2

Chloromethyl Methyl Ether1

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

1This document was prepared by the AEGL Development Team composed of Sylvia Milanez (Oak Ridge National Laboratory), Mark Follansbee (Syracuse Research Corporation), and Chemical Manager Ernest V. Falke (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).



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2 Chloromethyl Methyl Ether1 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 Sylvia Milanez (Oak Ridge National Laboratory), Mark Follansbee (Syracuse Research Corpo- ration), and Chemical Manager Ernest V. Falke (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 62

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63 Chloromethyl Methyl Ether 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 concen- trations that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, non- sensory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold levels for the general public, including susceptible subpopu- lations, 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 Chloromethyl methyl ether (CMME) is a man-made chemical that is highly flammable, and causes severe irritation of the respiratory tract, eyes, nose, and skin. Chronic occupational exposure has caused small-cell lung carcinoma with histology distinct from that caused by cigarette smoke, and with a shorter latency period. The U.S. Environmental Protection Agency (EPA) classifies technical-grade CMME as a human carcinogen. Upon contact with water, CMME hydrolyzes completely and irreversibly to form hydrochloric acid, methanol, and formaldehyde. Technical-grade CMME contains 1-10% bis- chloromethyl ether (BCME) as a contaminant. Because humans are exposed only to technical-grade CMME (a great deal of effort is needed to remove “all” BCME from CMME), and the human and animal inhalation-exposure data all involved technical-grade CMME, the AEGL values derived in this document will address the toxicity and carcinogenicity of technical-grade CMME. AEGL-1 values were not recommended because no studies were available in which toxicity was limited to AEGL-1 effects. AEGL-2 values for technical-grade CMME were based on an acute toxicity study in which rats and hamsters were exposed to CMME for 7 h at 12.5-225 ppm (contamination by BCME not given) and observed for 14 days (Drew et al. 1975). Toxic effects were not attributed to specific concentrations, but it was reported that animals that died, and to a lesser degree, animals that

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64 Acute Exposure Guideline Levels survived, had increased relative lung weights, pulmonary congestion, edema, hemorrhage, and acute necrotizing bronchitis. Therefore, 12.5 ppm was considered the lowest-observed-adverse-effect level (LOAEL) for serious or irreversible lung lesions in both species (also a no-observed-effect level [NOEL] for lethality in rats), and was divided by 3 to obtain an estimated no-observed- adverse-effect level (NOAEL) of 4.2 ppm. No data were available from which to determine the CMME concentration-time relationship to derive AEGL-2 values for time periods other than 7 h. ten Berge et al. (1986) showed that the concentration-time relationship for many irritant and systemically acting vapors and gases can be described by Cn × t = k, where the exponent n ranges from 0.8 to 3.5. To obtain protective AEGL-2 values, scaling across time was performed using n = 3 and n = 1 for exposure durations shorter and longer, respectively, than 7 h. The 30-min values were adopted for 10-min value to be protective of human health (see Section 4.4.3.). An uncertainty factor of 10 was used. A factor of 3 was applied for interspecies extrapolation because CMME caused a similar degree of lung toxicity in two animal species and is expected to cause similar toxicity in human lungs. A factor of 3 was applied for intraspecies variability as recommended by NRC (2001) for chemicals with a steep dose- response relationship, because the effects are unlikely to vary greatly among humans. An intraspecies uncertainty factor of 3 also was used in the derivation of AEGL-2 values for BCME. A modifying factor of 1.7 was applied because the BCME content in technical-grade CMME in the key study was unknown. The modifying factor was obtained by assuming 10% contamination with BCME (the maximum reported) and accounting for the greater toxicity of BCME (the rat LC50 [lethal concentration, 50% lethality] was 55 ppm for CMME and 7 ppm for BCME in the key study) in the following calculation: [0.1 × (55/7)] + [0.9 × 1] = 1.7. AEGL-3 values were based on the same study as the AEGL-2 values (Drew et al. 1975). The threshold for lethality from severe lung lesions, expressed as the BMCL05 (benchmark concentration, 95% lower confidence limit with 5% response), was approximately 18 ppm for hamsters and 19 ppm for rats; the lower value was used in the derivation. Data were not available to determine the concentration-time relationship, and scaling across time was performed using the ten Berge et al.(1986) equation described above for AEGL- 2. An uncertainty factor of 10 was used. A factor of 3 was applied for interspecies extrapolation because the NOEL for lethality was virtually the same in two species in the key study, and lethality is expected to occur by a similar mode of action in humans and animals. A factor of 3 was applied for intraspecies variability as recommended by NRC (2001) for chemicals with a steep dose-response relationship, as the effects are unlikely to vary greatly among humans. An intraspecies uncertainty factor of 3 also was used in the derivation of AEGL-3 values for BCME. A modifying factor of 1.7 was also applied because the content of BCME in technical-grade CMME in the key study was unknown. The AEGL values are summarized in Table 2-1.

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65 Chloromethyl Methyl Ether TABLE 2-1 Summary of AEGL Values for Chloromethyl Methyl Ether End Point Level 10 min 30 min 1h 4h 8h (Reference) AEGL-1a NRb NR NR NR NR (nondisabling) AEGL-2 0.60 ppm 0.60 ppm 0.47 ppm 0.30 ppm 0.22 ppm Estimated NOAEL (disabling) (2.0 (2.0 (1.5 (0.98 (0.72 for serious or irre- mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) versible lung lesions in rats and hamsters (Drew et al. 1975) AEGL-3 2.6 ppm 2.6 ppm 2.0 ppm 1.3 ppm 0.93 ppm Lethality threshold (lethal) (8.6 (8.6 (6.6 (4.3 (3.1 for hamsters and rats mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (Drew et al. 1975) a Data on odor threshold not found for CMME, but industrial experience indicates that 1.5 ppm is barely detectable and 23 ppm is easily detectable. b Not recommended (no studies were available in which toxicity was limited to AEGL-1 effects). Data were unavailable to conduct a carcinogenicity risk assessment for CMME, but an assessment was conducted for the related compound BCME (see Appendix D). If the assumptions are made that technical-grade CMME contains 10% BCME, and that the carcinogenicity of “pure” BCME is 10-fold more potent than “pure” CMME (Van Duuren et al. 1968, 1969; Gargus et al. 1969; Drew et al. 1975; Kuschner et al. 1975; Laskin et al. 1975), then it follows that technical-grade CMME has, at most, 9% of the carcinogenic activity of BCME. Thus, if a linear relationship between exposure concentration and cancer risk is assumed for CMME and BCME, the cancer risk associated with the AEGL-2 values are estimated to range from 5.5 × 10-5 to 9.6 × 10-4, and for AEGL-3 values the estimates range from 2.4 × 10-4 to 4.1 × 10-3, as shown in Appendix D. It is unknown, however, how valid the stated assumptions are to predict the carcinogenicity of CMME. Because of this uncertainty and the large differences in methods used to derive the AEGL values as compared with extrapolating the carcinogenic potency from a lifetime study to a single exposure, the non- carcinogenic end points were considered to be more appropriate for deriving AEGLs for CMME. 1. INTRODUCTION Technical grade CMME is a highly volatile, colorless, flammable liquid (CHRIS 1985). CMME vapor is severely irritating to the respiratory tract, eyes, nose, and skin, and exposure to high air concentrations causes sore throat, fever, chills, and difficulty breathing (Hake and Rowe 1963). The odor has been reported as barely detectable at 1.5 ppm and easily detectable at 23 ppm

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66 Acute Exposure Guideline Levels (Wagoner et al. 1972), concentrations shown to cause lung lesions or mortality in animals. Technical-grade CMME contains 1-10% BCME as a contaminant, which is a more potent human carcinogen than CMME and is believed to be responsible for most or all of the carcinogenic activity of technical-grade CMME (Travenius 1982; HSDB 2010). CMME decomposes so rapidly in aqueous solution that its half-life cannot be accurately measured. The half-life of CMME in pure water was estimated to be <1 seconds (sec) (Tou and Kallos 1974). In humid air (ambient temperature; 81% relative humidity), CMME and BCME were more stable, although the half- life depended on the surface coating of the container; the half-life was 7-25 h for BCME and 2.3 min to 6.5 h for CMME (Tou and Kallos 1974). It was reported that of the CMME decomposition products in water (methanol, formaldehyde, and hydrochloric acid [HCl]), the latter two can recombine to form BCME, and that vapors of HCl and formaldehyde, which are commonly used in industries and laboratories, can combine spontaneously in the air to form BCME (it has not been shown that CMME can be formed spontaneously in air or water). The hydrolysis of CMME is believed to be irreversible, whereas that of BCME is reversible, although the extent of conversion from CMME to BCME in water or air has not been well-characterized (Travenius 1982). CMME does not occur naturally, and human exposure occurs in only occupational settings. CMME is usually prepared “in-house” by passing HCl through a mixture of formalin and methanol, and is used industrially in the manufacture of ion-exchange resins, bactericides, pesticides, dispersing agents, water repellants, solvents for industrial polymerization reactions, and flame- proofing agents (Van Duuren 1989; Budavari et al. 1996; Kirwin and Galvin 1993). CMME is very reactive because of the high electronegativity of the oxygen and its attachment to the same carbon atom as chlorine; nucleophilic displacement of the halogen-bearing carbon atom occurs readily and, therefore, CMME and BCME are referred to as alkylating agents. CMME and BCME react spontaneously with nucleophilic substrates, such as DNA, without enzymatic conversion (Burchfield and Storrs 1977). CMME and BCME were recognized as potent human respiratory-tract carcinogens in the early 1970s by the U.S. industry, prompting facilities to develop hermetically isolated systems for their use (Travenius 1982; Collingwood et al. 1987). In 1973, BCME and CMME were listed by the Occupational Safety and Health Administration as part of the first 14 chemicals to be restricted by Federal regulations because of their human carcinogenicity, effective February 11, 1974 (39 Fed. Reg. 3756). Their use, storage, and handling must be in a controlled area (38 Fed. Reg. 10929). These regulations apply to all preparations containing CMME or BCME at ≥0.1% (by weight or volume). Subsequent studies examined the carcinogenicity of CMME and BCME in animals, although it has been practically impossible to assess the effect of CMME alone because, unless extraordinary measures are taken, it is contaminated with BCME.

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67 Chloromethyl Methyl Ether In 1993, the U.S. International Trade Commission listed only one company producing CMME in the United States, although the amount produced or sold was not published to avoid disclosure of individual company operations (USITC 1994). The amount of CMME produced in situ during the production of other chemicals, and the companies involved, was not determined. The physical and chemical properties of CMME are listed in Table 2-2. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality No quantitative information was located regarding acute exposure to CMME in humans. The vapors are severely irritating and painful to the eyes and nose. Vapor concentrations that are rapidly fatal are “irrespirable” (term used in reference; no further explanation given) for humans, and illness or death that results from exposure to CMME will occur several days after exposure from lung edema or secondary pneumonia (Hake and Rowe 1963). 2.2. Nonlethal Toxicity No short-term quantitative studies were located describing nonlethal effects of CMME exposure in humans. CMME vapor was reported to be very irritating and painful to the eyes and nose at 100 ppm, but exposure duration was not specified (Hake and Rowe 1963). One U.S. manufacturer set an in-house threshold limit value (TLV) of 1 ppm for CMME in the early years of its use, presumably because its odor was not detected or was not irritating at <1 ppm (Weiss 1992). This Michigan plant did not have an elevated incidence of respiratory-tract cancer in an industry-wide study by Collingwood et al. (1987). However, a 1-h exposure to CMME at1 ppm is presently considered dangerous to human health according to an in-house exposure standard of a large chemical company (Rohm & Haas, personal communication, February 1998). Chronic occupational exposure to CMME resulted in coughing, wheezing, blood-stained sputum, breathing difficulty (dyspnea), and weight loss (NIOSH 1988). Several long-term occupational exposure studies described nonlethal toxic end points; however, respiratory tract cancer was the principal focus of these studies. Leong et al. (1971) indicated that CMME (and BCME) are a health risk at concentrations that do not produce sensory irritation. 2.2.1 Odor Threshold and Awareness Industrial experience indicates that the odor of CMME is undetectable at 0.5 ppm, barely detectable at 1.5 ppm, easily detectable at 23 ppm, and strong at 100 ppm (Wagoner et al. 1972; AIHA 2000). Another source indicated that the highest tolerable concentration of CMME (or BCME) in air is 5 ppm (Travenius 1982).

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68 Acute Exposure Guideline Levels TABLE 2-2 Physical and Chemical Data for Chloromethyl Methyl Ether Parameter Value Reference Synonyms Chloromethoxymethane; Budavari et al. 1996 chloromethyl ether; monochloromethyl ether; chlorodimethyl ether; CMME CAS registry no. 107-30-2 IARC 1974 Chemical formula CH3OCH2Cl Budavari et al. 1996 Structure C(OC)Cl Molecular weight 80.51 Budavari et al. 1996 Physical state Liquid Budavari et al. 1996 Melting point -103.5°C Verschueren 1996 Boiling point 59°C at 760 mm Budavari et al. 1996 Density Vapor 2.8 (air = 1) CHRIS 1985 Liquid 1.0605 at 20/4°C (water = 1); IARC 1974 1.074 at 20/4°C (water = 1) Kirwin and Galvin 1993 Solubility in water Decomposes in water (half-life Nelson 1976; Travenius 1982 <0.5 sec) to methanol, formaldehyde, and HCl Vapor pressure 122 mm Hg at 20°C; IPCS 1998; HHMI 1995 260 mm Hg at.20°C Flammability/ 4.5-22.8 (estimated) AIHA 2000 explosive limits 1 mg/m3 = 0.304 ppm Conversion factors Verschueren 1996 1 ppm = 3.29 mg/m3 The data were not adequate to derive the level of distinct odor awareness per the guidance given by van Doorn et al. (2002). 2.2.2. Accidents Accidental industrial exposure to “rather high” concentrations of CMME caused sore throat, fever, and chills, and the person was not able to work for 8 days, at which time recovery appeared complete (Hake and Rowe 1963). Another subject who received “very slight exposure” had difficulty breathing for several days (Hake and Rowe 1963).

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69 Chloromethyl Methyl Ether 2.3. Neurotoxicity No studies reporting neurotoxic effects of CMME in humans were located. 2.4. Developmental and Reproductive Toxicity No studies on the developmental or reproductive effects in humans were located. 2.5. Genotoxicity The incidence of chromosomal aberrations was greater in the peripheral lymphocytes of workers exposed to CMME or BCME during the manufacture of ion-exchange resins than in control workers (Sram et al. 1983, 1985). The frequency of aberrations was not related to the years of exposure (1-10 years), but was related to the calculated dose of BCME exposure during the last 3 months (Sram et al. 1985). Zudova and Landa (1977) cytogenetically scored 22 peripheral lympho- cytes/person in 2 workers exposed for 2 years to CMME and BCME. Exposed workers had an average of 6.7% aberrant cells compared with 2% in the con- trols. Blood samples taken from 10 workers after their holidays (length not defined) had only 3.1% aberrant cells. CMME was cytotoxic (inhibited scheduled DNA synthesis) in human lymphocytes treated for 4 h with CMME at 10-2 M (97-99% pure), although the cytotoxicity was reversed in the presence of metabolic activation with rat liver phenobarbital-induced S-9 mix (Perocco et al. 1983). CMME (10-2 to 10-3 M or 5 microliters per milliliters [μL/mL]) also increased in vitro DNA repair in the presence of metabolic activation, seen by increased incorporation of tritiated thymidine (Perocco and Prodi 1981; Perocco et al. 1983). 2.6. Carcinogenicity EPA has designated technical-grade CMME (and BCME) as Group A (“human carcinogen”) on the basis of an increased incidence of respiratory-tract cancer in exposed workers (EPA 2005a). This was supported by evidence of respiratory-tract tumors in mice, rats, and hamsters exposed by inhalation (EPA 2005a). The American Conference of Industrial Hygienists has classified CMME as a “suspected human carcinogen” (Class A2), has assigned no values for a TWA or short-term exposure limit (STEL), and suggests that “it may be desirable to monitor exposures on the basis of BCME (TLV = 0.001 ppm)” (ACGIH 1991). International Agency for the Research on Cancer (IARC) places technical-grade CMME in Group 1 (“sufficient evidence for carcinogenicity to humans and to animals”) (IARC 1987). In epidemiologic studies, there was a

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70 Acute Exposure Guideline Levels clear trend of an increasing incidence of lung cancer with increasing dose (longer and/or more intense exposure). Several studies showed that the incidence of cancer peaked about 15-20 years post-exposure (Weiss 1982; Maher and DeFonso 1987). Exposed humans had elevated rates of respiratory-tract cancer, but not of other types of cancer. The cases occurred at a younger age than lung cancer in the general population, especially among nonsmokers. The cancer histology was most frequently small- cell carcinoma, with a high fraction of them being oat-cell carcinoma, in contrast to lung cancer caused by cigarette smoking, which is predominantly squamous- cell carcinoma (Weiss and Boucot 1975). The air concentrations of CMME in the workroom were almost never measured, although Travenius (1982) has estimated that they might have been 1-10 ppm, because higher concentrations would have been intolerable. 2.6.1. Case Reports A nonsmoking German research chemist exposed for 2 years to high concentrations of CMME and BCME died 12 years later (at age 45) of heart circulation failure as a result of pulmonary adenocarcinoma cachexia (Reznik et al. 1977). A 42-year old chemist exposed to CMME and BCME by inhalation for 7 years died from extensive pulmonary carcinoma (Bettendorf 1977). The air concentrations of CMME or BCME were not given in either report. 2.6.2. Epidemiologic Studies Langner (1977) reported CMME air concentrations of 0-12 ppm, with a mean of 0.7 ppm, from 230 measurements taken in 1957 at a U.S. anion exchange plant. CMME concentrations became progressively lower as processing and engineering controls were implemented to reduce exposure. The CMME contained 7-10% BCME. No excess respiratory-tract cancer or oat-cell lung cancer was found in workers during the plant’s 27 years of operation. Industrial workers exposed for months to years to CMME (containing BCME) had a dose-related increase in chronic bronchitis, although the exposure concentrations were not available (Weiss and Boucot 1975; Weiss 1976, 1977). There was no effect on the worker’s ventilatory function, as measured by the forced vital capacity (FVC) and the 1-sec forced expiratory volume (FEV1), suggesting the large airways were normal. The small airways did appear to be affected, because the end-expiratory flow rate was below predicted values in a dose-related manner. Cigarette smoking acted synergistically with CMME to produce chronic bronchitis and small-airway disorders among the workers (however, there was an inverse relationship between smoking and the induction of lung cancer by CMME; see Section 2.5.1.). When chemical exposure diminished, there was a decrease in coughing and an increase in dyspnea (shortness of breath, severity not described).

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71 Chloromethyl Methyl Ether In 1972, four workers at a California chemical plant (Diamond Shamrock Co., Redwood City) with 100-200 workers involved in anion-exchange resin production (exposed to CMME and BCME) died from lung cancer and two more workers developed lung cancer (Donaldson and Johnson 1972; Fishbein 1972). The concentration of CMME or BCME in the air was not specified. One of the workers that died, a 32-year old male, worked at the plant for only 2 years. Subsequent analysis of exfoliated cells of the sputum of the workers found no difference in metaplasia or atypia between in-plant workers not involved in CMME/BCME production and controls (Lemen et al. 1976). A significant association was found between abnormal cytology and exposure to CMME/BCME for more than 5 years (34% of anion-exchange workers vs. 11% of controls). In conjunction with the cytology survey, a retrospective cohort study of 136 men who worked at the plant for at least 5 years (mean was 10 years) was initiated. Five cases of bronchogenic cancer (three deaths) were found, compared with 0.54 cases expected (in white, age-matched men from Connecticut). The mean age at diagnosis was 47 years, and the predominant histology was small cell-undifferentiated carcinoma. The majority had smoked cigarettes. Workers exposed at least 6 months to low concentrations of CMME (containing 4-5% BCME) in a workplace in France from 1959-1971 did not have increased rates of respiratory-tract cancers (Schaffer et al. 1984). The actual concentrations of CMME in the air were not specified. The authors speculated that an increased cancer incidence might not have been found because a limited number of people were included in the study (670, of which 168 were exposed to CMME), and the observation period might have been too short. Technical-grade CMME (unspecified BCME content) was used in the production of anion exchange resins in a factory (Rohm & Haas) in Chauny, France, from 1958 to December 31, 1986 (Gowers et al. 1993). The air concen- trations of CMME in the factory were not measured, but concentrations of BCME were monitored from 1979 to 1984 with personal and stationary air- sampling devices. Approximate annual concentrations of BCME were 0.6-4.4 ppb, with an overall weighted average of 1.7 ppb. After standardization for age, workers with jobs involving exposure to CMME (258 men) had a greater incidence of lung cancer than nonexposed workers (945 men) in the same plant (rate ratio [RR] = 5.0; 95% confidence interval [CI] = 2.0-12.3) and a greater incidence than an external reference population (RR = 7.6; 95% CI = 4.3-13.5). Increased cumulative exposure was associated with an increased incidence of cancer but not with the time from first exposure to diagnosis, which was about 13 years. Exposed workers developed cancer an average of 10.5 years earlier than nonexposed workers. Of the cancers in exposed cases, 10/11 were small- cell, mostly oat-cell, carcinomas whereas in the nonexposed group only 1/8 cancers were small-cell carcinomas (16-33% were reported in the external reference population). Smoking history was not known, but reportedly a large fraction of the workers smoked. The observed-to-expected lung cancer ratio

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72 Acute Exposure Guideline Levels decreased as the exposure concentrations decreased over the years. The cancer cases found while exposure to BCME was monitored were probably due to previous, much higher exposures before engineering controls were put into place in 1984. The three cases of lung cancer (men aged 33-39) among about 45 workers who worked in the production of CMME (0.5-4% BCME) in one building of a large Philadelphia chemical plant (Rohm & Haas, about 2,500 employees) in 1962 prompted studies of cancer in potentially exposed workers. Air concentra- tions of CMME or BCME were not measured but were estimated retrospectively on a scale of 0-6, where 0 was “essentially” no exposure. Figueroa et al. (1973) studied a group of 125 men, some of whom were exposed to CMME in this Philadelphia plant. Of the 125 workers, 96 were current cigarette smokers, 13 were nonsmokers, 10 smoked cigars or pipes only, and six were former smokers (Weiss and Boucot 1975). Fourteen of the 125 men were lost to the study be- cause their employment was terminated. Fourteen cases of lung cancer developed in men aged 33-55 from 1962 to 1971; these men were exposed 3-14 years with one exception (uncertain duration; possibly one year). Thirteen cancers were oat-cell carcinomas, and one was of unknown histologic type. Three of the 13 cancers occurred in nonsmokers. The workers were periodically examined (chest photofluorogram and questionnaire) between 1963 and 1968, during which time four cancers developed in men aged 35-54 years (88 men were in this age group), which was a roughly an 8-fold increase in incidence of cancer over the control group. Brown and Selvin (1973) asserted that the actual increase was 44-fold, and that Figueroa et al. (1973) had used an inappropriate control group (too old) and that all 111 men (not just the 88 men between ages 35-54) should have been included. A 10-year prospective study of this same cohort of 125 men from January 1963 to December 1972 revealed a strong dose-response relationship for bronchogenic cancer (all small-cell carcinomas) among the men exposed for at least 3 months (Weiss and Boucot 1975; Weiss 1980). The exposed workers had symptoms, such as dose-related chronic bronchitis, and the end-expiratory flow rate was below predicted values in a dose-related manner (Weiss 1977). When chemical exposure diminished, there was a decrease in coughing and an increase in dyspnea (shortness of breath, severity not recorded). Significantly increased risk occurred only among men with moderate or heavy exposure; these workers had an inverse relationship between smoking and the incidence of lung cancer (Weiss and Boucot 1975; Weiss 1976, 1977; Weiss et al. 1979). This finding is in marked contrast to other industrial carcinogens (e.g., asbestos, uranium), where cancer was rarely induced without smoking being a cofactor (Travenius 1982). It is unknown how or whether chronic cigarette smoking was inhibiting development of cancer from CMME/BCME, but Weiss (1980) postulates that the additional or altered viscosity secretions or increased thickness of the mucous covering the bronchial epithelium of the cigarette smokers might protect the workers by chemically neutralizing or separating the CMME hydrolysis products from the lung epithelium.

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95 Chloromethyl Methyl Ether Tou, J.C., and G.J. Kallos. 1974. Kinetic study of the stabilities of chloromethyl methyl ether and bis(chloromethyl) ether in humid air. Anal. Chem. 46(12):1866-1869. Travenius, S.Z. 1982. Formation and occurrence of bis(chloromethyl)ether and its prevention in the chemical industry. Scand. J. Work Environ. Health 8(suppl. 3): 1-86. USITC (U.S. International Trade Commission). 1994. Pp. 3-42 in Synthetic Organic Chemicals - United States Production and Sales, 1993, 77th Annual Ed. Publi- cation 2810. U.S. International Trade Commission. November 1994 [online]. Available: http://www.usitc.gov/publications/soc/pub2810.pdf [accessed Nov. 8, 2011]. van Doorn, R., M. Ruijten, and T. Van Harreveld, T. 2002. Guidance for the Application of Odor in 22 Chemical Emergency Response, Version 2.1, August 29, 2002. Public Health Service of Rotterdam, The Netherlands. Van Duuren, B.L. 1989. Comparison of potency of human carcinogens: Vinyl chloride, chloromethylmethyl ether, and bis(chloromethyl)ether. Environ. Res. 49(2):143- 151. Van Duuren, B.L., B.M. Goldschmidt, L. Langseth, G. Mercado, and A. Sivak. 1968. Alpha-haloethers: A new type of alkylating carcinogen. Arch. Environ. Health 16(4):472-476. Van Duuren, B.L., A. Sivak, B.M. Goldschmidt, C. Katz, and S. Melchionne. 1969. Carcinogenicity of halo-ethers. J. Natl. Cancer Inst. 43(2):481-486. Van Duuren, B.L., C. Katz, B.M. Goldschmidt, K. Frenkel, and A. Sivak. 1972. Carcinogenicity of halo-ethers. II. Structure-activity relationships of analogs of bis(chloromethyl)ether. J. Natl. Cancer Inst. 48(5):1431-1439. Verschueren, K. ed. 1996. Chloromethyl methyl ether. P. 486 in Handbook of Environmental Data on Organic Chemicals, 3rd Ed. New York: Van Nostrand Reinhold. Wagoner, J.K., W.K. Johnson, H.M. Donaldson, P.J. Schuller, and R.E. Kupel. 1972. NIOSH Field Survey of Dow Chemical Company Chloromethylether Facilities (as cited in AIHA 2000). Weiss, W. 1976. Chloromethyl ethers, cigarettes, cough and cancer. J. Occup. Med. 18(3):194-199. Weiss, W. 1977. The forced end-expiratory flow rate in chloromethyl ether workers. J. Occup. Med. 19(9):611-614. Weiss, W. 1980. The cigarette factor in lung cancer due to chloromethyl ethers. J. Occup. Med. 22(8):527-529. Weiss, W. 1982. Epidemic curve of respiratory cancer due to chloromethyl ethers. J. Natl. Cancer Inst. 69(6):1265-1270. Weiss, W. 1992. Chloromethyl ethers. Pp. 941-945 in Environmental and Occupational Medicine, 2nd Ed., W.N. Rom, ed. Boston, MA: Little, Brown, and Company. Weiss, W., and K.R. Boucot. 1975. The respiratory effects of chloromethyl methyl ether. JAMA 234(11):1139-1142. Weiss, W., R.L. Moser, and O. Auerbach. 1979. Lung cancer in chloromethyl ether workers. Am. Rev. Respir. Dis. 120(5):1031-1037. Wu, W. 1988. Occupational cancer epidemiology in the People’s Republic of China. J. Occup. Med. 30(12):968-974. Zudova, Z., and K. Landa. 1977. Genetic risk of occupational exposures to haloethers. Mutat. Res. 46(3):242-243.

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96 Acute Exposure Guideline Levels APPENDIX A DERIVATION OF AEGL VALUES FOR CHLOROMETHLYL METHYL ETHER Derivation of AEGL-1 Values AEGL-1 values were not derived because no studies were available in which toxicity was limited to AEGL-1 effects. Derivation of AEGL-2 Values Key study: Drew et al. 1975 Toxicity end points: 4.2 ppm was NOAEL for serious or irreversible respiratory lesions in rats and hamsters. NOAEL obtained by dividing the LOAEL of 12.5 ppm by an adjustment factor of 3. Cn × t = k (n = 3 for longer to shorter Time scaling: exposure periods; n = 1 for shorter to longer exposure periods); extrapolation not performed for 10-min (4.2 ppm/17)3 × 7 h = 0.106 ppm3-h (4.2 ppm/17)1 × 7 h = 1.73 ppm3-h Uncertainty factors: 3 for interspecies variability 3 for intraspecies variability Combined uncertainty factor of 10 Modifying factor: 1.7 because BCME content in technical grade CMME in the key study was unknown. Calculated by assuming 10% BCME (the maximum contamination reported) and accounting for the greater toxicity of BCME (LC50 for rats was 55 ppm for CMME and 7 ppm for BCME in the key study): [0.1 × (55 ppm ÷ 7 ppm)] + [0.9 × 1] = 1.7.

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97 Chloromethyl Methyl Ether Calculations: 10-min AEGL-2 Set equal to 30-min value because of uncertainty in extrapolating a 7-h exposure to 10 min. C3 × 0.5 h = 0.106 ppm3-h 30-min AEGL-2: C = 0.60 ppm [2.0 mg/m3] C3 × 1 h = 0.106 ppm3-h 60-min AEGL-2: C = 0.47 ppm [1.5 mg/m3] C3 × 4 h = 0.106 ppm3-h 4-h AEGL-2: C = 0.30 ppm [0.98 mg/m3] C1 × 8 h = 1.73 ppm-h 8-h AEGL-2: C = 0.22 ppm [0.72 mg/m3] Derivative of AEGL-3 Values Key study: Drew et al. 1975 Toxicity end point: NOEL of 18 ppm for lethality from extreme lung irritation in hamsters (BMCL05) Cn × t = k (n = 3 for longer to shorter Time scaling: exposure periods; n = 1 for shorter to longer exposure periods); extrapolation not performed for 10-min (18 ppm/17)3 ×7 h = 8.31 ppm3-h (18 ppm/17)1 × 7 h = 7.41 ppm-h Uncertainty factors: 3 for interspecies variability 3 for intraspecies variability Combined uncertainty factor of 10 Modifying factor: 1.7 because BCME content in technical grade CMME in the key study was unknown. Calculated by assuming 10% BCME (the maximum contamination reported) and accounting for the greater toxicity of BCME (LC50 for rats was 55 ppm for CMME and 7 ppm for BCME in the key study): [0.1 × (55 ppm ÷ 7 ppm)] + [0.9 × 1] = 1.7.

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98 Acute Exposure Guideline Levels Calculations: 10-min AEGL-3: Set equal to 30-min value because of uncertainty in extrapolating a 7-h exposure to 10 min. C3 × 0.5 h = 8.31 ppm3-hr 30-min AEGL-3: C = 2.6 ppm [8.6 mg/m3] C3 × 1 h = 8.31 ppm3-h 60-min AEGL-3: C = 2.0 ppm [6.6 mg/m3] C3 × 4 h = 8.31 ppm3-h 4-h AEGL-3: C = 1.3 ppm [4.3 mg/m3] C1 × 8 h = 4.2 ppm-h 8-h AEGL-3: C = 0.93 ppm [3.1 mg/m3]

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99 Chloromethyl Methyl Ether APPENDIX B ACUTE EXPOSURE GUIDELINE LEVELS FOR CHRLOMETHYL METHYL ETHER Derivation Summary AEGL-1 VALUES 10 min 30 min 1h 4h 8h Not Not Not Not Not recommended recommended recommended recommended recommended Reference: Not applicable Test species/Strain/Number: Not applicable Exposure route/Concentrations/Durations: Not applicable Effects: Not applicable End point/Concentration/Rationale: Not applicable Uncertainty factors/Rationale: Not applicable Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Not applicable Time scaling: Not applicable Data adequacy: AEGL-1 values for technical grade CMME were not derived because there were no studies in which toxicity was limited to AEGL-1 effects. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 0.60 ppm 0.60 ppm 0.47 ppm 0.30 ppm 0.22 ppm Reference: Drew, R.T., S. Laskin, M. Kuschner, and N. Nelson. 1975. Inhalation carcinogenicity of alpha halo ethers. I. The acute inhalation toxicity of chloromethyl methyl ether and bis(chloromethyl)ether. Arch. Environ. Health 30(2):61-69. Test Species/Strain/Sex/Number: Male Sprague-Dawley rats and Syrian golden hamsters; number not specified but appeared to be 10 or more per concentration. Exposure route/Concentrations/Durations: Inhalation of 12.5-225 ppm for 7 h; observed for 14 d Effects: Concentration-related increases in relative lung weights. Congestion, edema, hemorrhage, and acute necrotizing bronchitis were evident in lungs of animals that died and, to a lesser degree, in animals surviving to 14 d (also assumed at 12.5 ppm). Mortality rates were: (Continued)

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100 Acute Exposure Guideline Levels AEGL-2 VALUES Continued 10 min 30 min 1h 4h 8h 0.60 ppm 0.60 ppm 0.47 ppm 0.30 ppm 0.22 ppm CMME Rats (%) Hamsters (%) (ppm) 100a 100a 225 141 100 70 70 100 60 54 43 33 225 (25)b 42 0 110 (10)b 26 0 12.5 0 0 LC50 = 55 ppm (from reference) LC50 = 65 ppm (from reference) BMCL05 = 19 ppm (probit BMCL05 = 18 ppm (probit analysis, if n = 20) analysis, if n = 20) a The lung-to-body weight ratio was greater than the control mean plus 3 standard deviations. b Appear to be typographic errors in the reference; suggested values are in parentheses. End point/Concentration/Rationale: NOAEL of 4.2 ppm for serious or irreversible lung lesions in rats and hamsters, estimated by applying an adjustment factor of 3 to the LOAEL of 12.5 ppm. Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 applied because CMME caused a similar degree of lung toxicity in two animal species, and is expected to cause similar toxicity in human lungs. Intraspecies: 3 recommended in the Standard Operating Procedures (NRC 2001) for chemicals with a steep dose-response relationship, because effects are unlikely to vary greatly among humans. Modifying factor: 1.7 used because the BCME content in technical grade CMME in the key study was unknown; obtained by assuming 10% BCME (the maximum reported) and accounting for the greater toxicity of BCME (LC50 for rats was 55 ppm for CMME and 7 ppm for BCME in the key study): [0.1 × (55/7)] + [0.9 × 1] = 1.7. Animal-to-human dosimetric adjustment: Not applied Time scaling: Cn × t = k. Default value of n = 3 when scaling from longer to shorter durations, and n = 1 when scaling from shorter-to-longer durations. The 30-min AEGL value was adopted for the 10-min value to protect human health (see Section 4.4.3.). Data adequacy: The key study was adequate and the two test species had similar results. The key study did not state the number of animals per concentration, which did not affect the AEGL-2 derivation.

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101 Chloromethyl Methyl Ether AEGL-3 VALUES 10 min 30 min 1h 4h 8h 2.6 ppm 2.6 ppm 2.0 ppm 1.3 ppm 0.93 ppm Reference: Drew, R.T., S. Laskin, M. Kuschner, and N. Nelson. 1975. Inhalation carcinogenicity of alpha halo ethers. I. The acute inhalation toxicity of chloromethyl methyl ether and bis(chloromethyl)ether. Arch. Environ. Health 30(2):61-69. Test species/Strain/Sex/Number: Male Sprague-Dawley rats and Syrian golden hamsters; number not given but appeared to be 10 or more per concentration. Exposure route/Concentrations/Durations: Inhalation of 12.5-225 ppm for 7 h; observed for 14 d. Effects: Concentration-related increases in relative lung weights. Congestion, edema, hemorrhage, and acute necrotizing bronchitis were evident in lungs of animals that died and, to a lesser degree, in animals surviving to 14 d (also assumed at 12.5 ppm). Mortality rates were: CMME (ppm) Rats (%) Hamsters (%) a 100a 225 100 141 100 70 70 100 60 54 43 33 b 42 225 (25) 0 110 (10)b 26 0 12.5 0 0 LC50 = 55 ppm (from reference) LC50 = 65 ppm (from reference) BMCL05 = 19 ppm (probit BMCL05 = 18 ppm (probit analysis, if n = 20) analysis, if n = 20) a The lung-to-body weight ratio was greater than the control mean plus 3 standard deviations. b Appear to be typographic errors in the reference; suggested values are in parentheses. End point/Concentration/Rationale: NOEL of 18 ppm for lethality from extreme lung irritation in hamsters (BMCL05). Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 applied because the NOEL for lethality was virtually the same in two species in the key study, and lethality is expected to occur by a similar mode of action in humans and animals. Intraspecies: 3 recommended in the Standard Operating Procedures (NRC 2001) for chemicals with a steep dose-response relationship, because effects are unlikely to vary greatly among humans. (Continued)

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102 Acute Exposure Guideline Levels AEGL-3 VALUES Continued 10 min 30 min 1h 4h 8h 2.6 ppm 2.6 ppm 2.0 ppm 1.3 ppm 0.93 ppm Modifying factor: 1.7 used because the BCME content in technical grade CMME in the key study was unknown; obtained by assuming 10% BCME (the maximum reported) and accounting for the greater toxicity of BCME (LC50 for rats was 55 ppm for CMME and 7 ppm for BCME in the key study): [0.1 × (55/7)] + [0.9 × 1] = 1.7. Animal-to-human dosimetric adjustment: Not applied Time scaling: Cn × t = k. Default value of n = 3 when scaling from longer to shorter durations, and n = 1 when scaling from shorter-to-longer durations. The 30-min AEGL value was adopted for the 10-min value to protect human health (see Section 4.4.3.). Data adequacy: The key study was adequate and the two test species had similar results. The key study did not state the number of animals per concentration. This could have slightly affected the calculated BMCL05 and AEGL-3 values. If it is assumed that n = 10 for all test concentrations, the BMCL05 is 15 ppm for rats and 16 ppm for hamsters, and if n = 30, the BMCL05 is 20 ppm for rats and 19 ppm for hamsters.

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103 Chloromethyl Methyl Ether APPENDIX C CMME Toxicity 1000.0 Human - No Effect Human - Discomfort 100.0 Human - Disabling Animal - No Effect ppm 10.0 Animal - Discomfort Animal - Disabling AEGL-3 1.0 Animal - Some Lethality AEGL-2 Animal - Lethal 0.1 0.1 AEGL 0 60 120 180 240 300 360 420 480 Minutes FIGURE C-1 Category plot of animal toxicity data compared with AEGL values. Multi- ple-exposure studies are not included in the plot.

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104 Acute Exposure Guideline Levels APPENDIX D CANCER ASSESSMENT OF CHLOROMETHYL METHYL ETHER AND bis-CHLOROMETHYL ETHER (BCME) Data were unavailable to conduct a carcinogenicity risk assessment for CMME, but an assessment was conducted for the related compound BCME. EPA (2002) performed a cancer assessment of the related compound BCME using data from Kuschner et al. (1975). The calculated inhalation unit risk for BCME was 6.2 ×10-2 per μg/m3, using the linearized multistage procedure, extra risk (EPA 2005b). The concentration of BCME corresponding to a lifetime risk of 1 × 10-4 is calculated as follows: (1 × 10-4) ÷ [6.2 × 10-2 (μg/m3)-1] = 1.6 ×10-3 μg/m3 To convert a 70-year exposure to a 24-h exposure, one multiplies by the number of days in 70 years (25,600). The concentration of BCME corresponding to a 1 × 10-4 risk from a 24-h exposure is: (1.6 × 10-3 μg/m3)(25,600 days) = 40.96 μg/m3 (0.041 mg/m3 or 0.0086 ppm) To account for uncertainty about the variability in the stage of the cancer process at which BCME or its metabolites act, a multistage factor of 6 is applied (Crump and Howe 1984): (40.96 μg/m3) ÷ 6 = 6.83 μg/m3 (0.0068 mg/m3 or 0.0014 ppm) If the exposure is reduced to a fraction of a 24-h period, the fractional exposure (f) becomes (1/f) × 24 h (NRC 1985). Extrapolation to 10 min was not calculated because of unacceptably large inherent uncertainty. Because the animal dose was converted to an air concentration that results in an equivalent human inhaled dose for the derivation of the cancer slope factor, no reduction of exposure concentrations is made to account for interspecies variability. The calculated concentration of BCME associated with a 1 ×10-4 cancer risk is shown in Table D-1 for a single exposure of 10 min to 8 h. For a 1 ×10-5 and 1 × 10-6 risk, the 1 × 10-4 values are reduced 10-fold or 100-fold, respectively. If the assumptions are made that technical CMME contains 10% BCME, and that “pure” BCME is 10-fold more potent a carcinogen than “pure” CMME (which is suggested by experimental data), then technical-grade CMME has 19% of the carcinogenic activity of BCME at most ([90% of technical-grade CMME with 10% BCME activity] + [10% of technical grade CMME with 100% BCME activity]). Thus, if a linear relationship between exposure concentration and cancer risk is assumed for CMME and BCME, the CMME concentration associated with a 1 × 10-4 cancer risk for a given exposure duration can be

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105 Chloromethyl Methyl Ether calculated by dividing the respective BCME concentration by 0.19, as shown in Table D-1. Also presented in the table is the cancer risk for the AEGL-2 and AEGL-3 concentrations from a single exposure for 30 min to 8 h. The risk for the AEGL-2 values ranges from 1.7 × 10-4 for a 30-min exposure to 9.6 × 10-4 for an 8-h exposure. The predicted carcinogenic risk for the AEGL-3 values is greater, ranging from 7.4 × 10-4 for a 30-min exposure to 4.1 × 10-3 for an 8-h exposure. It is unknown, however, how well the stated assumptions hold true and predict the carcinogenicity of CMME. Because of this uncertainty and the large differences in methods used to derive the AEGL values compared with extrapolating carcinogenic potency from a lifetime study to a single exposure, the noncarcinogenic end points were considered to be more appropriate for driv- ing the AEGL values for CMME. TABLE D-1 Estimated Cancer Risks Associated with a Single Exposure Chloromethyl Methyl Ether or bis-Chloromethyl Ether Exposure 10 min 30 min 1h 4h 8h BCME Concentration Not 0.069 ppm 0.035 ppm 0.0086 ppm 0.0043 ppm calculated 1 × 10-4 1 × 10-4 1 × 10-4 1 × 10-4 Estimated cancer risk CMME, containing 10% BCMEa Concentration Not 0.36 ppm 0.18 ppm 0.045 ppm 0.023 ppm calculated 1 × 10-4 1 × 10-4 1 × 10-4 1 × 10-4 Estimated cancer risk AEGL-2 value 0.60 ppm 0.60 ppm 0.47 ppm 0.30 ppm 0.22 ppm 1.7 × 10-4 2.6 × 10-4 6.7 ×10-4 9.6 × 10-4 Estimated Not cancer risk calculated AEGL-3 value 2.6 ppm 2.6 ppm 2.0 ppm 1.3 ppm 0.93 ppm 7.4 × 10-4 1.1 × 10-3 2.9 × 10-3 4.1 × 10-3 Estimated Not cancer risk calculated a Assumes BCME is a 10-fold more potent carcinogen than CMME.