4

tert-Octyl 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.), Chemical Manager Glenn Leach (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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4 tert-Octyl 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.), Chemical Manager Glenn Leach (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agen- cy). 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 conclu- sions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 99

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100 Acute Exposure Guideline Levels AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopula- tions, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic respons- es, could experience the effects described at concentrations below the corre- sponding AEGL. SUMMARY tert-Octyl mercaptan is a colorless liquid with a disagreeable odor. It is used in polymer modification and as a lubricant additive. It is generally prepared via acid-catalyzed synthesis. It is moderately irritating to the eyes, and may cause headache, nausea, vomiting, and central nervous system (CNS) effects, resulting in dizziness, convulsions, unconsciousness, and respiratory depression (HSDB 2006). Data were insufficient to derive AEGL-1 values for tert-octyl mercaptan. Therefore, AEGL-1 values are not recommended. Data on tert-octyl mercaptan were also insufficient to derive AEGL-2 val- ues. In the absence of appropriate chemical-specific data, AEGL-3 values were divided by 3 to derive AEGL-2 values for tert-octyl mercaptan. This approach is justified by the chemical’s steep concentration-response curve for lethality in rats. AEGL-3 values were based on a 4-h BMCL05 (benchmark concentration, 95% confidence limit with 5% response) value for tert-octyl mercaptan of 11.5 ppm, calculated from combined data on female rats (Temple University 1982). This concentration is considered a threshold for lethality and is based on the most sensitive test animals (females). An intraspecies uncertainty factor of 3 was applied and is considered sufficient because the point of departure is based on data from the more sensitive female animals and the steep concentration- response curve for lethality suggests limited intraindividual variability. An inter- species uncertainty factor of 3 was also applied because the limited data suggest

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tert-Octyl Mercaptan 101 no difference in species sensitivity between rats and mice. Therefore, the total uncertainty factor was 10. Values were scaled across time using the equation Cn × t = k, where default values of n = 3 when extrapolating to shorter durations and n = 1 when extrapolating to longer durations were used to derive values protective of human health (NRC 2001). The 30-min AEGL-3 value was adopt- ed as the 10-min value because of the uncertainty in extrapolating a 4-h point of departure to a 10-min value. AEGL values for tert-octyl mercaptan are presented in Table 4-1. 1. INTRODUCTION tert-Octyl mercaptan is a colorless liquid with a disagreeable odor. It is used in polymer modification and as a lubricant additive. It is generally prepared via acid-catalyzed synthesis. It is moderately irritating to the eyes, and may cause headache, nausea, vomiting, and CNS effects, resulting in dizziness, con- vulsions, unconsciousness, and respiratory depression (HSDB 2006). The chemical and physical properties of tert-octyl mercaptan are presented in Table 4-2. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality Human lethality data on tert-octyl mercaptan were not found. 2.2. Nonlethal Toxicity Human nonlethal toxicity data on tert-octyl mercaptan were not found. No odor threshold data were available either. 2.3. Case Reports No case reports on tert-octyl mercaptan were found. 2.4. Developmental and Reproductive Effects Data on the developmental and reproductive toxicity of tert-octyl mercap- tan in humans were not available. 2.5. Genotoxicity No information regarding the genotoxicity of tert-octyl mercaptan in hu- mans was available.

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102 Acute Exposure Guideline Levels TABLE 4-1 AEGL Values for tert-Octyl Mercaptan End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1a NR NR NR NR NR Insufficient data (nondisabling) AEGL-2 0.77 ppm 0.77 ppm 0.60 ppm 0.40 ppm 0.19 ppm One-third the (disabling) (4.6 (4.6 (3.6 (2.4 (1.1 AEGL-3 values. mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 2.3 ppm 2.3 ppm 1.8 ppm 1.2 ppm 0.58 ppm Threshold for (lethal) (14 (14 (11 (7.2 (3.5 lethality (BMCL05) in mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) female rats (Temple University 1982) a The absence of AEGL-1 values does not imply that concentrations below AEGL-2 val- ues will be without effect. Abbreviations: BMCL05, benchmark concentration, 95% confidence limit with 5% re- sponse; NR, not recommended. TABLE 4-2 Chemical and Physical Data on tert-Octyl Mercaptan Parameter Value Reference Synonyms tert-octanethiol; 2-methyl-2-heptanethiol; HSDB 2006 2-pentanethiol, 2,4,4-trimethyl- CAS registry no. 141-59-3 HSDB 2006 Chemical formula C8H18S HSDB 2006 Molecular weight 146.30 HSDB 2006 Physical state Colorless liquid HSDB 2006 Boiling point 154 -166°C HSDB2006 Flash point 43°C Shertzer 2001 Density/specific gravity 0.848 at 15.5°C HSDB 2006 Relative vapor density 5.0 (air = 1) HSDB 2006 Solubility in water 31 mg/L at 25°C HSDB 2006 Saturated vapor 6,842 ppm Calculated concentration (neat) (41,052 mg/m3) Vapor pressure 5.20 mm Hg at 25°C HSDB 2006 3 Conversion factors in air 1 ppm = 6.0 mg/m 1 mg/m3 = 0.17 ppm 2.6. Carcinogenicity No information was available regarding the carcinogenicity of tert-octyl mercaptan in humans.

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tert-Octyl Mercaptan 103 2.7. Summary No human data on tert-octyl mercaptan were found. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Rats Fairchild and Stokinger (1958) exposed groups of five Wistar-derived male rats (body weight 180 -220g) to tert-octyl mercaptan at 38, 40, 44, 55, 64, 78, or 110 ppm (analytic concentrations) for up to 4 h, followed by a 15-day observation period. Vapor was generated by either bubbling a stream of nitrogen gas through a midget fritted-glass bubbler, which contained liquid tert-octyl mercaptan, or by passage of nitrogen into a borosilicate glass nebulizer containing the tert-octyl mercaptan. Target concentrations were maintained in an 18-L glass chamber by varying the ratio of air flow volume and tert-octyl mercaptan containing com- pressed nitrogen. Tert-octyl mercaptan concentrations during exposure periods were measured by absorption of vapors in either isopropyl alcohol or acetone con- taining an excess of silver nitrate and titrating the uncombined silver amperometri- cally. Chamber concentrations during tests were uniform after the first 30 min; mean variation was approximately 4%. Clinical signs included respiratory stimula- tion, followed by CNS stimulation initially characterized by a “threshold effect” consisting of localized minimal convulsive movements in the form of repeated facial and ear twitches. Seizures were observed at all concentrations; the severity, frequency, and latency period for the onset of seizures were concentration related. Propulsive and retropulsive thrusts of the trunk were also observed, followed by circumscribed clonic convulsions of the forebody and forelimbs, resulting in a sitting position while pawing in the air. These effects were followed by general- ized clonic seizures of the forelimbs and hindlimbs that caused a loss of upright position. Exophthalmus with conjunctival congestion and salivation accompanied the seizures. Muscle relaxation, irregular labored breathing, and coma preceded death. An LC50 (lethal concentration, 50% lethality) value of 51 ppm was calculat- ed by the investigators. A BMC01 of 34.4 ppm and BMCL05 of 31.8 ppm were also calculated. Mortality data from this study are presented in Table 4-3. Groups of five male and five female Sprague-Dawley rats were exposed to tert-octyl mercaptan at 0, 7, 15, 19, 29, 59, 71, or 110 ppm for 4 h, followed by a 14-day observation period (Temple University 1982). Exposures were conducted in an 11.4-ft3 stainless-steel chamber. Vapor was generated by heating liquid tert- octyl mercaptan and passing air through at a constant rate. Chamber delivery sys- tem parameters were set at values calculated to produce target chamber concentra- tions. Analyses of tert-octyl mercaptan concentrations in the test atmospheres were performed by colorimetric titration four to 20 times during each 4-h exposure.

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104 Acute Exposure Guideline Levels Clinical signs were noted in females at concentrations of 19 ppm and higher. The animals seized the wire mesh bottom of the exposure chamber with their teeth and claws, their backs were arched and tails extended, and they remained rigidly in this position until death or until the survivors were pried loose by the investigator. Sal- ivation and a final convulsive leap were sometimes observed. Clinical signs in- cluded tremors and prostration in two of five males exposed at 71 ppm and all males exposed at 110 ppm. Animals that survived the first 24 h after exposure also survived until the end of the 14-day observation period. All surviving rats gained weight by the end of the observation period, and gross necropsy revealed no ab- normalities. LC50 values of 33 ppm (males and females combined), 59 ppm (males), and 17 ppm (females) were calculated by the investigators. BMC01 values of 59.7 ppm (males) and 13.8 ppm (females) ppm and BMCL05 values of 52 ppm (males) and 11.3 ppm (females) were also calculated. Mortality data from this study are presented in Table 4-4. TABLE 4-3 Mortality in Wistar Rats Exposed to tert-Octyl Mercaptan for 4 Hours Concentration (ppm) Mortality Comments 38 0/5 Seizures within 45 min to 1.5 h; average of 2 mild seizures 40 1/6 Seizures within 45 min to 1.5 h 44 1/5 Seizures within 45 min to 1.5 h 55 3/5 Seizures within 45 min to 1.5 h 64 5/5 Seizures within 20-30 min, at intervals of several minutes; all dead within 3 h, 10 min 78 6/6 Seizures within 20-30 min, at intervals of several minutes; all dead within 2 h, 50 min 110 6/6 Seizures within 10-15 min, at close intervals (2-3 min apart); all dead within 2 h, 45 min LC50 51 ppm (46.5-54.5 ppm) BMCL05 31.8 ppm BMC01 34.4 ppm Abbreviations: BMC01, benchmark concentration with 1% response; BMCL05, bench- mark concentration, 95% lower confidence limit with 5% response; LC50, lethal concen- tration, 50% lethality. Source: Adapted from Fairchild and Stokinger 1958.

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tert-Octyl Mercaptan 105 TABLE 4-4 Mortality in Sprague-Dawley Rats Exposed to tert-Octyl Mercaptan for 4 Hours Mortality Concentration (ppm) Male Female Combined 0 0/5 0/5 0/10 7 ± 0.7 0/5 0/5 0/10 15 ± 3.0 0/5 1/5 1/10 19 ± 3.0 0/5 5/5 5/10 29 ± 2.0 0/5 5/5 5/10 59 ± 3.0 0/5 5/5 5/10 71 ± 1.0 4/5 5/5 9/10 110 ± 3.0 5/5 5/5 10/10 LC50 59 ppm 17 ppm 33 ppm (16-66 ppm) BMCL05 52 ppm 11.3 ppm 4.8 ppm BMC01 59.7 ppm 13.8 ppm 4.6 ppm Abbreviations: BMC01, benchmark concentration with 1% response; BMCL05, bench- mark concentration, 95% lower confidence limit with 5% response; LC50, lethal concen- tration, 50% lethality. Source: Temple University 1982. Because of the results of the study above indicated that females are much more sensitive than male rats to acute lethality from tert-octyl mercaptan, anoth- er study was conducted in female rats. Groups of 10 female Sprague-Dawley rats were exposed to tert-octyl mercaptan at 12, 14, 17, 18, or 19 ppm for 4 h, followed by a 14-day observation period (Temple University 1982). The exper- imental methods were similar to those described for the previous study. Tremors and clonic convulsions were observed in all test groups. All animals that sur- vived the first 24 h after exposure also survived until the end of the observation period. No signs of hemorrhage or other signs of visible pathology were found in rats that died. At the end of the 14-day observation period, 19 of 21 surviving rats gained weight, and gross necropsy revealed no abnormalities. An LC50 value of 17 ppm (15-19 ppm) was calculated by the investigators. A BMC01 value of 10.7 ppm and BMCL05 value of 10.1 ppm was also calculated. Mortality data from this study are presented in Table 4-5. When the data on female rats presented in Tables 4-4 and 4-5 are com- bined to calculate benchmark levels, a 4-h BMCL05 of 11.5 ppm and BMC01 of 14.7 ppm result (see Appendix C). Combining the data is acceptable because the data sets are from the same laboratory and used similar experimental methods. Groups of five male and five female Charles River CD rats were exposed to tert-octyl mercaptan at 23, 24, 25, 73, 77, or 79 ppm (nominal concentrations) for 4 h, followed by a 14-day observation period (Amoco 1979). Exposures were conducted in a 160-L cubical, stainless steel and glass chamber. Test vapors

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106 Acute Exposure Guideline Levels were generated by passing air at a rate of 10 L/min through a round-bottom flask containing tert-octyl mercaptan in a heating jacket. Chamber concentrations were calculated from the ratio of the rate of vapor dissemination to the rate of total chamber airflow. Clinical signs included convulsions, with females affect- ed more frequently and with greater severity than males; clinical signs were ob- served at 73 ppm or higher in males and at 24 ppm or higher in females. All surviving rats lost weight on day 1 post-exposure compared with pre-exposure values. Male survivors gained weight by the end of the observation period; how- ever, female survivors only maintained their body weight. Rats dying during exposure had red- or pink-colored lungs or lungs with red patches or scattered red pin points at necropsy. No gross pathologic effects were noted in animals killed at the end of the observation period. LC50 values of 50 ppm (males and females combined), 79 ppm (males), and 24 ppm (females) were calculated by the investigators. BMC01 values of 65.9 ppm (males) and 21.5 ppm (females) ppm and BMCL05 values of 63.9 ppm (males) and 21.0 ppm (females) were also calculated. Data from this study are presented in Table 4-6. A group of 10 male Wistar rats was exposed to tert-octyl mercaptan at 330 ppm (nominal concentration) and observed until death (Pharmacology Research Inc. 1970). All of the rats died; deaths occurred within 19, 22, 26, 27, 30, 32, 40, and 49 min of exposure. Clinical signs included muscular spasms, violent clonic convulsions, prostration, and terminal dyspnea. Fairchild and Stokinger (1958) administered tert-octyl mercaptan by oral gavage in ethanol, intraperitoneal injection, or dermal application to Wistar- derived male rats, followed by 15-day observation periods. An oral LD50 (lethal dose, 50% lethality) of 85.3 mg/kg, an intraperitoneal LD50 of 12.9 mg/kg, and a dermal LD50 of 1,954 mg/kg were reported. TABLE 4-5 Mortality in Female Sprague-Dawley Rats Exposed to tert-Octyl Mercaptan for 4 Hours Concentration (ppm) Mortality 12 ± 0.6 1/10 14 ± 0.5 3/10 17 ± 1.4 5/10 18 ± 0.7 10/10 19 ± 1.7 10/10 LC50 17 ppm (15-19 ppm) BMCL05 10.1 ppm BMC01 10.7 ppm Abbreviations: BMC01, benchmark concentration with 1% response; BMCL05, bench- mark concentration, 95% lower confidence limit with 5% response; LC50, lethal concen- tration, 50% lethality. Source: Temple University 1982.

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tert-Octyl Mercaptan 107 TABLE 4-6 Mortality in Charles-River Rats Exposed to tert-Octyl Mercaptan for 4 Hours Mortality Concentration (ppm) Male Female Combined 23 0/5 0/5 0/10 24 0/5 1/5 1/10 25 0/5 5/5 5/10 73 0/5 5/5 5/10 77 4/5 5/5 9/10 79 5/5 5/5 10/10 LC50 79 ppm 24 ppm 50 ppm BMCL05 63.9 ppm 21.0 ppm * BMC01 65.9 ppm 21.5 ppm * Abbreviations: BMC01, benchmark concentration with 1% response; BMCL05, bench- mark concentration, 95% lower confidence limit with 5% response; LC50, lethal concen- tration, 50% lethality. *P-value <0.1; therefore, not reported. Source: Amoco 1979. Nine of 10 rats administered tert-octyl mercaptan at 50 mg/kg in sesame oil by stomach tube died within 30-143 min after intubation (Pharmacology Re- search Inc. 1970). The surviving rat was observed for 5 days. Clinical signs in- cluded muscular spasms, violent clonic convulsions, prostration, and terminal dyspnea. 3.1.2. Mice Fairchild and Stokinger (1958) exposed groups of 10 Swiss-derived male mice (body weight 25 -28 g) to tert-octyl mercaptan at 38, 40, 44, 55, 64, or 78 ppm (analytic concentrations) for up to 4 h, followed by a 15-day observation period. Vapor was generated and the test chamber analyzed in the same manner as the study in rats. Clinical signs in the mice were similar to those described for the rat in Section 3.1.1. An LC50 value of 47 ppm was calculated by the investi- gators. A BMC01 of 34.4 ppm and BMCL05 of 33.6 ppm were also calculated. Mortality data from this study are presented in Table 4-7. Groups of five male MF1 mice were exposed to tert-octyl mercaptan at 42, 58, 84, 117, or 167 ppm (nominal concentrations) for 1 h, followed by a 6-day observation period (Pharmacology Research Inc. 1969). Clinical signs were noted at all test concentrations and included hypertonicity, hypersensitivity, and multiple clonic-tonic convulsions. Mortality was 0/5, 2/5, 4/5, 5/5, and 5/5 at concentrations of 42, 58, 84, 117, and 167 ppm, respectively. All deaths oc- curred during exposure. An LC50 value of 69 ppm was calculated by the investi- gators. A BMC01 of 37.6 ppm and BMCL05 of 28.4 ppm were also calculated. No further details were available.

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108 Acute Exposure Guideline Levels TABLE 4-7 Mortality in Male Swiss Mice Exposed to tert-Octyl Mercaptan for 4 Hours Concentration (ppm) Mortality Comments 38 0/10 – 40 2/10 – 44 4/10 – 55 9/10 – 64 10/10 All dead within 3 h 78 10/10 All dead within 1 h, 35 min LC50 47 ppm (45.3-48.7 ppm) BMCL05 33.6 ppm BMC01 34.4 ppm Abbreviations: BMC01, benchmark concentration with 1% response; BMCL05, bench- mark concentration, 95% lower confidence limit with 5% response; LC50, lethal concen- tration, 50% lethality. Source: Adapted from Fairchild and Stokinger 1958. 3.1.3. Rabbits Fairchild and Stokinger (1958) administered single dermal applications of tert-octyl mercaptan at 213, 427, or 854 mg/kg to groups of two New Zealand white rabbits, followed by a 72-h observation period. Both rabbits in the 854- mg/kg group died within 8 h, and none of the rabbits in the 213- or 427-mg/kg groups died. Ten albino rabbits were administered a single dermal application of tert- octyl mercaptan at 200 mg/kg for 4 h, followed by a 5-day observation period (Pharmacology Research Inc. 1970). No mortality or signs of toxicity were ob- served, and animals had normal body weight gain. 3.1.4. Summary of Animal Lethality Data Inhalation lethality studies of tert-octyl mercaptan in rats and mice are available. Lethality data suggest a steep concentration-response curve for tert- octyl mercaptan. In studies of male rats exposed to tert-octyl mercaptan for 4 h, mortality was 0% at 38 ppm and 100% at 64 ppm (Fairchild and Stokinger 1958), 0% at 59 ppm and 80% at 71 ppm (Temple University 1982), and 0% at 73 ppm and 100% at 79 ppm (Amoco 1979). In a study of female rats exposed to tert-octyl mercaptan for 4 h, mortality was10% at 12 ppm and 100% at 18 ppm. In mice exposed for 4 h, mortality was 0% at 38 ppm and 100% at 64 ppm (Fairchild and Stokinger 1958). Rat data suggest that females are much more sensitive to tert-octyl mercaptan than males; calculated 4-h LC50 values were 59 ppm for male rats and 17 ppm for female rats in one study (Temple University 1982) and 79 ppm for males and 24 ppm for females in another (Amoco 1979).

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tert-Octyl Mercaptan 109 Clinical signs were indicative of CNS stimulation followed by central depres- sion and finally death from respiratory failure. 3.2. Nonlethal Toxicity No animal data on the nonlethal toxicity of tert-octyl mercaptan were found. 3.3. Developmental and Reproductive Effects No animal developmental and reproductive data on tert-octyl mercaptan were found. 3.4. Genotoxicity No genotoxicity data on were found. 3.5. Carcinogenicity No carcinogenicity data on tert-octyl mercaptan were found. 4. SPECIAL CONSIDERATIONS 4.1. Metabolism and Disposition Metabolism and disposition data for tert-octyl mercaptan were not available. 4.2. Mechanism of Toxicity Most mercaptans act similarly to hydrogen sulfide and cyanide by inter- rupting electron transport through inhibition of cytochrome oxidase, and general signs of acute mercaptan poisoning are indicative of central depression and res- piratory paralysis, followed by death from respiratory failure (NIOSH 1978). However, data suggest that tert-octyl mercaptan acts differently because an ini- tial effect of CNS stimulation is observed. Fairchild and Stokinger (1958) re- ported that the stimulatory effects of tert-octyl mercaptan were typical of other CNS stimulants such as picrotoxin and metrazol, and that the compound ap- peared to act at various levels of the cerebrospinal axis. Convulsive seizures were spontaneous in origin (not triggered by external stimuli), and tert-octyl mercaptan had an analeptic action on the higher CNS centers, as evidenced by the fact that subconvulsant doses stimulated the respiratory and vasomotor cen- ters (Fairchild and Stokinger 1958). The analeptic action was demonstrated by the ability of tert-octyl mercaptan to counteract depression produced by barbitu- rates. Even though the CNS stimulation is unique to tert-octyl mercaptan, the

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tert-Octyl Mercaptan 119 APPENDIX B ACUTE EXPOSURE GUIDELINE LEVELS FOR tert-OCTYL MERCAPTAN AEGL-1 VALUES Data are insufficient to derive AEGL-1 values for tert-octyl mercaptan; therefore, AEGL-1 values are not recommended. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 are without effect. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 0.77 ppm 0.77 ppm 0.60 ppm 0.40 ppm 0.19 ppm (4.6 mg/m3) (4.6 mg/m3) (3.6 mg/m3) (2.4 mg/m3) (1.1 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. AEGL-3 VALUES 10 min 30 min 1h 4h 8h 2.3 ppm 2.3 ppm 1.8 ppm 1.2 ppm 0.58 ppm (14 mg/m3) (14 mg/m3) (11 mg/m3) (7.2 mg/m3) (3.5 mg/m3) Reference: Temple University. 1982. Initial Submission: Final Report on a Study to Establish an LC50 Concentration of t-Octyl Mercaptan in Adult Sprague-Dawley Rats of Both Sexes (Final), September 17, 1982. Submitted to EPA by Atochem North America, Inc., King of Prussia, PA with Cover Letter Dated 12/23/91. EPA Document No. 88920000497. Microfiche No. OTS0534950. Test species/Strain/Sex/Number: Rat, Sprague-Dawley, females, 10/group Exposure route/Concentrations/Durations: Inhalation; 7, 15, 19, 29, 59, 71, 110 ppm and 12, 14, 17, 18, 19 ppm for 4 h Effects: Concentration (ppm) Mortality 7 0/5 15 1/5 19 5/5 29 5/5 59 5/5 71 5/5 110 5/5 12 1/10 14 3/10 (Continued)

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120 Acute Exposure Guideline Levels AEGL-3 VALUES Continued 17 5/10 18 10/10 19 10/10 BMCL05 = 11.5 ppm BMC01 = 14.7 ppm End point/Concentration/Rationale: Threshold for lethality, BMCL05 of 11.5 ppm Uncertainty factors/Rationale: Interspecies: 3, data suggest no difference in species sensitivity between rats and mice (4-h LC50 is 51 ppm for male rats and 47 ppm male mice [Fairchild and Stokinger 1958]). Intraspecies: 3, considered sufficient because the point of departure is from the more sensitive female rats. Calculated 4-h LC50 values were 59 ppm for male rats and 17 ppm for female rats in one study (Temple University 1982) and 79 ppm for males and 24 ppm for females in another (Amoco 1979). Also, the steep concentration-response curve implies limited intraindividual variability. In studies of male rats exposed to tert-octyl mercaptan for 4 h, mortality was 0% at 38 ppm and 100% at 64 ppm (Fairchild and Stokinger 1958), 0% at 59 ppm and 80% at 71 ppm (Temple University 1982), and 0% at 73 ppm and 100% at 79 ppm (Amoco 1979). In a study of female rats exposed to tert-octyl mercaptan for 4 h, mortality was10% at 12 ppm and 100% at 18 ppm. In mice exposed for 4 h, mortality was 0% at 38 ppm and 100% at 64 ppm (Fairchild and Stokinger 1958). Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Not applicable Time scaling: Cn × t = k; default values of n = 3 when extrapolating to shorter durations and n = 1 when extrapolating to longer durations to derive values protective of human health (NRC 2001). The 30-min AEGL-3 value was adopted as the 10-min value because of the uncertainty in extrapolating a 4-h point of departure to 10-min value. Data adequacy: Well-conducted studies in rats and mice. Additional studies of females in species other than rats species would be useful.

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tert-Octyl Mercaptan 121 APPENDIX C BENCHMARK CALCULATION FOR TERT-OCTYL MERCAPTAN Temple University (1982): Combined female data for two studies Probit Model (Version: 2.9; Date: 09/23/2007) Input Data File: C:\BMDS\UNSAVED1.(d) Gnuplot Plotting File: C:\BMDS\UNSAVED1.plt Fri Jun 13 10:37:19 2008 BMDS MODEL RUN The form of the probability function is: P[response] = Background + (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), where CumNorm(.) is the cumulative normal distribution function Dependent variable = COLUMN2 Independent variable = COLUMN1 Slope parameter is restricted as slope >= 1 Total number of observations = 13 Total number of records with missing values = 0 Maximum number of iterations = 250 Relative Function Convergence has been set to: 1e-008 Parameter Convergence has been set to: 1e-008 User has chosen the log transformed model Default Initial (and Specified) Parameter Values Background = 0 Intercept = -2.865 Slope = 1.09606 Asymptotic Correlation Matrix of Parameter Estimates Background Intercept Background 1 -0.19 Intercept -0.19 1 (***The model parameter(s) -slope have been estimated at a boundary point, or have been specified by the user, and do not appear in the correlation matrix).

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122 Acute Exposure Guideline Levels Parameter Estimates Standard 95.0% Wald Confidence Interval Variable Estimate Error Lower Confidence Limit Upper Confidence Limit Background 0.13443 0.0579167 0.0209153 0.247945 Intercept -50.7551 0.346663 -51.4345 -50.0756 Slope 18 NA NA: indicates that this parameter has hit a bound implied by some inequality constraint and thus has no standard error. Analysis of Deviance Table Model Log (likelihood) No. Parameters Deviance Test DF P-value Full model -18.793 13 Fitted model -22.802 2 8.01802 11 0.7117 Reduced model -60.1424 1 82.6988 12 <0.0001 AIC: 49.6039 Goodness of Fit Scaled Estimated Dose Probability Expected Observed Size Residual 0.0000 0.1344 0.672 0 5 -0.881 7.0000 0.1344 0.672 0 5 -0.881 15.0000 0.1537 0.768 1 5 0.287 19.0000 0.9893 4.946 5 5 0.233 29.0000 1.0000 5.000 5 5 0.000 59.0000 1.0000 5.000 5 5 0.000 71.0000 1.0000 5.000 5 5 0.000 110.0000 1.0000 5.000 5 5 0.000 12.0000 0.1344 1.344 1 10 -0.319 14.0000 0.1349 1.349 3 10 1.528 17.0000 0.6502 6.502 5 10 -0.996 18.0000 0.9119 9.119 10 10 0.983 19.0000 0.9893 9.893 10 10 0.329 Chi-square = 6.19; DF = 11; P-value = 0.8602 Benchmark Dose Computation Specified effect = 0.05 Risk type = Extra risk Confidence level = 0.95 BMD = 15.3075 BMDL = 11.5133

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tert-Octyl Mercaptan 123 Probit Model (Version: 2.9; Date: 09/23/2007) Input Data File: C:\BMDS\UNSAVED1.(d) Gnuplot Plotting File: C:\BMDS\UNSAVED1.plt Fri Jun 13 10:40:03 2008 BMDS MODEL RUN The form of the probability function is: P[response] = Background + (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), where CumNorm(.) is the cumulative normal distribution function Dependent variable = COLUMN2 Independent variable = COLUMN1 Slope parameter is restricted as slope >= 1 Total number of observations = 13 Total number of records with missing values = 0 Maximum number of iterations = 250 Relative Function Convergence has been set to: 1e-008 Parameter Convergence has been set to: 1e-008 User has chosen the log transformed model Default Initial (and Specified) Parameter Values Background = 0 Intercept = -2.865 Slope = 1.09606 Asymptotic Correlation Matrix of Parameter Estimates Background Intercept Background 1 -0.19 Intercept -0.19 1 (***The model parameter(s) -slope have been estimated at a boundary point, or have been specified by the user, and do not appear in the correlation matrix). Parameter Estimates Standard 95.0% Wald Confidence Interval Variable Estimate error Lower confidence limit Upper confidence limit Background 0.13443 0.0579167 0.0209153 0.247945 Intercept -50.7551 0.346663 -51.4345 -50.0756 Slope 18 NA NA: indicates that this parameter has hit a bound implied by some inequality constraint and thus has no standard error.

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124 Acute Exposure Guideline Levels Probit Model with 0.95 Confidence Level Probit 1 BMD Lower Bound 0.8 Fraction Affected 0.6 0.4 0.2 0 BMDL BMD 0 20 40 60 80 100 dose 10:37 06/13 2008 FIGURE C-1 Probit model with 0.95 confidence level. Analysis of Deviance Table Model Log (likelihood) No. Parameters Deviance Test DF P-value Full model -18.793 13 Fitted model -22.802 2 8.01802 11 0.7117 Reduced model -60.1424 1 82.6988 12 <0.0001 AIC: 49.6039 Goodness of Fit Scaled Estimated prob- Dose ability Expected Observed Size Residual 0.0000 0.1344 0.672 0 5 -0.881 7.0000 0.1344 0.672 0 5 -0.881 15.0000 0.1537 0.768 1 5 0.287 19.0000 0.9893 4.946 5 5 0.233 29.0000 1.0000 5.000 5 5 0.000 59.0000 1.0000 5.000 5 5 0.000 71.0000 1.0000 5.000 5 5 0.000 110.0000 1.0000 5.000 5 5 0.000 12.0000 0.1344 1.344 1 10 -0.319 14.0000 0.1349 1.349 3 10 1.528 17.0000 0.6502 6.502 5 10 -0.996 18.0000 0.9119 9.119 10 10 0.983 19.0000 0.9893 9.893 10 10 0.329 Chi-square = 6.19; DF = 11; P-value = 0.8602

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tert-Octyl Mercaptan 125 Benchmark Dose Computation Specified effect = 0.01 Risk type = Extra risk Confidence level = 0.95 BMD = 14.7388 BMDL = 10.2853

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126 Acute Exposure Guideline Levels APPENDIX D CATEGORY PLOT FOR tert-OCTYL MERCAPTAN Chemical Toxicity - TSD Animal Data Tert-Octyl Mercaptan 1000 100 No Effect Discomfort ppm 10 Disabling Partially Lethal AEGL-3 1 Lethal AEGL-2 0 0 60 120 180 240 300 360 420 480 Minutes FIGURE D-1 Category plot of toxicity data and AEGL values for tert-octyl mercaptan. The decimal point is lost on this log-scale plot.

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TABLE D-1 Data Used in Category Plot for tert-Octyl 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 0.77 10 AEGL AEGL-2 0.77 30 AEGL AEGL-2 0.60 60 AEGL AEGL-2 0.40 240 AEGL AEGL-2 0.19 480 AEGL AEGL-3 2.3 10 AEGL AEGL-3 2.3 30 AEGL AEGL-3 1.8 60 AEGL AEGL-3 1.2 240 AEGL AEGL-3 0.58 480 AEGL Rat Male 1 38 240 2 Seizures Rat Male 1 40 240 PL Mortality 1/6; seizures Rat Male 1 44 240 PL Mortality 1/5; seizures Rat Male 1 55 240 PL Mortality 3/5; seizures Rat Male 1 64 240 3 Mortality 5/5; seizures Rat Male 1 78 240 3 Mortality 6/6; seizures (Continued) 127

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128 TABLE D-1 Continued Source Species Sex No. Exposures ppm Minutes Category Effect Rat Male 1 110 240 3 Mortality 6/6; seizures Rat Male/Female 1 7 240 0 No effects Rat Male/Female 1 15 240 PL Mortality: male 0/5; female 1/5 Rat Male/Female 1 19 240 PL Mortality: male 0/5; female 5/5 Rat Male/Female 1 29 240 PL Mortality: male 0/5; female 5/5 Rat Male/Female 1 59 240 PL Mortality: male 0/5; female 5/5 Rat Male/Female 1 71 240 PL Mortality: male 4/5; female 5/5 Rat Female 1 12 240 PL Mortality 1/10 Rat Female 1 14 240 PL Mortality 3/10 Rat Female 1 17 240 PL Mortality 5/10 Rat Female 1 18 240 3 Mortality 10/10 Rat Female 1 19 240 3 Mortality 10/10 Rat Male/Female 1 23 240 2 Convulsions Rat Male/Female 1 24 240 PL Mortality: male 0/5; female 1/5 Rat Male/Female 1 25 240 PL Mortality: male 0/5; female 5/5 Rat Male/Female 1 73 240 PL Mortality: male 0/5; female 5/5 Rat Male/Female 1 77 240 PL Mortality: male 4/5; female 5/5 Rat Male/Female 1 79 240 3 Mortality: male 5/5; female 5/5 Mouse Male 1 38 240 2 Seizures Mouse Male 1 40 240 PL Mortality 2/10 Mouse Male 1 44 240 PL Mortality 4/10

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Mouse Male 1 55 240 PL Mortality 9/10 Mouse Male 1 64 240 3 Mortality 10/10 Mouse Male 1 78 240 3 Mortality 10/10 Mouse Male 1 42 60 2 Convulsions Mouse Male 1 58 60 PL Mortality 2/5 Mouse Male 1 84 60 PL Mortality 4/5 Mouse Male 1 117 60 3 Mortality 5/5 Mouse Male 1 167 60 3 Mortality 5/5 For category: 0 = no effect, 1 = discomfort, 2 = disabling, 3 = lethal; PL = partially lethality. 129