both 1 800 240 3 Mortality (10/10) DuPont 1992 Rat Male 1 250 240 1 Pneumonitis in 2 rats, considered coincidental Rat Male 1 500 240 2 Focal atelectasis Rat Male 1 750 180 3 Mortality (2/2), coma Rat Male 1 1,000 180 3 Mortality (2/2), shallow respiration, cyanosis, coma Rat Male 1 2,000 20 3 Mortality (2/2), coma Latven 1977 Rat Male 1 1,000 60 2 Clinical signs Rat Male 1 1,400 60 SL Mortality (1/6) Rat Male 1 2,000 60 SL Mortality (5/6) Rat Male 1 2,800 60 3 Mortality (6/6) Zieve et al. 1974 Rat Male 1 1,600 15 2 CD50 (coma induction) Ljunggren and Norberg 1943 Rat Female 1 500 30 0 Rat Female 1 700 30 1 Rat Female 1 1,500 30 2 Rat Female 1 10,000 14 3 Mortality (1/1) For category: 0 = no effect, 1 = discomfort, 2 = disabling, 3 = lethal; SL = some lethality.