4

Epichlorohydrin
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

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1This document was prepared by the AEGL Development Team composed of Kowetha Davidson (Oak Ridge National Laboratory), Heather Carlson-Lynch (SRC, Inc.), Chemical Manager Richard Thomas (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 Epichlorohydrin1 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 Ko- wetha Davidson (Oak Ridge National Laboratory), Heather Carlson-Lynch (SRC, Inc.), Chemical Manager Richard Thomas (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Envi- ronmental 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 sci- entifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 190

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Epichlorohydrin 191 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 Epichlorohydrin is a colorless liquid at room temperature; its vapor is ex- plosive when mixed with air. It has a sweet, pungent or chloroform-like odor. Epichlorohydrin has many uses, but it is used primarily in the manufacture of epoxy resins. Most humans would not detect the odor of epichlorohydrin at concentra- tions below 10 ppm. The odor recognition level for epichlorohydrin is about 25 ppm; however, odor detection levels reported in the literature range from 0.08- 25 ppm. The level of distinct odor awareness for epichlorohydrin is 46 ppm. No reports of human deaths from exposure to epichlorohydrin were found. Epichlo- rohydrin is irritating to mucous membranes, causing burning of the eyes, nose, and pharynx in humans. A few breaths or a 30-min exposure at high (unknown) concentrations have caused irritation to eyes, throat, and respiratory tract and gastrointestinal disturbances that may be delayed in onset. Irreversible respirato- ry and hepatic damage, but no renal damage, have been observed in humans. Humans exposed to epichlorohydrin at 20 ppm for 1 h experienced burning of the eyes and nose; 40 ppm for less than 2 h caused throat irritation, 68 ppm for 2 min was irritating to the pharynx, and 100 ppm was reported to be intolerable and potentially associated with pulmonary edema and renal damage. Exposure to epichlorohydrin at 136 ppm for 2 min was irritating to the eyes and pharynx and caused a cooling sensation in the eyes and mouth.

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192 Acute Exposure Guideline Levels Inhalation exposure of laboratory animals (rats, mice, and hamsters) to epichlorohydrin causes effects similar to those reported for humans. In acute lethality studies, death was caused by effects on the respiratory center of the central nervous system and severe respiratory irritation manifested as pulmonary hemorrhage and edema. Death usually occurred a few hours or a few days after exposure. Before death, the animals showed signs of cyanosis, muscle relaxation of the extremities, gasping, labored breathing, depressed or increased respira- tion, lethargy, fine tremors, and clonic convulsions. In addition, animals showed degenerative lesions of the nasal epithelium and kidneys and damage to the low- er respiratory tract. Evidence of nasal irritation and renal lesions also were seen after acute inhalation exposure to epichlorohydrin at nonlethal concentrations. AEGL-1 values were derived from the no-effect level (17 ppm) for irrita- tion in four subjects exposed to epichlorohydrin vapor for 2 min (Kobernick et al. 1983). The total uncertainty factor was 10; a factor of 10 was applied to ac- count for intraspecies variability. Although mild irritation experienced by hu- mans would most likely be confined to the nasal passages and eyes, a factor of 10 was used to provide sufficient protection for asthmatic individuals. Adjusting the point-of-departure by 10 yields an AEGL value of 1.7 ppm. That concentra- tions was used for all of the AEGL durations because the irritant effects of epichlorohydrin are not expected to become more severe with time at that con- centration. The AEGL-1 value is below the level of odor recognition (25 ppm) and the level of odor awareness (46 ppm). Therefore, odor is not a factor for early warning of exposure to epichlorohydrin. The available human and animal studies reporting nonlethal effects were not suitable for deriving AEGL-2 values. Therefore, AEGL-2 values were de- rived by reducing the AEGL-3 values by a factor of 3; that approach is used when a steep concentration-response curve is observed. The AEGL-2 value of 53 ppm for a 30-min exposure was also used for the 10-min exposure, because concentrations of 100 ppm or higher may cause pulmonary edema and renal damage. The 10-min, 30-min, and 1-h AEGL-3 values were based on the 1-h rat LC01 (lethal concentration, 1% lethality) of 721 ppm (Dietz et al. 1985). A total uncertainty factor of 10 was applied. A factor of 3 was selected for interspecies differences on the basis of LC50 values for rats, mice, guinea pigs, and rabbits, which showed little variability among species. A factor of 3 was applied for intraspecies variability, on the basis of mechanistic information and information on occupational exposures. Epichlorohydrin is an epoxide and direct alkylating agent. These effects are likely involved in the observed irritation and systemic toxicity, and are not expected to vary considerably in the population. In addition, use of higher total uncertainty factor 30 would result in an 8-h AEGL-3 value of 6.6 ppm. That concentration is inconsistent with occupational data; exposures to epichlorohydrin at 15-54 ppm were apparently not life-threatening (Pet’ko et al. 1966 [as cited in NIOSH 1976]; de Jong et al. 1988). Time scaling was per- formed using the equation Cn × t = k (ten Berge et al. 1986), where n = 0.87. The

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Epichlorohydrin 193 value of the exponent n was derived from rat LC50 (lethal concentration, 50% lethality) values for 1-, 4-, 6-, and 8-h exposures. The 4- and 8-h AEGL-3 values were based on the 6-h rat LC01 of 274 ppm (Laskin et al. 1980). The same uncertainty factors and time-scaling method were the same as those used to derive the 10-min, 30-min, and 1-h AEGL-3 values. Two inhalation studies in rats found squamous cell carcinomas of the na- sal cavity after exposure to epichlorohydrin vapor. The studies showed that short-term exposure at high concentrations were more effective in inducing neo- plasms than lifetime exposure at low concentrations. AEGL values calculated from the cancer unit risk for epichlorohydrin are 14,000, 4,500, 2,300, 560, and 280 ppm for 10-min, 30-min, 1-h, and 4-h, to 8-h exposures, respectively. Those values are for risks of 1 in 10,000 (10-4), the level of risk most relevant for emergency exposure and response purposes. The concentrations greatly exceed values for AEGL-2 and AEGL-3. The AEGL values for epichlorohydrin are presented in Table 4-1. 1. INTRODUCTION Epichlorohydrin is a colorless liquid at room temperature that is flamma- ble (Berdasco and Waechter 2012). It is very reactive with metals such as zinc and aluminum, anhydrous metal halides, strong acids and bases, and alcohol- containing materials; it attacks steel in the presence of moisture (WHO 1984). Epichlorohydrin has a sweet, pungent or chloroform-like odor (Berdasco and Waechter 2012). Additional chemical and physical properties of epichlorohydrin are presented in Table 4-2. Epichlorohydrin is manufactured at three sites in Louisiana and Texas. Epichlorohydrin is also manufactured in Thailand (ABC-Thailand, Ltd. 2013), France (Solvay 2011), and China (Alibaba 2013; ZSITC 2013). Epichlorohydrin is primarily used in the manufacture of epoxy and phenoxy resins (ACGIH 2001). It is also used in the synthesis of glycerol, and in the production of sur- face active agents, pharmaceuticals, insecticides, agricultural chemicals, textile chemicals, coatings, adhesives, ion-exchange resins, solvents, plasticizers, glyc- idyl esters, ethynyl-ethylenic alcohols, and fatty-acid derivatives. It is used as a solvent in the rubber and paper industries (Santodonato et al. 1980). Epichlorohydrin is a bifunctional alkylating epoxide (Laskin et al. 1980). It causes severe irritation and sensitization when the liquid comes in contact with the skin (Berdasco and Waechter 2012); contact dermatitis has been report- ed after occupational exposure to epichlorohydrin (HSE 1991). Severe ocular irritation, skin irritation, and delayed contact skin sensitization have been found in animals after topical application of undiluted or diluted epichlorohydrin (Ber- dasco and Waechter 2012). Epichlorohydrin is moderately toxic by the oral route with LD50 (lethal dose, 50% lethality) values of 90-238 mg/kg in rats, guinea pigs, and mice (Berdasco and Waechter 2012).

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194 Acute Exposure Guideline Levels The database that can be used to derive AEGL values for epichlorohydrin consists of acute and repeat-exposure inhalation studies in multiple species and a carcinogenicity study in rats. TABLE 4-1 AEGL Values for Epichlorohydrin End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 1.7 ppm 1.7 ppm 1.7 ppm 1.7 ppm 1.7 ppm No-effect level (nondisabling) (6.4 (6.4 (6.4 (6.4 (6.4 for irritation mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (Kobernick et al. 1983). AEGL-2 53 ppm 53 ppm 24 ppm 14 ppm 6.7 ppm Three-fold (disabling) (200 (200 (91 (53 (25 reduction of mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 values, except for 10 min. AEGL-3 570 ppm 160 ppm 72 ppm 44 ppm 20 ppm Lethality threshold (lethal) (2,200 (600 (270 (170 (76 (Dietz et al. 1985; mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) Laskin et al. 1980) TABLE 4-2 Physical and Chemical Data on Epichlorohydrin Parameter Value Reference Synonyms 2-(Chloromethyl) oxirane; 1-chloro-2,3- HSDB 2009 epoxypropane; 3-chloro-1,2-epoxypropane; α-epichlorohydrin CAS registry no. 106-89-8 HSDB 2009 Chemical formula C3H5ClO HSDB 2009 Molecular weight 92.53 HSDB 2009 Physical state Colorless liquid HSDB 2009 Melting point -25.6°C HSDB 2009 Boiling point 117.9°C HSDB 2009 Density (vapor) 3.29 HSDB 2009 Solubility 65.9 g/L of water at 25°C; miscible with HSDB 2009 ether, alcohol, chloroform, trichloroethylene, carbon tetrachloride Vapor pressure 16.4 mm Hg at 25°C HSDB 2009 Flammability limits 3.8% volume to 21% volume in air HSDB 2009 Concentration in saturated air 1.7% at 25°C HSDB 2009 Flash point (open cup) 40.6°C Sienel et al. 2000 Log Kow 0.45 HSDB 2009 Henry’s Law constant 3.0 × 10-5 atm-m3/mol at 25°C HSDB 2009 Conversion factors 1ppm = 3.78 mg/m3 NIOSH 2011 1 mg/m3 = 0.265 ppm

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Epichlorohydrin 195 2. HUMAN TOXICITY DATA 2.1. Acute Lethality No data were available on the lethality of inhaled epichlorohydrin in hu- mans. 2.2. Nonlethal Toxicity 2.2.1. Odor Threshold AIHA (1989) reported the range of odor threshold values for epichlorohy- drin of 0.08-12 ppm, and Ruth (1986) reported a range of 50-80 mg/m3 (13-21 ppm). Kobernick et al. (1983) reported that four subjects detected an at 17 ppm, and two identified the odor as epichlorohydrin. Amoore and Hautala (1983) re- ported an odor detection level of 0.93 ppm for humans. Berdasco and Waechter (2012) reported a mean odor threshold of 10 ppm and an odor recognition level of 25 ppm. The odor threshold during and after a 5-min exposure of uncondi- tioned personnel to epichlorohydrin was 10-12 ppm for 50% of the subjects and 25 ppm for 100% of the subjects (Shell Oil Co. 1977). Shell Oil Co. (1977) also reported that epichlorohydrin is not detected by its odor at 5 ppm, the permissi- ble exposure limit established by the Occupational Safety and Health Admin- istration (29 CFR 1910.100 [2012]). The level of odor awareness determined by the method of Ruijten et al. (2009) for epichlorohydrin is 46 ppm. 2.2.2. Experimental Studies, Case Reports, and Anecdotal Data Anecdotal information on effects of epichlorohydrin in humans has been reported in various sources. In a toxicology book, a chapter stated that humans exposed to epichlorohydrin vapor at 20 ppm for 1 h experienced burning of the eyes and nasal mucosa, that exposure at 40 ppm caused ocular and throat irrita- tion that lasted about 48 h, and that 100 ppm was intolerable to man, with poten- tial for pulmonary edema and renal lesions (Lefaux 1968). The statements were attributed to an individual (C.U. Dernehl) without a specific reference. Lefaux (1968) also indicated that chronic low-level exposure caused fatigue, gastroin- testinal pain, conjunctivitis, and profuse nasal discharge, citing another individ- ual (I. Sax). The anecdotal information was repeated in later references, includ- ing that of Wexler (1971). In another book chapter, Deichmann and Gerarde (1969) reported that humans exposed to epichlorohydrin at 40 ppm for less than 2 h experienced throat irritation; no data or citation was provided to support the statement. Enterline et al. (1990) reported that during the early years (assumed to be 1948-1955) of epichlorohydrin use and production, concentrations of the chemical at a Shell chemical facility were “sufficiently high to be a source of irritation (10-20 ppm)”; the publication did not specify whether exposure con- centrations were measured in that range or assumed to be in that range on the

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196 Acute Exposure Guideline Levels basis of worker reports of irritation. In another book chapter on epoxy com- pounds, Berdasco and Waechter (2012) reported that marked nasal and ocular irritation occurred only at epichlorohydrin concentrations exceeding 100 ppm; no background or reference for this statement was provided. In a toxicity and safety bulletin on epichlorohydrin (prepared in 1977 and submitted to the U.S. Environmental Protection Agency [EPA] under TSCA Section 8ECP in 1992), Shell Oil Co. (1977) reported that overexposure to epichlorohydrin vapor is manifested first by complaints of ocular, nasal, and throat irritation and possibly sneezing and bleeding of the nose in more serious cases. On the basis of indus- trial experience, Shell Oil Co. (1977) noted that no cases of serious pulmonary injury or systemic toxicity had been observed during the manufacture or han- dling of epichlorohydrin, and ocular conditions resulting from exposure to the vapor or contact with liquid epichlorohydrin were not serious and caused no loss of vision. No information on exposure conditions or concentrations was provid- ed. In a summary of warning properties, the bulletin stated that “one report indi- cated eye and nose irritation only at levels exceeding 100 ppm while another stated that 40 ppm at the site of a spill caused immediate eye, nose, and throat irritation”; references were not provided for these statements. Two case reports of accidental human exposure (Schultz 1964; NIOSH 1976) were identified in the available literature; neither included measurement or estimation of exposure concentrations. Schultz (1964) reported a case of irre- versible hepatic and respiratory damage caused by accidental exposure of a worker to epichlorohydrin. A 39-year-old man took several deep breaths of a substance stored in a container under pressure that was later identified as epichlorohydrin. Initial symptoms included slight burning of the eyes and throat that increased in sensation along with a gradual swelling of the face, malaise, vomiting, and severe headache several hours later. He experienced shortness of breath and a feeling of suffocation the following night (probably more than 24 h after the accident). Clinical examination about 2 days after the accident showed inflammation of mucous membranes in the upper respiratory tract and a painful- ly enlarged liver, slight jaundice, increased serum bilirubin, and positive urine urobilinogen. Five and 8 months after the accident, clinical findings included bronchial changes in the right lung, elevated blood pressure, and evidence of abnormal liver function. Two years after the accident, the patient complained of nonspecific epigastric pain; a clinical examination showed pronounced fatty liver, abnormal liver function, and chronic asthmatic bronchitis. The fatty liver and chronic asthma-like bronchitis were attributed to exposure to epichlorohy- drin because there were no preexisting conditions related to these findings. There was no evidence of renal damage. NIOSH (1976) reported on a case of a 53-year-old worker exposed to a high but unknown concentration of epichlorohydrin for 30 min (written commu- nication by Thoburn, May 1976, no additional citation information). Several hours after exposure he experienced burning of the nose and throat, cough, chest congestion, runny nose, eye tenderness, and headache followed by nausea. The man was hospitalized briefly, and the symptoms diminished within 3-4 days;

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Epichlorohydrin 197 however, he reported more frequent upper-respiratory-tract infections followed by a productive cough. Clinical tests showed that the residual volume was in- creased by 40% (suggesting air trapping in the lungs) and arterial pO2 of 77 mm Hg instead of 96 mm Hg. The report did not state how long after exposure these symptoms persisted. NIOSH (1976) also reviewed a Russian study (Pet’ko et al. 1966, as cited in NIOSH 1976) of worker health in a facility producing epichlorohydrin. Workers were generally exposed at concentrations of 3.1-5.5 ppm, but concen- trations during a mechanical failure reached about 55 ppm. NIOSH indicated that the study did not report the sampling method, and no further information on the sampling or analyses that resulted in these concentrations was provided by NIOSH (1976). Apart from two cases of dermatitis, Pet’ko et al. (1966, as cited in NIOSH 1976) concluded that medical examination of 49 men and 33 women in the epichlorohydrin-production areas showed no changes attributable to occu- pational exposure. In the single controlled-exposure study, four human subjects were exposed to epichlorohydrin at concentrations of 17, 68, or 136 ppm for 2 min in a 6.5-ft3 chamber (Kobernick et al. 1983). Three subjects exposed at 68 ppm reported no irritating effect, and one reported irritation to the pharynx. Two subjects exposed at 136 ppm reported a cooling sensation in the eyes and mouth and two reported irritation to the eyes or pharynx. 2.2.3. Epidemiologic Studies Epidemiologic studies of epichlorohydrin have involved the analysis of mortality or morbidity data from two cohorts from the Shell Oil Company in its Texas and Louisiana facilities, both of which produced epichlorohydrin (Enter- line et al. 1990; Tsai et al. 1990, 1996). Dow Chemical workers engaged in epichlorohydrin production also have been the subject of mortality studies (Ol- sen et al. 1994). Tsai et al. (1990) conducted a study on the prevalence of morbidity among workers engaged in the manufacture of epichlorohydrin from January 1, 1981, to December 31, 1988. Morbidity included all illnesses resulting in work absence of more than 5 days. The only illness showing a significantly elevated standard- ized morbidity ratio involved skin and subcutaneous tissue, particularly in work- ers classified as having light to moderate exposure to epichlorohydrin. Light- and moderate-exposure categories (defined as the 95% upper confidence limit of the geometric mean of personal air samples) were >0.1 ppm but ≤0.5 ppm, and >0.5 ppm but ≤1.0, respectively. The investigators noted that skin conditions were more often associated with causes unrelated to epichlorohydrin exposure, such as physical trauma and poison ivy. Although a concern existed for a possible association between exposure to epichlorohydrin and heart disease among workers engaged in the manufacture or use of epichlorohydrin, a statistically significant increase in the standard mor-

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198 Acute Exposure Guideline Levels tality ratio (SMR) was not observed. However, Enterline et al. (1990) reported an increase in the SMR for heart disease among workers classified as having heavy exposure compared with workers in the low-exposure category. There was no significant increase compared with the reference population (local white males). Epichlorohydrin concentrations for the exposure categories were not reported, but concentrations during the early production years were high enough to cause irritation. In a subsequent study of the same cohort followed for an ad- ditional 10 years, Tsai et al. (1996) found a nonsignificant increase in the SMRs for heart disease among workers with moderate to heavy exposure to epichloro- hydrin compared with those having no to light exposure. Other epidemiologic studies have been conducted on workers with poten- tial exposure to epichlorohydrin, but none demonstrated an association between epichlorohydrin and mortality experience due to any cause (Barbone et al. 1992, 1994; Olsen et al. 1994). Barbone et al. (1992, 1994) did not report exposure concentrations. Olsen et al. (1994) estimated that the 8-h time-weighted average (TWA) concentration of epichlorohydrin was below 1 ppm at an epoxy resin plant, and was 1-5 ppm at a glycerine department between 1957-1969; concen- trations after 1970 were estimated to be less than 1 ppm. The publication did not report how the TWA estimates were derived, but did indicate that industrial hy- giene records were reviewed. 2.3. Developmental and Reproductive Toxicity Milby et al. (1981) investigated the association between fertility, as meas- ured by sperm count and hormone concentrations, and potential exposure to epichlorohydrin at the two Shell chemical plants that produced epichlorohydrin. The control group consisted of workers from the same plant who had no known exposure to epichlorohydrin or any chemical known to be toxic to the testes. The investigators found no association between potential exposure to epichlorohy- drin and sperm count or levels of testosterone, luteinizing hormone, or follicle stimulating hormone. Exposures in one of the plants (sampling for epichlorohy- drin was conducted at only one) were categorized into four groups. Three of the four categories were exposures less than 1.0 ppm, and the fourth was 1.0 ppm or greater; no information on maximum exposure concentration was provided. Venable et al. (1980) compared the fertility status, as measured by several sperm parameters (including sperm count/cc and percent normal forms) and hormone concentrations, in 64 men employed in the three-carbon production units at Dow Chemical (Texas Division) with 63 men who had not worked with chlorinated hydrocarbons for at least 5 years prior to the study. None of the pa- rameters showed statistically significant differences that could be attributed to work environment or exposure to epichlorohydrin. The 8-h TWA exposures to epichlorohydrin were estimated to be less than 1 ppm in all groups; no further exposure information was provided.

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Epichlorohydrin 199 2.4. Carcinogenicity EPA’s Integrated Risk Information System assessment of carcinogenicity for epichlorohydrin, which was revised in 1994, considered the human data to be inadequate for evaluating the carcinogenicity of epichlorohydrin and classified epichlorohydrin as a B2 carcinogen (probable human carcinogen) on the basis of sufficient evidence of carcinogenicity in animals (EPA 1994). More recent epidemiologic studies than those evaluated by the EPA have been conducted on cohorts with potential exposure to epichlorohydrin during its manufacture or use. Barbone et al. (1994) reported an association between occu- pational exposure to epichlorohydrin, particularly acute exposure, and central nervous system neoplasms (in decedents and living). However, only four cases had potential exposure to epichlorohydrin and three of the four were also poten- tially exposed to anthraquinone dye intermediates or azo dyes. Other epidemio- logic studies produced no convincing evidence of an association between poten- tial occupational exposure to epichlorohydrin and cancer at any site including lung cancer (Enterline et al. 1990; Tsai et al. 1990, 1996; Barbone et al. 1992; Olsen et al. 1994). IARC (1999) reviewed and evaluated the epidemiologic and supporting data on epichlorohydrin and concluded that human data were inadequate for evaluating carcinogenicity of the chemical. It classified epichlorohydrin as 2A, probably carcinogenic in humans, on the basis of adequate evidence of carcino- genicity in animals. 2.5. Genotoxicity Kučerová et al. (1977) analyzed the peripheral lymphocytes of 35 workers occupationally exposed to epichlorohydrin for 1 or 2 years (exposure range was 0.13-1.32 ppm [0.5-5.0 mg/m3]) and compared the frequency of chromosomal aberrations with the preemployment frequency. They observed that the overall percentage of chromosomal aberrations (chromatid and chromosome beaks and exchanges; gaps excluded) were statistically significantly increased after 1 year (1.91/100 cells) and 2 years of employment (2.96/100 cells) compared with the preemployment frequency (1.42/100 cells). The frequency of chromosome breaks in lymphocytes was 2.17/100 cells or 3.26/100 cells after employment for 1 or 2 years, respectively, compared with the preemployment frequency of 1.60/100 cells. The overall percentage of cells with aberrations was 1.91% or 2.69% after employment for 1 or 2 years, respectively, compared with 1.37% before employment. Sram et al. (1980) conducted a follow-up analysis of peripheral lympho- cytes in 28 workers (23 were previously analyzed by Kučerová et al. [1977]) occupationally exposed to epichlorohydrin for an additional 2 years (total expo- sure duration of 4 years). Matching subjects from the working and general popu- lation were analyzed as control groups. Sram et al. (1980) found 3.12% aberrant

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200 Acute Exposure Guideline Levels cells (breaks and exchanges; gaps excluded) in exposed workers compared with 2.06% for the matching controls and 1.33% for the general population. All com- parison groups were significantly different from each other including the two controls. The percentage of aberrant cells in the subgroup of 23 workers studied by Kučerová et al. (1977) was 3.02%. Sram et al. (1980) reported that the con- centration of epichlorohydrin in the work environment was about 0.26 ppm (1 mg/m3). Sram et al. (1983) conducted a follow-up study on the workers after an additional 4 years of exposure (total of 8 years); this group consisted of 33 workers and included the 28 previously analyzed by Sram and coworkers. The concentration of epichlorohydrin decreased from 0.26 ppm to 0.10 ppm. The percentage of aberrant cells in exposed workers decreased to 2.00%; the per- centage in the matching controls was 1.68%. Chromatid and chromosome breaks were observed, but not exchanges. Picciano (1979) compared the frequency of chromosome aberrations in peripheral lymphocytes from 93 workers occupationally exposed to epichloro- hydrin with the frequency in 75 preemployment individuals (control). The fre- quencies of chromatid and chromosome breaks, marker chromosomes (rings, dicentrics, and translocations), severely damaged cells, and abnormal cells were increased in exposed workers. The greatest increases were in frequencies of cells with more than 12 chromatid breaks, cells with more than four chromosome breaks, the percent of individuals with more than 12 abnormal cells, and the percent of individuals with severely damaged cells. The investigators did not report the intensity or duration of exposure to epichlorohydrin. de Jong et al. (1988) reported increased chromosome aberrations in the lymphocytes of workers involved in the manufacture of epichlorohydrin, eth- ylene oxide (ETO), and propylene oxide at one plant and epichlorohydrin and allyl chloride at another. They found increases in the percentage of aberrant cells (includes gaps) of 1.46% and 0.93% for the two worker groups, respectively, compared with 0.11% for a control population. The increase in the frequency of aberrations in exposed workers relative to the control population could not be attributed to epichlorohydrin alone. Shell Oil Co. (1994) reported significant increases in the frequencies of sister chromatid exchanges, cells with high frequencies of sister chromatid ex- changes, and chromosome aberrations and aberrant cells in workers exposed to epichlorohydrin. Worker exposures were measured to be 0.11-0.23 ppm for 11.15 h each day and higher concentrations of 0.19-2.57 ppm during three epi- sodes of 15 min each per day (it is presumed that the authors intended to report 11.25, not 11.15 h, for a total duration of 12 h per day). Giri (1997) reviewed data on chromosome aberrations in human cultured cells and noted that epichlorohydrin showed positive evidence of clastogenicity in different types of in vitro test systems.

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Epichlorohydrin 251 APPENDIX B CARCINOGENICITY ASSESSMENT FOR EPICHLOROHYDRIN The unit risk or q1* for inhalation exposure to epichlorohydrin is 1.2 × 10-6 3 -1 (μg/m ) (EPA 1994). That value was derived from a carcinogenicity study in which rats developed nasal tumors after exposure to epichlorohydrin at 0, 10, or 30 ppm for 6 h/day, 5 days/week for a lifetime (Laskin et al. 1980). This study was summarized in Section 3.4. Data summary: Groups of 100 male Sprague-Dawley rats were exposed to epichlorohydrin at 10 or 30 ppm for 6 h/day, 5 days/week for a lifetime. A total of 150 sham-exposed or untreated animals served as controls. One of 100 rats in the 30- ppm group developed squamous cell carcinomas of the nasal cavity; none of the 10- ppm or control animals developed nasal tumors. The unit risk (q1*) derived from the linearized multistage model is (1.2 × 10-6 μg/m3)-1. The calculations for AEGL values following the method presented by NRC (1986) are presented below. To calculate a virtually safe dose (VSD of d) at a cancer risk of 10-6: d = 10-6 ÷ (1.2 × 10-6 µg/m3)-1 = 8.3 × 101 g/m3 To calculate the total cumulative dose for a total lifetime exposure of 70 years, which is equivalent to 25,600 days: total d = d × 25,600 = (8.33 × 101 µg/m3) × 25,600 = 2.13 × 106 µg/m3. Adjustment to allow for uncertainties in assessing potential cancer risks due to short-term exposure under the multistage model (Crump and Howe 1984), the total dose is divided by a factor of 6: 2.13 × 106 µg/m3 ÷ 6 = 3.56 × 105 µg/m3 = 3.56 × 102 mg/m3 = 94 ppm Therefore, a 24-h exposure concentration associated with a 10-4 risk is 94 ppm. The 10-4 cancer risk associated with exposures for 10, 30, 60, 240, and 480 min can be calculated from the following equation: PC × t = k, where c = concentration, t = time, and k is a constant. The AEGL values are compared with cancer risk-based values associated with risks of 10-4, 10-5, and 10-6 below:

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252 Acute Exposure Guideline Levels Risk 10 min 30 min 1h 4h 8h AEGL values (ppm) AEGL-1 1.7 1.7 1.7 1.7 1.7 AEGL-2 53 53 24 14 6.7 AEGL-3 570 160 72 44 20 Cancer risk-based values (ppm) 10-6 140 45 23 5.6 2.8 -5 10 1,400 450 230 56 28 10-4 14,000 4,500 2,300 560 280

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Epichlorohydrin 253 APPENDIX C DERIVATION OF THE LEVEL OF DISTINCT ODOR AWARENESS FOR EPICHLOROHYDRIN The level of distinct odor awareness (LOA) represents the concentration above which it is predicted that more than one-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 due to odor perception. The LOA derivation follows the guidance given by Ruijten et al. (2009). The odor detection threshold (OT50) for epichlorohydrin is calculated from the odor threshold of 10 ppm (50% of unconditioned personnel) reported by Shell Oil Co. (1977) and adjusted by Ruijten et al. (2009): 10 ppm × 40 ppm ÷ 100 ppm = 4.0 ppm The concentration (C) leading to an odor intensity (I) of distinct odor de- tection (I = 3) is derived using the Fechner function: I = kw x log(C ÷ OT50) + 0.5 For the Fechner coefficient, the default kw = 2.33 will be used because of the lack of chemical specific data. 3 = 2.33 × log (C ÷ 4.0) + 0.5, which can be rearranged to log (C/4.0) = (3 - 0.5) ÷ 2.33 = 1.07, and results in C = (101.07) × 4.0 = 34.4 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, may in- crease the odor detection threshold by a factor of 4. In addition, it takes into ac- count that odor perception is very fast (about 5 seconds), which leads to the per- ception of concentration peaks. On the basis of current knowledge, a factor of 1/3 is applied to adjust for peak exposure. Adjustments for distraction and peak exposure lead to a correction factor of 4/3 = 1.33. LOA = C × 1.33 = 34.4 ppm × 1.33 = 46 ppm (Ruijten et al. [2009]) Therefore, the LOA for epichlorohydrin is 46 ppm.

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254 Acute Exposure Guideline Levels APPENDIX D ACUTE EXPOSURE GUIDELINE LEVELS FOR EPICHLOROHYDRIN Derivation Summary AEGL-1 VALUES 10 min 30 min 1h 4h 8h 1.7 ppm 1.7 ppm 1.7 ppm 1.7 ppm 1.7 ppm (6.4 mg/m3) (6.4 mg/m3) (6.4 mg/m3) (6.4 mg/m3) (6.4 mg/m3) Key reference: Kobernick, J.L., J.H. Nair, III., U.C. Pozzani, L.D. Roger, Jr., and J.S. West. 1983. 1983. Epichlorohydrin Repeated Inhalation, Preliminary Metabolic Studies, Revision of Acute Toxicity Data, and Human Sensory Response. Special Report 33-41. Mellon Institute, January 28, 1983. Submitted to EPA, Washington, DC, by Union Carbide Corporation, Danbury, CT with Cover Letter Dated December 9, 1983 EPA Document No. 878212138, Microfiche No. OTS0206066. Test species/Strain/Number: Humans Exposure route/Concentration/Durations: Inhalation; 17, 68, or 136 ppm for 2 min. Effects: 17 ppm: 2/4 detected odor, 0/4 experienced irritation 68 ppm: 2/4 had pharyngeal irritation; 4/4 detected odor 136 ppm: 2/4 had pharyngeal irritation and ocular irritation End point/Concentration/Rationale: Irritation (no-effect level); none of the four subjects experienced irritation. Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 1, human study Intraspecies: 10, although irritation would likely be confined to the eyes and nasal passage (portal of entry), and variability in this response is expected to be limited to variability in pharmacodynamics, a factor of 10 was applied to provide sufficient protection for asthmatic persons. Modifying factor: 1 Animal-to-human dosimetric adjustment: Not applicable Time scaling: Not applicable Data adequacy: The subjects were exposed for only 2 min; however, the irritating properties of epichlorohydrin are not expected to vary considerably in an exposed human population.

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Epichlorohydrin 255 AEGL-2 VALUES 10 min 30 min 1h 4h 8h 53 ppm 53 ppm 24 ppm 14 ppm 6.7 ppm (200 mg/m3) (200 mg/m3) (91 mg/m3) (53 mg/m3) (25 mg/m3) Data adequacy: The animal and human data on epichlorohydrin pertaining to nonlethal end points were not adequate. for deriving AEGL-2 values. Therefore, AEGL-3 values were divided by a factor of 3 to estimate the AEGL-2 values. Because of the steepness of the dose-response curve, this method should provide a reasonable estimate of the values and provide an adequate margin of safety relative to lethality and adequate protection against pulmonary edema. Further, long-term studies showed that high concentrations for shorter durations are more effective than lower concentrations for longer durations; therefore, the 3-fold reduction should provide adequate protection against disabling or serious effects. The 10-min value was set equal to the 30-min AEGL-2 value because human and animal data suggested that pulmonary edema and renal damage could occur at concentrations greater than 100 ppm for short intervals. AEGL-3 VALUES 10 min 30 min 1h 4h 8h 570 ppm 160 ppm 72 ppm 44 ppm 20 ppm (2,200 mg/m3) (600 mg/m3) (270 mg/m3) (170 mg/m3) (76 mg/m3) Key reference: Dietz, F.K., M. Key reference: Laskin, S., A.R. Sellakumar, Grandjean, and J.T. Young. 1985. M. Kuschner, N. Nelson, S. La Mendola, Epichlorohydrin: 1-Hour LC50 G.M. Rusch, G.V. Katz, N.C. Dulak, and Determination in Fischer-344 Rats. R.E. Albert. 1980. Inhalation carcinogenicity Lake Jackson Research Center, Health of epichlorohydrin in noninbred Sprague- & Environmental Sciences - Texas, Dawley rats. J. Natl. Cancer Inst. 65(4): Dow Chemical, Freeport, TX. 751-757. Test species/Strain/Sex/Number: Rats; Test species/Strain/Sex/Number: Rats; Fischer-344; males and females; Sprague-Dawley; male; 20/group. 6/group. Exposure route/Concentration/Duration: Exposure route/Concentration/Duration: Inhalation; 552, 1,008, 1,970, or 3,995 Inhalation; 283, 303, 339, 369, 421, or ppm (male and female) and 2,865 and 445 ppm for 6 h. 3,275 ppm (male only) for 1 h. Effects: Weight loss (all concentrations); Effects: Acute respiratory irritation; ocular and nasal irritation, respiratory pulmonary hemorrhage and edema; difficulty, and secretion of porphyrin-like elevated lung:body weight at ~339 ppm; material, corneal cloudiness (~1,970 mortality: 0/20, 1/20, 1/20, 15/20, 16/20, ppm); central nervous system effects and and 17/20, respectively. cyanosis (~3,275 ppm); mortality: 0/12, 0/12, 2/12, 0/6, 0/6, 12/12, respectively. Point of departure: 1-h rat LC01 of Point of departure: 6-h rat LC01 of 274 ppm. 721 ppm. (Continued)

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256 Acute Exposure Guideline Levels AEGL-3 VALUES Continued Uncertainty factors: Total uncertainty factor: 10 Interspecies: 3, LC50 values for rats, mice, guinea pigs, and rabbits were 573-820 ppm for a 4-h exposure. Humans appear to be more sensitive than rats but are within a factor of about 2.5. A concentration of 50 ppm for 66-262 min caused squinting, hypoactivity, and salivation in animals; 20 ppm for 1 h caused burning of eyes and nose in humans. Epichlorohydrin is an epoxide and direct alkylating agent and effects are not expected to differ by more than a factor of 3. Intraspecies: 3, the irritation and systemic toxicity caused by epichlorohydrin are likely to involve its alkylating activity. Therefore, the concentrations causing severe pulmonary irritation are not expected to vary considerably in the population. The systemic toxicity may be modulated by the detoxification enzymes, most likely epoxide hydrolase or glutathione-S-transferase. The structural similarity of epichlorohydrin to ETO suggests that metabolism involves glutathione-S-transferase, which is genetically polymorphic in human. This similarity in structure provides additional support for a factor of 3. The use of an intraspecies uncertainty factor of 3 is also supported by data on human exposures to epichlorohydrin. Use of higher total uncertainty factor of 30 would result in an 8-h AEGL-3 value of 6.6 ppm; however, occupational exposures as high as 15-54 ppm have occurred (Pet’ko et al. 1966 [cited in NIOSH 1976]; de Jong et al. 1988) and were apparently not life-threatening. Time scaling: Cn × t = k, where n = 0.87 (derived from LC50 data for the rat exposed for 1, 4, 6, or 8 h).

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Epichlo orohydrin 2 257 AP PPENDIX E GORY PLOT FOR EPICH CATEG HLOROHYDR RIN FIGUR E-1 Category plot of toxicity data and AEGL values for epich RE y L hlorohydrin.

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258 TABLE E-1 Data Used in Category Plot for Epichlorohydrin Source Species Sex No. Exposures ppm Minutes Category Comments AEGL-1 1.7 10 AEGL AEGL-1 1.7 30 AEGL AEGL-1 1.7 60 AEGL AEGL-1 1.7 240 AEGL AEGL-1 1.7 480 AEGL AEGL-2 53 10 AEGL AEGL-2 53 30 AEGL AEGL-2 24 60 AEGL AEGL-2 14 240 AEGL AEGL-2 6.7 480 AEGL AEGL-3 570 10 AEGL AEGL-3 160 30 AEGL AEGL-3 72 60 AEGL AEGL-3 44 240 AEGL AEGL-3 20 480 AEGL Kobernick et al. 1983 Human 1 17 2 0 Human 1 68 2 1 Throat irritation. Human 1 136 2 1 Ocular, throat and nasal irritation. Berdasco and Waechter 2012 Rat Males 1 2,165 60 SL LC50 Rat Females 1 3,617 60 SL LC50 Rat 1 500 240 SL LC50 Rat 1 250 480 SL LC50

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Dietz et al. 1985 Rat Both 1 552 60 1 Rat Both 1 1,008 60 1 Rat Both 1 1,970 60 SL Mortality (2/12) Rat Both 1 3,995 60 3 Mortality (12/12) Grigorowa et al. 1974 Rat Males 1 635 240 SL LC50 Rat Males 1 582 240 SL LC50 Kimmerle 1967 Rat 1 132 240 0 Rat 1 331 240 0 Rat 1 661 240 SL Mortality (5/10), moderate irritation to mucus membranes. Rat 1 2,646 240 3 Mortality (10/10) Kobernick et al. 1983 Rat Both 1 580 240 3 Mortality (12/12) Rat Both 1 580 240 SL Mortality (15/30) Slott et al. 1990 Rat Both 1 1,160 240 3 Mortality (6/6) Laskin et al. 1980 Rat Males 1 100 240 0 Rat Males 1 303 360 SL Mortality (1/20) Rat Males 1 339 360 SL Mortality (1/20), acute respiratory irritation with hemorrhage and severe edema. Rat Males 1 369 360 SL Mortality (15/20), acute respiratory irritation with hemorrhage and severe edema. Rat Males 1 421 360 SL Mortality (16/20), acute respiratory irritation with hemorrhage and severe edema. (Continued) 259

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260 TABLE E-1 Continued Source Species Sex No. Exposures ppm Minutes Category Comments Rat Males 1 445 360 SL Mortality (17/20), acute respiratory irritation with hemorrhage and severe edema. Weil et al. 1963 Rat 1 250 480 SL Mortality (4/6) Freuder and Leake 1941 Mouse 1 8,300 30 3 100% mortality Mouse 1 16,600 30 3 100% mortality Grigorowa et al. 1974 Mouse Males 1 794 120 SL LC50 Kobernick et al. 1983 Mouse Males 1 1,160 240 3 Irritation of mucous membranes, increased respiration, lethargy, and labored breathing. Kimmerle 1967 Mouse Males 1 132 240 0 Mouse Males 1 331 240 0 Mouse Males 1 661 240 SL Mortality (1/20) Mouse Males 1 2,646 240 3 Mortality (20/20) Buckley et al. 1984 Mouse 1 687 360 SL Kobernick et al. 1983 Guinea pig Males 1 290 240 1 Irritation of mucous membranes. Guinea pig Males 1 580 240 SL Mortality (2/6), irritation of mucous membranes. Guinea pig Males 1 1,160 240 3 Mortality (4/4) Kimmerle 1967 Guinea pig Males 1 132 240 0 Guinea pig Males 1 331 240 SL Mortality (4/5) Guinea pig Males 1 661 240 SL Mortality (4/5)

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Guinea pig Males 1 2,646 240 3 Mortality (5/5) Kobernick et al. 1983 Rabbit Males 1 290 240 1 Irritation of mucous membranes. Rabbit Males 1 580 240 SL Mortality (2/3), irritation of mucous membranes. Rabbit Males 1 1,160 240 3 Mortality (3/3) Kobernick et al. 1983 Dog 1 290 240 1 Irritation of mucous membranes. Dog 1 580 240 3 Mortality (1/1) Dog 1 1,160 240 3 Mortality (1/1) Monkey 1 290 240 1 Irritation of mucous membranes. Industrial Bio-Test Rat Both 1 9.7 360 0 Laboratories 1977a Rat Both 1 23 360 0 Rat Both 1 48.8 360 1 Rat Both 1 97.3 360 1 Rat Both 1 209.8 360 2 Gardner et al. 1985 Rat 1 101 15 0 For category 0 = no effect, 1 = discomfort, 2 = disabling, SL = some lethality, 3 = lethal 261