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Ethyl Mercaptan
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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

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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.), Chemical Manager Iris Camacho (U.S. Environmental Protection Agency and National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).



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1 Ethyl 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 Cheryl Bast (Oak Ridge National Laboratory), Gary Diamond (SRC, Inc.), Chemical Manager Iris Camacho (U.S. Environmental Protection Agency and National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the doc- ument 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). 13

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14 Acute Exposure Guideline Levels 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 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 Ethyl mercaptan is an odorous, colorless liquid. The disagreeable odor has been described as penetrating, persistent, and garlic- or leek-like, similar to de- caying cabbage. It is found in illuminating gas, in “sour” gas in West Texas oil fields, and in petroleum distillates from which it may be separated by chemical or physical methods. It is used as an intermediate and starting material in the manufacture of plastics, insecticides, and antioxidants, and as an odorant to serve as a warning property for natural gas (O’Neil et al. 2006). Ethyl mercaptan depresses the central nervous system and affects the res- piratory center, similar to hydrogen sulfide, producing death by respiratory pa- ralysis. Clinical signs of exposure are ocular and mucous membrane irritation, headache, dizziness, staggering gait, nausea, and vomiting. Paralysis of locomo- tor muscles has also been observed. Its primary mechanism of action appears to be interference with cytochrome oxidase. AEGL-1 values for ethyl mercaptan were based on a no-effect level of 10 ppm for respiratory changes associated with odor avoidance in rabbits exposed for 20 min (Shibata 1966a). Two uncertainty factors of 3 were applied to ac- count for interspecies differences and intraspecies variability, and are considered sufficient because use of the full factor of 10 for either type of uncertainty would yield AEGL-1 values of 0.3 ppm or less, concentrations that are inconsistent with human data. A single AEGL-1 value was used across exposure durations

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Ethyl Mercaptan 15 because prolonged exposure to ethyl mercaptan is unlikely to result in an en- hanced effect. The level of distinct odor awareness (LOA) for ethyl mercaptan is 1.4 ×10-4 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 ex- perience at least a distinct odor intensity, and about 10% of the population will experience a strong odor intensity. Because of its relatively high vapor pressure (442 mm Hg at 20°C) (NIOSH 2011), ethyl mercaptan has the potential to gener- ate toxic air concentrations very quickly in the event of a spill. The LOA should help chemical emergency responders assess the public awareness of exposure to ethyl mercaptan from its odor. No robust data on ethyl mercaptan consistent with the definition of AEGL-2 were available. Therefore, the AEGL-2 values for ethyl mercaptan were based on a 3-fold reduction in the AEGL-3 values. This calculation is con- sidered an estimate of a threshold for irreversible effects and is appropriate be- cause of the steep concentration-response curve for ethyl mercaptan toxicity. AEGL-3 values are based on a calculated 4-h LC01 (lethal concentration, 1% lethality) of 2,250 ppm in mice (Fairchild and Stokinger 1958). The corre- sponding 4-h LC01 value for rats is 3,808 ppm. An intraspecies uncertainty fac- tor of 3 was applied, and is considered sufficient because of the steepness of the lethality concentration-response curve which implies limited individual variabil- ity. An interspecies uncertainty factor of 3 was also applied because the limited data suggest that the mouse is the most sensitive species. Although an interspe- cies uncertainty factor of 10 might normally be applied because of the limited data, a total uncertainty factor of 30 would yield AEGL-3 values that are incon- sistent with the total data set (the values would be in the range of AEGL-3 val- ues for hydrogen sulfide [NRC 2010]). Furthermore, the 30-min AEGL-3 value would be 150 ppm, a value that is inconsistent with the finding that a single hu- man exposed to ethyl mercaptan at 112 ppm for 20 min exhibited only a slightly irregular and decreased breathing rate (Shibata 1966b). Thus, the total uncertain- ty factor is 10. The 30-min AEGL-3 value was adopted as the 10-min value be- cause of the uncertainty associated with extrapolating a 4-h point of departure to a 10-min value. AEGL values for ethyl mercaptan are presented in Table 1-1. 1. INTRODUCTION Ethyl mercaptan is used as an intermediate and starting material in the manufacture of plastics, insecticides, and antioxidants, and as an odorant to serve as a warning property for natural gas (O’Neil et al. 2006). Ethyl mercaptan is an odorous, colorless liquid. The disagreeable odor has been described as penetrating, persistent, and garlic- or leek-like, similar to de- caying cabbage (O’Neil et al. 2006). It is found in illuminating gas, in “sour” gas in West Texas oil fields, and in petroleum distillates from which it may be separated by chemical or physical methods (O’Neil et al. 2006).

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16 Acute Exposure Guideline Levels TABLE 1-1 AEGL Values for Ethyl Mercaptan End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 1.0 ppm 1.0 ppm 1.0 ppm 1.0 ppm 1.0 ppm No-effect level (nondisabling) (2.5 (2.5 (2.5 (2.5 (2.5 for respiratory mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) changes associated with odor avoidance in rabbits (Shibata 1966a). AEGL-2 150 ppm 150 ppm 120 ppm 77 ppm 37 ppm 3-fold reduction (disabling) (380 (380 (310 (200 (94 of AEGL-3 mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) values. AEGL-3 450 ppm 450 ppm 360 ppm 230 ppm 110 ppm LC01 in mice (lethal) (1,100 (1,100 (910 (580 (280 (Fairchild and mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) Stokinger 1958). Abbreviation: LC01, lethal concentration, 1% lethality. Ethyl mercaptan is produced commercially by the reaction of sodium ethyl sulfate with potassium hydrosulfide, or catalytically from ethanol and hydrogen sulfide (O’Neil et al. 2006). The total production of methane, ethane, propane, butane, octane, nonane, decane, hexadecane, and miscellaneous thiols was 264,797,000 pounds in 1976, and an estimated 23,130 U.S. workers were exposed to ethyl mercaptan from 1972-1974 (NIOSH 1978). The physical and chemical properties of ethyl mercaptan are presented in Table 1-2. Because of its relatively high vapor pressure (442 mm Hg at 20°C), ethyl mercaptan has the potential to generate toxic air concentrations very quick- ly in the event of a spill. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality No information concerning human lethality from acute exposure to ethyl mercaptan was found. 2.2. Nonlethal Toxicity 2.2.1. Odor Threshold and Odor Awareness Katz and Talbert (1930) conducted two trials, each exposing six human subjects to a range of ethyl mercaptan concentrations via a nosepiece. The sub- jects described the odor as that of decayed cabbage and very disagreeable. A description of the odor intensity of ethyl mercaptan is presented in Table 1-3. No ocular or nasal irritation was reported in subjects exposed to ethyl mercaptan at concentrations up to 1,000 ppm for less than 10 seconds.

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Ethyl Mercaptan 17 TABLE 1-2 Physical and Chemical Data for Ethyl Mercaptan Parameter Value Reference Synonyms Ethanethiol; ethyl sulfhydrate; HSDB 2011 ethylthioalcohol thioethanol; thioethyl alcohol; mercaptoethane CAS registry no. 75-08-1 HSDB 2011 Chemical formula C2H5SH HSDB 2011 Molecular weight 62.14 HSDB 2011 Physical state Colorless liquid O’Neil et al. 2006 Odor Garlic-, leek-, or skunk-like O’Neil et al. 2006; NIOSH 2011 Melting point -147.8°C HSDB 2011 Boiling point 35.1°C HSDB 2011 Flash point -48.3°C (closed cup) HSDB 2011 Density/Specific gravity 0.8315 at 25°C HSDB 2011 Solubility 15,603 mg/L at 25°C in water, HSDB 2011 soluble in acetone, dilute alkali, alcohol, ether, and petroleum naphtha Saturated vapor 7.0 × 105 ppm Calculated concentration (neat) (1.8 × 106 mg/m3) at 25°C Vapor pressure 442 mm Hg at 20°C HSDB 2011 Incompatibility Strong oxidizers NIOSH 2011 Conversion factors in air 1 mg/m3 = 0.39 ppm 1 ppm = 2.54 mg/m3 NIOSH 2011 TABLE 1-3 Odor Intensity of Ethyl Mercaptan Concentration (ppm) Intensity Description Trial 1 Trial 2 0 No odor 2.1 ×10-5 6.0 × 10-6 1 Detectable 9.7 × 10-4 2.6 × 10-4 2 Faint 4.5 × 10-2 1.1 × 10-2 3 Median, easily noticeable 2.1 × 100 4.9 × 10-1 4 Strong 9.7 × 101 2.1 × 101 5 Most intense 4.5 × 103 9.20 × 102 Source: Adapted from Katz and Talbert 1930.

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18 Acute Exposure Guideline Levels Wilby (1969) exposed three individuals to ethyl mercaptan at 12 concen- trations representing a 100-fold range. An odor recognition threshold was de- termined for each subject on the basis of three trials. The mean odor-threshold concentration for ethyl mercaptan was 4.0 × 10-4 ppm, with a standard deviation of 2.6 × 10-4 ppm and a coefficient of variation of 0.65. No other effects were noted. Blinova (1965) conducted a series of experiments whereby a total of nine human subjects inhaled ethyl mercaptan through a mask connected to a 1,000-L chamber in which a known concentration of ethyl mercaptan had been estab- lished. No other information on atmosphere generation or analytic methods was provided. The concentration range of minimum perceptible odor was 2.2 × 10-3 to 1.1 × 10-2 ppm, and the range of imperceptible odor (olfactory fatigue) was reported as 1.8 × 10-3 to 7.2 × 10-3 ppm. Other experimental protocols and re- sults from this study are summarized in Table 1-4. NIOSH (1978) cites an Italian study wherein humans (no details provided) experienced olfactory fatigue and mucosal irritation during experimental expo- sure to ethyl mercaptan at 4 ppm (1 mg/m3) for 3 h/day for 5 days. These effects were transient with cessation of exposure. Subjects exposed at 0.4 ppm did not experience these effects (Gobbato and Terribile 1968). This Italian-language study provides support for the effect levels reported by Blinova (1965). Amoore and Hautala (1983) reported an odor threshold of 7.6 × 10-4 ppm for ethyl mercaptan. This value is the geometric mean calculated from reliable published odor threshold values. Nagata (2003) reported an odor threshold of 8.7 × 10-6 ppm for ethyl mer- captan. This value was determined by a validated method and included a butanol standard for comparison. Therefore, it is considered most appropriate for calcu- lation of the level of distinct odor awareness (LOA). TABLE 1-4 Effects of Ethyl Mercaptan in Humans Concentration (ppm) Duration Subjects Effects 4.0 3 h/d for 10 d 1 female Odor, olfactory fatigue, mucosal irritation 0.4 3 h/d for 10 days 1 female None (one month after above exposure) 4.0 3 h/d for 5 d 2 subjects Odor, olfactory fatigue, (sex not reported) mucosal irritation 4.0 3 h/d for 5 d 2 subjects Same as above, but (one month after (sex not reported) less pronounced above exposure) 0.4 3 h/d for 5 d 2 subjects None (sex not reported) 0.4 3 h/d for 5 d 2 subjects None (one month after (sex not reported) above exposure) Source: Blinova 1965.

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Ethyl Mercaptan 19 The LOA for ethyl mercaptan is 1.4 × 10-4 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 odor intensity. The LOA should help chemical emergency responders in assessing the public awareness of the exposure to ethyl mercaptan from its odor; however, the potential for odor fatigue should also be considered (Shertzer 2012). 2.2.2. Case Report Twenty-eight male and two female high school students (16- to 18-years old), whose classroom was connected by a door to a chemical storeroom, were accidentally exposed to ethyl mercaptan vapor during morning classes (Pichler 1918). The class was dismissed approximately 1 h after the students began com- plaining about a bad odor emanating from the adjacent room. Ten students (eight male and two female) complained of dull headache, general discomfort, and abdominal pain, and three students vomited and had diarrhea. All symptoms resolved by the afternoon, and the students reportedly slept normally that night. The class met in the same room the next day for 3 h. Even though the classroom and storeroom had been ventilated, eight of the students with symptoms the pre- vious day developed headaches, but to a lesser degree. Two of the students did not return to school for several days. Examination of one male student showed “changes” around the eyes and a palpable liver, and protein, erythrocytes, and a few leukocytes were detected in the urine. There were no epithelial cells or casts in the urine and the other urinary parameters returned to normal within 5-6 weeks. It was estimated that 3 g of ethyl mercaptan had vaporized in 325-m3 rooms resulting in an approximate concentration of 4 ppm. 2.2.3. Experimental Study Shibata (1966b) exposed two adult men to ethyl mercaptan at 50 ppm for 20 min and one adult man to 112 ppm for 20 min. Respiration frequency, pulse rate, and blood pressure were monitored continuously for 10 min before and throughout exposure. In one subject exposed at 50 ppm, breathing frequency decreased immediately with exposure and returned to the pre-exposure inhala- tion rate after termination of exposure. The second subject exposed at 50 ppm experienced no change in breathing rate. The subject exposed at 112 ppm had a slightly irregular and decreased breathing rate. Minute volume and tidal volume increased in all three subjects. Pulse rate increased slightly in only one subject (50 ppm), and there was no effect on blood pressure and no electrocardiographic abnormalities in any subject. The only subjective response was odor recognition only during the first few breaths, suggesting that olfactory fatigue and accom- modation occurred.

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20 Acute Exposure Guideline Levels 2.3. Developmental and Reproductive Toxicity Developmental and reproductive studies of human exposure to ethyl mer- captan were not available. 2.4. Genotoxicity Genotoxicity studies of human exposure to ethyl mercaptan were not available. 2.5. Carcinogenicity Carcinogenic studies of human exposure to ethyl mercaptan were not available. 2.6. Summary Data on human exposure to ethyl mercaptan are limited. Case reports of deaths from accidental exposure to ethyl mercaptan were not available. Nonle- thal toxicity data include a case report where high school students accidentally exposed to ethyl mercaptan experienced reversible dull headache, general dis- comfort, abdominal pain, vomiting, and diarrhea. Other data included odor- detection (identification) and olfactory-fatigue data but no accompanying health effects information, and a study showing slight changes in breathing rate in three individuals exposed to ethyl mercaptan for 20 min. Atmospheric generation and exposure concentration parameters were not described in detail for any of the human studies. 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 Fairchild and Stokinger (1958) exposed groups of 10 Swiss-derived male mice (body weight 25-28 g) to ethyl mercaptan at 2,600, 3,150, 3,573, 4,438, or 4,832 ppm for 4 h, followed by a 15-day observation period. Vapor generation was achieved by either bubbling a stream of nitrogen gas through a midget frit- ted-glass bubbler, which contained liquid ethyl mercaptan, or by passage of ni- trogen into a borosilicate glass nebulizer containing the ethyl mercaptan. Target concentrations were maintained in an 18-L glass chamber by varying the ratio of volume flow of compressed air and compressed nitrogen. Ethyl mercaptan con- centrations during exposure periods were measured by absorption of vapors in

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Ethyl Mercaptan 21 either isopropyl alcohol or acetone containing an excess of silver nitrate and titrating the uncombined silver amperometrically. Chamber concentrations dur- ing tests were uniform after the first 30 min; mean variation for all exposures was approximately 4%. Clinical signs included increased respiration and rest- lessness (hyperactivity), uncoordinated movement, staggering gait, muscular weakness, partial skeletal muscle paralysis beginning in the hind limbs, light to severe cyanosis, tolerance of a prone position, and mild to heavy sedation. Ani- mals exposed to “maximal lethal concentrations” typically died from respiratory arrest during exposure or shortly after removal from the chamber. Animals ex- posed to “minimal lethal concentrations” typically died while in a semiconscious condition of “long duration”. Surviving animals often remained in a semicon- scious state of sedation and lethargy for 4- to 6-h post-exposure before showing signs of recovery. An LC50 value (lethal concentration, 50% lethality) of 2,770 ppm, LC05 value (lethal concentration, 5% lethality) of 2,498 ppm, and LC01 value of 2,250 ppm were calculated by the method of Litchfield and Wilcoxon (1949). A BMC01 (benchmark concentration with 1% response) of 1,921 ppm and BMCL05 (benchmark concentration, 95% lower confidence limit with 5% response) of 1,545 ppm were also calculated. Mortality data are summarized in Table 1-5. 3.1.2. Rats Fairchild and Stokinger (1958) exposed groups of five or six Wistar- derived male rats (body weight 180-220 g) to ethyl mercaptan at 2,600, 3,150, 3,573, 4,438, 4,832, 4,868, 5,100, or 5,125 ppm for 4 h, followed by a 15-day observation period. Vapor generation and test chamber analysis is similar to that described for studies in mice (see Section 3.1.1). Clinical signs included in- creased respiration and restlessness (hyperactivity), incoordinated movement, staggering gait, muscular weakness, partial skeletal muscle paralysis beginning in the hind limbs, light to severe cyanosis, tolerance of a prone position, and mild to heavy sedation. Animals exposed to “maximal lethal concentrations” typically died from respiratory arrest during exposure or shortly after removal from the chamber. Animals exposed to “minimal lethal concentrations” typically died while in a semiconscious condition of “long duration”. Surviving animals often remained in a semiconscious state of sedation and lethargy for 4- to 6-h post-exposure before showing signs of recovery. An LC50 value of 4,420 ppm, LC05 value of 4,120 ppm, and LC01 value of 3,808 ppm were calculated by the method of Litchfield and Wilcoxon (1949). Mortality data are summarized in Table 1-5. Fairchild and Stokinger (1958) also administered ethyl mercaptan by oral gavage or intraperitoneal injection to Wistar-derived male rats, followed by 15- day observation periods. An oral LD50 (lethal dose, 50% mortality) of 682 mg/kg and an intraperitoneal LD50 of 226 mg/kg were reported.

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22 Acute Exposure Guideline Levels TABLE 1-5 Mortality in Mice and Rats Exposed to Ethyl Mercaptan for 4 Hours Concentration (ppm) Mice Rats 2,600 4/10 0/5 3,150 7/10 0/5 3,573 10/10 0/5 4,438 10/10 1/5 4,832 10/10 4/6 4,868 – 2/5 5,100 – 5/5 5,125 – 2/6 LC01 2,250 ppm 3,808 ppm LC05 2,498 ppm 4,120 ppm LC50 2,770 ppm 4,420 ppm Source: Adapted from Fairchild and Stokinger 1958. 3.2. Nonlethal Toxicity 3.2.1. Rats Groups of three to five male Holtzman or Sprague-Dawley rats (weighing 285-325 g) were individually exposed in a 4-L glass desiccator to ethyl mercap- tan at concentrations of 2.7-3.8% (approximately 27,000-38,000 ppm) for 15 min or less (Zieve et al. 1974). The target concentrations were achieved by in- jecting the required amount of ethyl mercaptan through a rubber septum in the lid of the chamber. The concentration of ethyl mercaptan in the chamber atmos- phere was not analyzed, rather concentrations were calculated from the dose injected. A CD50 value (concentration causing coma induction in 50% of ani- mals, as measured by complete loss of the righting reflex) of 3.3% (33,000 ppm) was determined. No rats lost the righting reflex at ethyl mercaptan concentra- tions of about 3.0% (30,000 ppm), but all rats lost the righting reflex at about 3.7% (37,000 ppm). The rats exhibited a brief excitement phase before becom- ing “groggy”. At the CD50, the excitement phase lasted about 2 min, the groggy and lethargic phase lasted about 1 min, and finally frank coma ensued within 1 to 2 min. At lower concentrations, the excitement and pre-coma phases were prolonged and at higher concentrations, the entire sequence occurred more quickly. When rats were removed from exposure immediately after becoming comatose, the coma generally did not last more than 30 min and the rats ap- peared and remained alert and active on recovery. Blood concentrations of ethyl mercaptan found in comatose animals were greater than 200 nmoles/mL; how- ever, there was no clear concentration-response relationship between inhaled concentrations and blood levels.

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Ethyl Mercaptan 23 No mortality was observed in rats exposed head only to ethyl mercaptan at 991 ppm for 4 h or in rats exposed whole body at 27 ppm for 4 h (Shertzer 2012). 3.2.2. Rabbits Shibata (1966a) exposed groups of two male rabbits (weighing 3 kg) to ethyl mercaptan at 10, 100, or 1,000 ppm by breathing mask for 20 min. Breath- ing rate (measured by observed thorax movement) and minute expiratory vol- ume (measured by wet spirometry) were monitored throughout the exposure periods. Tidal volume was then calculated by dividing the minute expiratory volume by the breathing rate. At 100 and 1,000 ppm, respiratory rate and expira- tory volume were decreased and tidal volume was increased. Approximate changes in respiratory function parameters (estimated from graphs) at the end of the exposure period in the 1,000-ppm group were: 20% decrease in expiratory volume, 40% decrease in respiratory rate, and 40% increase in tidal volume. Approximate changes in the 100 ppm group were: 10% decrease in expiratory volume, 10% decrease in respiratory rate, and 20% increase in tidal volume. The respiratory changes in rabbits at 1,000 and 100 ppm for 20 min are suggestive of odor avoidance. At 10 ppm, respiratory rate and ventilation rate showed unstable fluctuation and tidal volume was increased slightly during the last half of the exposure period. All respiratory indicators returned to pre-exposure levels by the end of the 35-min observation period, except for the respiratory rate of animals exposed at 1,000 ppm, which was still decreased by approximately 25%. The changes in breathing rate and tidal volume in rabbits exposed to ethyl mercaptan at 100 ppm or higher for 20 min are similar to the effects reported in the human study by the same investigator (Shibata 1966b). However, the authors note (Shi- bata 1966b, translated by OPPT): It is difficult to compare the rabbit study and human study. The rabbit’s body weight is about one-twentieth that of humans and the expiratory volume is about one-ninth that of humans; therefore, rabbit’s expiratory volume per body weight is greater than humans, which indicates that the rabbit’s inspiratory volume is about twice as much as that of humans if they are exposed to the same concentration of gas. Therefore rabbits would be affected more than humans. The differences in respiratory center sensitivity of rabbits and humans should also be considered as well. Fairchild and Stokinger (1958) instilled ethyl mercaptan (0.1mL) into the conjunctival sac of the right eye of one male New Zealand white rabbit. The left eye served as a control. Slight to moderate irritation was observed and resolved within 48 h.

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Ethyl Mercaptan 33 exposure to ethyl mercaptan lack data on exposure concentrations. There were insufficient data to establish a chemical-specific time-scaling relationship for ethyl mercaptan. 9. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2004. Ethyl mer- captan (CAS Reg. No.75-08-1). Documentation of the Threshold Limit Values and Biological Exposure Indices. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. ACGIH (American Conference of Governmental Industrial Hygienists). 2012. Ethyl mer- captan (CAS Reg. No.75-08-1). Threshold Limit Values and Biological Exposure Indices. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. Amoore, J.E., and E. Hautala. 1983. Odor as an aid to chemical safety: Thresholds com- pared with threshold limit values and volatilities for 214 industrial chemicals in air and water dilution. J. Appl. Toxicol. 3(6):272-290. Blinova, E.A. 1965. On the normalization of concentrations of substances with strong odors in the air and work places [in Russian]. Gig. Sanit. 30(1):18-22. Chen, S., L. Zieve, and V. Mahadevan. 1970. Mercaptans and dimethyl sulfide in the breath of patients with cirrhosis of the liver. Effect of feeding methionine. J. Lab. Clin. Med. 75(4):628-635. 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]. 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. Foster, D., K. Ahmed, and L. Zieve. 1974. Action of methanethiol on NA, K-ATPase: Implications for hepatic coma. Ann. NY Acad. Sci. 242:573-576. Gobbato, F., and P.M. Terribile. 1968. Toxicological property of mercaptans [in Italian]. Folia Med. 51: 329-341 (as cited by NIOSH 1978). Hazleton Laboratories, Inc. 1983. Mouse Lymphoma Forward Mutation Assay: Ethyl Mercaptan (Ethanethiol). Final Report, April 28, 1983. Submitted to EPA by Phil- lips Petroleum Company, Bartlesville, OK, with Cover Letter Dated 8/24/92. EPA Document No. 88-920010738. Microfiche No. OTS0571884. Hazleton Laboratories, Inc. 1984. In vitro Sister Chromatid Exchange in Chinese Ham- ster Ovary Cells: Ethyl Mercaptan. Final Report, December 11, 1984. Submitted to EPA by Phillips Petroleum Company, Bartlesville, OK, with Cover Letter Dated 8/24/92. EPA Document No. 88-920010738. Microfiche No. OTS0571884. 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 (as cited in NIOSH 1978). HSDB (Hazardous Substances Data Bank). 2011. Ethyl Mercaptan (CAS Reg. No. 75- 08-1). TOXNET, Specialized Information Services, U.S. National Library of Med- icine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/html gen?HSDB [accessed Sept. 2012].

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34 Acute Exposure Guideline Levels 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. Washing- ton, DC: U.S. Government Printing Office. Litchfield, J.T., and F. Wilcoxon. 1949. A simplified method of evaluating dose-effect experiments. J. Pharmacol. Exp. Ther. 96(2):99-113. MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst 2004: Ethaanthiol. Den Haag: SDU Uitgevers [online]. Available: http://www.las rook.net/lasrookNL/maclijst2004.htm [accessed June 21, 2013]. Nagata, Y. 2003. Measurement of odor threshold by triangle odor bag method. Pp. 118- 127 in Odor Measurement Review. Office of Odor, Noise and Vibration, Envi- ronmental Management Bureau, Ministry of the Environment, Government of Ja- pan. September 2003 [online]. Available: http://www.env.go.jp/en/air/odor/mea sure/02_3_2.pdf [accessed June 20, 2013]. NIOSH (National Institute for Occupational Safety and Health). 1978. Criteria for Recom- mended Standard. Occupational Exposure to n-Alkane Monothiols, Cyclohexanethi- ol, and Benzenethiol. DHEW(NIOSH) No. 78-213. U.S. Department of Health Edu- cation and Welfare, Public Health Service, Center for Disease Control, National Institute for Occupational Safety and Health, Atlanta, GA. September [online]. Available: http://www.cdc.gov/niosh/pdfs/78-213a.pdf [accessed June 20, 2013]. NIOSH (National Institute for Occupational Safety and Health). 1994. Documentation for Immediately Dangerous to Life or Health Concentrations (IDLHs): Ethyl mercap- tan. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Atlanta, GA [online]. Available: http://www.cdc.gov/niosh/idlh/75081.html [accessed June 20, 2013]. NIOSH (National Institute for Occupational Safety and Health). 2011. NIOSH Pocket Guide to Chemical Hazards: Ethyl mercaptane. U.S. Department of Health and Hu- man Services, Centers for Disease Control and Prevention, National Institute for Oc- cupational Safety and Health, Cincinnati, OH [online]. Available: http://www.cdc. gov/niosh/npg/npgd0280.html [accessed June 20, 2013]. NRC (National Research Council). 1993. Guidelines for Developing Community Emergen- cy 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. NRC (National Research Council). 2010. Hydrogen sulfide. Pp. 173-218 in Acute Expo- sure Guideline Levels for Selected Airborne Chemicals, Vol. 9. Washington, DC: The National Academies Press. O'Neil, M.J., P.E. Heckelman, C.B. Koch, and K.J. Roman, eds. 2006. The Merck Index, 14th Ed. Whitehouse Station, NJ: Merck. Pichler, K. 1918. Intoxication due to inhalation of ethyl mercaptan [in German]. Zen- tralbl. Inn. Med. 39: 689-693. Ruijten, M.W.M.M., R. van Doorn, and A.P. van Harreveld. 2009. Assessment of Odour Annoyance in Chemical Emergency Management. RIVM Report 609200001/2009. RIVM (National institute for Public Health and the Environment), Bilthoven, The Netherlands [online]. Available: http://www.rivm.nl/bibliotheek/rapporten/6092 00001.pdf [accessed Dec. 13, 2010]. Shertzer, H.G. 2012. Organic sulfur compounds. Pp. 1039-1078 in Patty’s Toxicology, 6th Ed., E. Bingham, and B. Cohrssen, eds. New York: Wiley.

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Ethyl Mercaptan 35 Shibata, Y. 1966a. Studies on the influence of ethylmercaptan upon the living body: Part 2. On the respiratory function and clinical findings in rabbits which inhaled ethyl mercaptan gas [in Japanese]. Shikoku Acta Med. 22(6):834-843. Shibata, Y. 1966b. Studies on the influence of ethylmercaptan upon the living body: Part 3. Inhalation experiment of ethyl mercaptan gas in the human body [in Japanese]. Shikoku Acta Med. 22(6):844-850. 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. Snow, G.A. 1957. The metabolism of compounds related to ethanethiol. Biochem. J. 65(1):77-82. Tansy, M.F., F.M. Kendall, J. Fantasia, W.E. Landin, R. Oberly, and W. Sherman. 1981. Acute and subchronic toxicity studies of rats exposed to vapors of methyl mercap- tan and other 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 re- sponse relationship of irritant and systemically acting vapours and gases. J. Haz- ard. Mater. 13(3):301-309. Vahlkamp, T., A.J. Meijer, J. Wilms, and R.A. Chamuleau. 1979. Inhibition of mito- chondrial electron transfer in rats by ethane thiol and methanethiol. Clin. Sci. 56(2):147-156. Wilby, F.V. 1969. Variation in recognition odor threshold of a panel. J. Air Pollut. Con- trol Assoc. 19(2): 96-100. Zieve, L., W.M. Doizaki, and J. Zieve. 1974. Synergism between mercaptans and ammo- nia 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.

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36 Acute Exposure Guideline Levels APPENDIX A DERIVATION OF AEGL VALUES FOR ETHYL MERCAPTAN Derivation of AEGL-1 Values Key study: Shibata, Y. 1966a. Studies on the influence of ethylmercaptan upon the living body: II. On the respiratory function and clinical findings in rabbits which inhaled ethyl mercaptan gas. Shikoku Acta Med. 22(6): 834-843. Toxicity end point: No-effect level for respiratory changes associated with odor avoidance in rabbits, 10 ppm for 20 min Scaling: Values held constant across time Uncertainty factor: 3 for interspecies differences 3 for intraspecies variability All AEGL-1 durations: 10 ppm ÷ 10 = 1.0 ppm Derivation of AEGL-2 Values In the absence of relevant data to derive AEGL-2 values and because ethyl mercaptan has a steep concentration-response curve, AEGL-3 values were divided by 3 to estimate a threshold for inability to escape. 10-min AEGL-2: 450 ppm ÷ 3 = 150 ppm 30-min AEGL-2: 450 ppm ÷ 3 = 150 ppm 1-h AEGL-2: 360 ppm ÷ 3 = 120 ppm 4-h AEGL-2: 230 ppm ÷ 3 = 77 ppm 8-h AEGL-2: 110 ppm ÷ 3 = 37 ppm Derivation of AEGL-3 Values Key study: Fairchild, E.J., and H.E. Stokinger. 1958. Toxicologic studies on organic sulfur compounds. I. Acute toxicity of some aliphatic and aromatic thiols (mercaptans). Am. Ind. Hyg. Assoc. J. 19(3):171-189.

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Ethyl Mercaptan 37 Toxicity end point: 4-h LC01 of 2,250 ppm was used as an estimated lethality threshold in mice. Time scaling: Cn × t = k (default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations); time scaling not performed for the 10-min AEGL-3 value because of the uncertainty in extrapolating a 4 h point of departure to a 10-min value. (2,250 ppm)3 × 4 h = 4.56 × 1010 ppm-h (2,250 ppm)1 × 4 h = 9,000 ppm-h Uncertainty factors: 3 for interspecies differences 3 for intraspecies variability 10-min AEGL-3: 450 ppm (30-min AEGL-3 value adopted) 30-min AEGL-3: C3 × 0.5 h = 4.56 × 1010 ppm-h C3 = 9.12 × 1010 ppm C = 4,501 ppm 4,501 ppm ÷ 10 = 450 ppm 1-h AEGL-3: C3 × 1 h = 4.56 × 1010 ppm-h C3 = 4.56 × 1010 ppm C = 3,572 ppm 3,572 ppm ÷ 10 = 360 ppm 4-h AEGL-3: C3 × 4 h = 4.56 × 1010 ppm-h C3 = 1.14 × 1010 ppm C = 2,251 ppm 2,251 ppm ÷ 10 = 230 ppm 8-h AEGL-3: C1 × 8 h = 9,000 ppm-h C1 = 1,125 ppm C = 1,125 ppm 1,125 ppm ÷ 10 = 110 ppm

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38 Acute Exposure Guideline Levels APPENDIX B ACUTE EXPOSURE GUIDELINE LEVELS FOR ETHYL MERCAPTAN Derivation Summary AEGL-1 VALUES 10 min 30 min 1h 4h 8h 1.0 ppm 1.0 ppm 1.0 ppm 1.0 ppm 1.0 ppm (2.5 mg/m3) (2.5 mg/m3) (2.5 mg/m3) (2.5 mg/m3) (2.5 mg/m3) Key reference: Shibata, Y. 1966a. Studies on the influence of ethyl mercaptan upon the living body: II. On the respiratory function and clinical findings in rabbits which inhaled ethyl mercaptan gas. Shikoku Acta. Med. 22(6):834-843. Test species/Strain/Sex/Number: Rabbits, males, 2/group Exposure route/Concentrations/Durations: Inhalation; 10, 100, 1,000 ppm for 20 min Effects: 10 ppm: Unstable fluctuation in respiratory rate. 100 ppm: Decreased respiratory rate (10%) and expiratory volume (10%); increased tidal volume (20%). 1,000 ppm: Decreased respiratory rate (40%) and expiratory volume (20%); increased tidal volume (40%). End point/Concentration/Rationale: No-effect level for respiratory changes associated with odor avoidance, 10 ppm Uncertainty factors/Rationale: Use of the full factor of 10 for either interspecies differences or intraspecies variability would yield AEGL-1 values of 0.3 ppm or lower, concentrations that are inconsistent with human data. Interspecies: 3 Intraspecies: 3 Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Not applicable Time scaling: Values held constant across time because effects are not expected to vary greatly over time. Data adequacy: The study was considered adequate for derivation of AEGL-1 values. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 150 ppm 150 ppm 120 ppm 77 ppm 37 ppm (380 mg/m3) (380 mg/m3) (310 mg/m3) (200 mg/m3) (94 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 curve for ethyl mercaptan (lethality in mice exposed for 4 h was 40% at 2,600 ppm, 50% at 2,770 ppm, and 100% at 3,573 ppm; in rats, the LC01 value was 3,808 and the LC50 value was 4,420 ppm).

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Ethyl Mercaptan 39 AEGL-3 VALUES 10 min 30 min 1h 4h 8h 450 ppm 450 ppm 360 ppm 230 ppm 110 ppm (1,100 mg/m3) (1,100 mg/m3) (910 mg/m3) (580 mg/m3) (280 mg/m3) Reference: Fairchild, E.J., and H.E. Stokinger. 1958. Toxicologic studies on organic sulfur compounds. I. Acute toxicity of some aliphatic and aromatic thiols (mercaptans). Am. Ind. Hyg. Assoc. J. 19(3):171-189. Test species/Strain/Sex/Number: Mice, Swiss-derived, male, 10/group Exposure route/Concentrations/Durations: Inhalation; 0, 2,600, 3,150, 3,573, 4,438, or 4,832 ppm for 4 h Effects: Concentration (ppm) Mortality 0 0/10 2,600 4/10 3,150 7/10 3,573 10/10 4,438 10/10 4,832 10/10 LC50 = 2,770 ppm LC01 = 2,250 ppm End point/Concentration/Rationale: Estimated lethality threshold in mice, 4-h LC01 of 2,250 ppm Uncertainty factors/Rationale: Intraspecies: 3, considered sufficient because of steep concentration-response curve (lethality in mice exposed for 4 h was 40% at 2,600 ppm, 50% at 2,770 ppm, and 100% at 3,573 ppm; in rats, the LC01 value was 3,808 and the LC50 value was 4,420 ppm), which implies limited individual variability. Interspecies: 3, because the mouse is the most sensitive species. Also, although an interspecies uncertainty factor of 10 might normally be applied because of limited data, AEGL-3 values calculated with a total uncertainty factor of 30 would lead to values approaching or equivalent to the AEGL-3 values for hydrogen sulfide. For example, if a total uncertainty factor of 30 is applied, an 8-h AEGL-3 value for ethyl mercaptan would be 37 ppm, which is slightly higher than the 8-h AEGL-3 value for hydrogen sulfide of 31 ppm (NRC 2010). Because a robust database exists for hydrogen sulfide and because data suggest that ethyl mercaptan is less toxic than hydrogen sulfide (4-h LC50 is 4,420 ppm for ethyl mercaptan and 444 ppm for hydrogen sulfide), it would be inconsistent with the total data set to have AEGL-3 values for ethyl mercaptan that are in the range of the AEGL-3 values for hydrogen sulfide. Furthermore, use of a total uncertainty factor of 30 would yield a 30-min AEGL-3 value of 150 ppm, which is inconsistent with the finding that a single human exposed to ethyl mercaptan at 112 ppm for 20 min exhibited only a slightly irregular and decreased breathing rate (Shibata 1966b). Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Insufficient data (Continued)

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40 Acute Exposure Guideline Levels AEGL-3 VALUES Continued Time scaling: Cn × t = k; default value of n = 3 was used for extrapolation to the shorter durations (30 min, 1 h, and 4 h) and n = 1 for extrapolation to the longer duration (8 h). The 30-min value was adopted as the 10-min AEGL-3 value because of the uncertainty associated with extrapolating a 4-h exposure to a 10-min value. Data adequacy: The study was well conducted and used a sufficient number of animals.

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Ethyl Mercaptan 41 APPENDIX C DERIVATION OF THE LEVEL OF DISTINCT ODOR AWARENESS FOR ETHYL MERCAPTAN 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 Ruijten et al. (2009). The odor detection threshold (OT50) for ethyl mercaptan was reported to be 0.0000087 ppm (Nagata 2003). 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 ÷ 0.0000087) + 0.5 log (C ÷ 0.0000087) = ([3 - 0.5] ÷ 2.33) log (C ÷ 0.0000087) = 1.07 C = (101.07) × 0.0000087 C = 0.000102 ppm The resulting concentration is multiplied by an empirical field correction factor. It takes into account that, in everyday life, factors 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 current knowledge, a factor of 1/3 is applied to adjust for peak exposure. Adjustment for distraction and peak exposure lead to a correction factor of 4 ÷ 3 = 1.33. LOA = C × 1.33 LOA = 0.000102 ppm × 1.33 LOA = 0.00014 ppm

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42 Ac cute Exposure Guideline Levels AP PPENDIX D FIGUR D-1 Category plot of toxicity data and AEGL values for ethy mercaptan. RE y y L yl TABLE D-1 Data Us in Category Plot of AEGL Values for E E sed y L Ethyl Mercapta an No. of Source Species Sex x Exposure ppm es Miin Category y AEGL-1 1 10 AEGL AEGL-1 1 30 AEGL AEGL-1 1 60 AEGL AEGL-1 1 0 240 AEGL AEGL-1 1 480 0 AEGL AEGL-2 150 10 AEGL AEGL-2 150 30 AEGL AEGL-2 120 60 AEGL AEGL-2 77 0 240 AEGL AEGL-2 37 480 0 AEGL AEGL-3 450 10 AEGL AEGL-3 450 30 AEGL

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Ethyl Mercaptan 43 AEGL-3 360 60 AEGL AEGL-3 230 240 AEGL AEGL-3 110 480 AEGL Shibata 1966a Rabbit Male 1 10 20 0 Rabbit Male 1 100 20 1 Rabbit Male 1 1,000 20 1 Fairchild and Mouse Male 1 2,600 240 2 Stokinger 1958 Mouse Male 1 3,150 240 SL Mouse Male 1 3,573 240 3 Mouse Male 1 4,438 240 3 Mouse Male 1 4,832 240 3 Katz and Talbert 1930 Human Male 1 0.00002 0 Human Male 1 920 1 Wilby 1969 Human Male 1 0.0004 0 Blinova 1965 Human Male 1 4 180 1 Pichler 1918 Human Male Shibata 1966b Human Male 1 50 20 1 Human Male 1 112 20 1 Amoore and Hautala 1983 Human 1 0.0008 1 Nagata 2003 Human 1 0.00001 1 Zieve et al. 1974 Rats Rats Blinova 1965 Human 1 0.4 180 0 NIOSH 1978 Human 5 4.0 180 1 Human 5 0.4 180 0 Katz and Talbert 1930 Human 1 1,000.0 0.17 0 For category: 0 = no effect, 1 = discomfort, 2 = disabling, 3 = lethal; SL = some lethality.