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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11 (2012)

Chapter: 1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels

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Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
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Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
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Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
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Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
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Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
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Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
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Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 19
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 20
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 21
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
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Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 23
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 24
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 25
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 26
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 27
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 28
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 29
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 30
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 31
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 32
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 33
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 34
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 35
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 36
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 37
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 38
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 39
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 40
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 41
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 42
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 43
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 44
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 45
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 46
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 47
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 48
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 49
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 50
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 51
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 52
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 53
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 54
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 55
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 56
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 57
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 58
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 59
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
×
Page 60
Suggested Citation:"1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels." National Research Council. 2012. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 11. Washington, DC: The National Academies Press. doi: 10.17226/13374.
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1 bis-Chloromethyl 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). 13

14 Acute Exposure Guideline Levels effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold levels for the general public, including susceptible subpopulations, 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 correspond- ing AEGL. SUMMARY bis-Chloromethyl ether (BCME) is a synthetic chemical that is a severe respiratory, eye, nose, and skin irritant that can lead to pulmonary edema and congestion, corneal necrosis, dyspnea, and death. Chronic occupational exposure has caused small-cell lung carcinoma, which has a histology distinct from smoking-associated lung cancer and a shorter latency period. The U.S. Environ- mental Protection Agency (EPA) classifies BCME as a human carcinogen based on sufficient human carcinogenicity data, and the Occupational Safety and Health Administration (OSHA) federal regulations limit its use, storage, and handling to controlled areas. AEGL-1 values were not recommended for BCME because effects ex- ceeding the severity of AEGL-1 occurred at concentrations that did not produce sensory irritation in humans or animals. The AEGL-2 was based on a study in which rats were exposed for 7 h to BCME at a concentration of 0.7, 2.1, 6.9, or 9.5 ppm and hamsters were exposed for 7 h to BCME at 0.7, 2.1, 5.6, or 9.9 ppm, followed by lifetime observation (Drew et al. 1975). All groups of treated rats had increased lung-to-body weight ratios, indicative of respiratory lesions, which were considered irreversible because they were seen after lifetime observation. There also was an increased incidence of tracheal epithelial hyperplasia in rats and of pneumonitis in hamsters at 0.7 ppm, and both species had increased mortality and lung lesions

bis-Chloromethyl Ether 15 at ≥2.1 ppm. The lowest concentration tested was a lowest-observed-adverse- effect level (LOAEL) for irreversible respiratory-tract lesions, and an adjustment factor of 3 was applied to estimate a no-observed-adverse-effect level (NOAEL) of 0.23 ppm. This point-of-departure is supported by two other experiments by Drew et al. (1975) that had similar LOAELs for irreversible or serious lung lesions. No data were available from which to determine the BCME 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 when extrapolat- ing to shorter time points than 7 h and n = 1 when extrapolating to longer time points than 7 h. The 10-min values were not extrapolated because of unacceptably large inherent uncertainty; the 30-min value were adopted for the 10-min value to be protective of human health. A total uncertainty factor of 10 was used. An uncertainty factor of 3 was applied for interspecies extrapolation because BCME caused a similar toxic response in two species at the same test concentration in the key study and is expected to cause toxicity similarly in human lung. An uncertainty 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. Using the intraspecies default uncertainty factor of 10 would reduce the 4- and 8-h AEGL-2 values to below 0.010 ppm, which was shown to be a no-effect level from 129 exposures in rats and mice (Leong et al. 1981). AEGL-3 values were derived from the single-exposure scenario of a study in which rats and hamsters were received 1, 3, 10, or 30 six-hour exposures to BCME at 1 ppm, and observed for a lifetime (Drew et al. 1975). After one exposure, rats and hamsters had slightly increased incidences of lung lesions, whereas three exposures produced lung lesions and increased mortality. This study was chosen because it had the highest BCME concentration that caused no mortality after lifetime observation. Because no data were available from which to determine the BCME concentration-time relationship, scaling across time was performed as for AEGL-2 values, using n = 3 and n = 1 for durations shorter and longer, respectively, than 6 h. The 10-min values were set equal to the 30-min values to be protective of human health. A total uncertainty factor of 10 was used. An uncertainty factor of 3 was applied for interspecies extrapolation because the no-observed-effect level (NOEL) for lethality was 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. An uncertainty 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. AEGLs values are summarized in Table 1-1 below. An inhalation cancer slope factor for BCME was derived by EPA (2002). It was used to calculate the concentration of BCME associated with a 1 × 10-4 cancer risk from a single exposure for 10 min to 8 h, as shown in Appendix B,

16 Acute Exposure Guideline Levels and in Table 1-2 below. The concentrations are similar to the AEGL-2 values for exposures ≤1 h, but are up to 5-fold lower than AEGL-2 values for exposures of 4-8 h. The carcinogenic end points were not considered appropriate for AEGL derivation because the data did not show that tumor formation could result from a single exposure. Additionally, a direct comparison of BCME cancer risk and AEGL values is of unknown validity because the two sets of numbers are calculated using different methodologies (the cancer risk calculation involves a linear extrapolation from 25,600 days to 0.5 to 8 h whereas the calculation of AEGL values involves extrapolation from a single 7-h exposure using either n = 3 or n = 1, and different uncertainties are addressed by the two methods). The estimated cancer risks associated with the AEGL-2 and AEGL-3 values are shown in Table 1-2. TABLE 1-1 Summary of AEGL Values for bis-Chloromethyl Methyl Ether End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 NRa NR NR NR NR (nondisabling) AEGL-2 0.055 ppm 0.055 ppm 0.044 ppmb 0.028 ppmb 0.020 ppmb NOAEL for (disabling) (0.26 (0.26 (0.21 (0.13 (0.095 irreversible lung mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) lesions in rats and hamsters (Drew et al. 1975) AEGL-3 0.23 ppmb 0.23 ppmb 0.18 ppmb 0.11 ppmb 0.075 ppmb Lethality NOEL for (lethal) (1.1 (1.1 (0.86 (0.52 (0.36 rats and hamsters mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (Drew et al. 1975) a Not recommended (effects exceeding the severity of AEGL-1 effects occurred at con- centrations that did not produce sensory irritation in humans or animals). b These concentrations are estimated to have a cancer risk greater than 1 × 10-4, on the basis of an inhalation cancer slope factor derived by EPA (2002). TABLE 1-2 Estimated Cancer Risks Associated with a Single Exposure to bis-Chloromethyl Ether Exposure 10 min 30 min 1h 4h 8h BCME Not calculated 0.069 ppm 0.035 ppm 0.0086 ppm 0.0043 ppm concentration: 1.0 × 10-4 1.0 × 10-4 1.0 × 10-4 1.0 × 10-4 Estimated cancer risk: AEGL-2 value: 0.055 ppm 0.055 ppm 0.044 ppm 0.028 ppm 0.020 ppm Estimated Not calculated 8.0 × 10-5 1.3 × 10-4 3.3 × 10-4 4.7 × 10-4 cancer risk: AEGL-3 value: 0.23 ppm 0.23 ppm 0.18 ppm 0.11 ppm 0.075 ppm Estimated Not calculated 3.3 × 10-4 5.1 × 10-4 1.3 × 10-3 1.7 × 10-3 cancer risk:

bis-Chloromethyl Ether 17 1. INTRODUCTION BCME is a colorless, flammable liquid with a “suffocating” and irritating odor (O’Neil et al. 2001; NTP 2011). It is used industrially as a chloromethylating agent in the manufacture of ion-exchange resins, bactericides, pesticides, dispersing agents, water repellants, solvents for industrial polymerization reactions, and flame-proofing agents (O’Neil et al. 2001; NTP 2011). BCME is a contaminant (≤10%) of the related and similarly used chemical, chloromethyl methyl ether (CMME) (Langner 1977). BCME does not occur naturally, and human exposure by inhalation is limited to occupational settings. BCME is produced by saturating a paraformaldehyde solution with cold sulfuric acid and hydrochloric acid (HCl) (IARC 1974). A low yield (~0.01-0.001%) of BCME has been shown to form spontaneously from the commonly used chemicals HCl and formaldehyde; for example, mixtures of 500-5,000 ppm each of HCl and formaldehyde produced BCME at <0.5-179 ppb (Kallos and Solomon 1973; Frankel et al. 1974; Albert et al. 1982; Sellakumar et al. 1985). BCME is hydrolyzed to HCl and formaldehyde upon contact with water, where it is believed to exist in equilibrium with its hydrolysis products, with about 20% of the original compound (Van Duuren et al. 1972). The BCME half- life in water is 10-60 seconds (sec) at 20°C (Van Duuren et al. 1972; Tou and Kallos 1974). In humid air, at ambient temperature and 81% relative humidity, BCME is more stable, having a half-life of 7-25 h depending on the surface coating of the container (Tou and Kallos 1974). Collier (1972) reported that BCME at 10 and 100 ppm was stable for at least 18 h in air with 70% relative humidity. Frankel et al. (1974) also found BCME was stable for 18 h in a Saran bag containing moist air (40% relative humidity, 24°C). BCME vapor is a severe respiratory, eye, nose, and skin irritant, and has caused pulmonary edema and congestion, corneal necrosis, dyspnea, and blood- stained sputum in humans (O’Neil et al. 2001). BCME is an alkylating agent and has been shown to react in vitro with guanine and adenine of calf thymus DNA (Goldschmidt et al. 1975). BCME and CMME were recognized as potent human respiratory carcinogens in the early 1970s, prompting facilities to develop hermetically isolated systems for their use (Travenius 1982; Collingwood et al. 1987). In 1973, BCME and CMME were listed by OSHA as part of the first group of chemicals to be restricted by federal regulations because of their human carcinogenicity. The use, storage, and handling of preparations containing BCME at ≥0.1% (by weight or volume) must be in a controlled area (29 CFR 1910.1008 [1996]). BCME is classified as a human carcinogen by EPA, the American Conference of Governmental Hygienists (ACGIH), the International Agency for the Research on Cancer (IARC), and the National Institute of Occupational Safety and Health (NIOSH). As of 1982, BCME is no longer produced as a commercial product in the United States. Small amounts may be produced or repackaged as a chemical intermediate or laboratory chemical, and it might be inadvertently released

18 Acute Exposure Guideline Levels during industrial operations (HSDB 2005). Five U.S. suppliers and three non- U.S. suppliers of BCME were identified in 2005 (ChemSources 2005). Selected chemical and physical properties of BCME are listed in Table 1-3. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality Exposure to BCME at 100 ppm for 1-2 min might produce fatal lung injury, whereas a concentration of 100 ppm would incapacitate a person in a few seconds (Flury and Zernik 1931). Thiess et al. (1973) reported a case of a chemical laboratory worker who died after being splashed from an explosive reaction formed when aluminum chloride was added to a reactor that contained BCME in methylene chloride. The worker developed severe conjunctival irritation, corneal opacity, facial-skin irritation, and second and third degree burns on parts of his body within hours of exposure. His optic nerve atrophied and he developed double pneumonia which progressed into pulmonary fibrosis that resulted in death. BCME concentrations were not measured. TABLE 1-3 Chemical and Physical Data for bis-Chloromethyl Ether Parameter Value Reference Synonyms BCME; bis-CME; chloromethyl ether; NIOSH 2005 dichlorodimethyl ether; oxybis(chloromethane); dichloromethyl ether CAS registry no. 542-88-1 NIOSH 2005 Chemical formula (CH2Cl)2 O NIOSH 2005 Structure O(CCl)CCl NIOSH 2005 Molecular weight 114.96 O’Neil et al. 2001 Physical state Colorless liquid O’Neil et al. 2001 Melting point -41.5°C HSDB 2005 Boiling point 106°C O’Neil et al. 2001 Density (water = 1) 1.315 at 20/4°C O’Neil et al. 2001 Vapor density 4.0 (air = 1) HSDB 2005 Solubility in water Decomposes to HCl and formaldehyde O’Neil et al. 2001 Vapor pressure 30 mm Hg at 22°C HSDB 2005 Flammability limits Flash point <23°C; estimated lower AIHA 2000; (volume % in air) explosives limit = 6.5%; estimated NIOSH 2005 upper explosives limit = 21.9% Conversion factors 1 mg/m3 = 0.21 ppm; 1 ppm = 4.75 mg/m3 HSDB 2005

bis-Chloromethyl Ether 19 2.2. Nonlethal Toxicity 2.2.1. Odor Threshold and Awareness BCME has a “suffocating” odor (O’Neil et al. 2001). A several-hour exposure to a concentration of BCME (specified only as <3 ppm) did not reach the threshold of perception, but caused severe eye damage several hours after exposure ceased (Travenius 1982). Leong et al. (1971) stated that BCME is a health risk at concentrations that do not produce sensory irritation. Travenius (1982) reported that the highest tolerable concentration of BCME in air is 5 ppm. BCME was found to be distinctly irritating at 3 ppm (Flury and Zernik 1931). The data were not adequate to derive a level-of-distinct-odor awareness according to the guidance of van Doorn et al. (2002). 2.2.2. Occupational Exposure Thirteen accidental exposures to unknown concentrations of BCME occurred from leaking pipes or vessels in a German chemical plant (Thiess et al. 1973). Two of the exposures resulted in severe chemical burns of the cornea that did not completely heal, and some local skin burning. The other 11 exposures were milder, resulting in short-term irritation of the upper respiratory tract, headaches, and nausea. It was not reported whether there was simultaneous exposure to other airborne chemicals. An overall 8-h time-weighted average concentration for BCME of 0.34 ppb (quarterly range of 0.01-3.1 ppb) was measured for seven workers in an anion exchange plant between 1972 and 1975 (Langner 1977). CMME containing up to 10% BCME was used in closed systems of the plant. No cases of oat-cell respiratory cancer were reported in workers at the plant over its 27 years of operation. Unwin and Groves (1996) detected BCME at concentrations of 0.03-15.4 ppb at three industrial plants in the United Kingdom. Air samples were taken near reaction vessels where BCME formation was anticipated, and from the continuous online air sampling system. No irritation or other toxicity were reported in the workers, although health effects were not specifically addressed in the study. Studies in which BCME exposure was associated with respiratory cancer are described in Section 2.5. 2.3. Neurotoxicity No studies reporting neurotoxic effects of BCME in humans were found.

20 Acute Exposure Guideline Levels 2.4. Developmental/Reproductive Effects No developmental or reproductive human studies with BCME were found. 2.5. Genotoxicity The incidence of chromosomal aberrations was greater in the peripheral lymphocytes of workers exposed to 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 BCME exposure during the last 3 months. An 11-fold increase in the frequency of transformed cells occurred in human lung WI-38 cells cultured with BCME at 0.008-25 milligrams per millili- ter (mg/mL) in the presence of exogenous activation (Styles 1978). Human neonatal foreskin fibroblasts had a 3-14 fold increase in anchorage-independent cells after incubation with BCME at 0.1-8 micrograms per milliliter (µg/mL) (Kurian et al. 1990). DNA repair was increased in human skin fibroblasts exposed to BCME at ≥0.16 μg/mL, although the quantitative response was not provided (Agrelo and Severn 1981). 2.6. Carcinogenicity BCME is classified as a human carcinogen by EPA, ACGIH, IARC, and NIOSH. EPA (2002) places BCME in classification A (“human carcinogen”) on the basis of sufficient human carcinogenicity data. ACGIH (1991) places BCME in group A1 (“confirmed human carcinogen”), IARC (1987) places it in Group I (“sufficient evidence of carcinogenicity in humans”), and NIOSH (2005) states that BCME is a carcinogen, with no further classification. 2.6.1. Case Reports Reznik et al. (1977) reported a case of a chemist who developed bronchial adenocarcinoma and died 12 years after over 2 years of work on an experiment in which BCME and CMME were reaction byproducts. Air concentrations of BCME or CMME were unknown but the chemical reaction with triphenyl hydroxymethyl phosphonium chloride was conducted “on a scale of 1-2 mol.” Three workers from a small BCME manufacturing facility in the United Kingdom died from lung cancer (Roe 1985). The exposure concentrations and the total number of men exposed were not given, but it was stated that “between 5 and 8 individuals were employed at any one time on a process involving a chloromethylation stage.” The ages of the men at diagnosis were 35-40 years.

bis-Chloromethyl Ether 21 Two of the 3 men had oat-cell carcinoma, and the third had anaplastic squamous-cell carcinoma. Two cases of small-cell lung cancer were attributed to BCME exposure in a Japanese manufacturing facility (Fujio et al. 1986). BCME concentration was not reported. Each case involved a male smoker of approximately 50 years old. One worker was exposed to BCME for 2 years and the other for 8 years. The latter worker died within a year after diagnosis despite treatment with radiation and chemotherapy; the other worker seemingly recovered. 2.6.2. Epidemiologic Studies In 1972, four workers at a California chemical plant (Diamond Shamrock Co., Redwood City) with 100-200 workers exposed to BCME from anion- exchange resin production died from lung cancer, and two more workers developed lung cancer (Donaldson and Johnson 1972; Fishbein 1972). The ages of the workers at death were 31-48. The concentration of BCME in the air was not reported. One of the workers that died, a 32-year old man, worked at the plant only 2 years. Subsequent cytologic analysis of exfoliated cells in the sputum of 125 current white male employees found a significant association between abnormal cytology (metaplasia and atypia) and exposure to BCME for more than 5 years (34% of anion-exchange workers vs. 11% of controls), whereas there was no difference between in-plant workers not involved in an- ion-exchange resin production and controls (Lemen et al. 1976). In concert with this cytology survey, a retrospective cohort study of 136 men who worked in the plant for 5 or more years between Jan. 1, 1955 and Mar. 31, 1972 (mean exposure was 10 years) was conducted. During this 17-year period, nine workers died: five from heart disease, one from lymphosarcoma, and three from bronchogenic cancer. Two more workers were diagnosed with bronchogenic cancer. The five cases among 136 workers represented a 9-fold increase in lung cancer from the expected mortality rate of 0.54 cases in white, age-matched men from Connecticut. The histologic type of carcinoma in four of five cases was small-cell undifferentiated carcinoma (the fifth case was large-cell undifferentiated carcinoma). The mean latency period was 15 years and the mean age of the cancer patients was 47 years, the majority of whom were smokers. The majority (>60%) of the workers were followed for less than 10 years after exposure, suggesting that the actual cancer incidence might have been greater. Five of 32 workers exposed to unreported concentrations of BCME in a Japanese dyestuff factory for 4-7 years during 1955-1970 died of lung cancer, compared with the expected incidence of 0.024 (Sakabe 1973). One of the five cases was confirmed as being of the oat-cell carcinoma type. The latency period was 8-14 years after initial exposure. The men were smokers and their ages were 37-47 at the time of death. A subsequent epidemiologic study of this and a second Japanese dyestuff factory where BCME was manufactured and used

22 Acute Exposure Guideline Levels between 1960 and 1968, found a total of 13 cases of lung cancer among 35 exposed men at the two factories (Nishimura et al. 1990). The overall mean exposure period was 7.2 years, the latency period was 13.5 years, and age at death was 46.1 years. The histologic types of the eight cases not previously described by Sakabe (1973) were: small-cell carcinoma in five cases, adenoma in three cases, and large-cell carcinoma in one case. In a retrospective study for years 1956-1962, Thiess et al. (1973) reported that six of 18 testing facility workers and two of 50 production workers developed lung cancer after 6-9 years of exposure to BCME at unknown concentrations. Most of the workers were smokers. The tumor latency period was 8-16 years. Five of the eight cases were diagnosed as oat-cell carcinomas. Air concentrations of BCME, but not CMME, were measured in a factory in Chauny, France, that used CMME to produce anion exchange resins (because BCME is more stable) (Gowers et al. 1993). This study is described in greater detail in the technical support document for CMME (see Chapter 2 of this re- port). For 1979-1984, mean yearly concentrations of BCME were found to be 0.6-4.4 ppb (1.7 ppb, overall weighted average) by mass spectrometry of personal and stationary air samples (n = 96-175 per year). Workers exposed previously to much higher BCME concentrations had an increased incidence of lung cancer with small-cell histology relative to nonexposed workers. Xue et al. (1988) reported the results of an epidemiologic investigation of lung cancer incidence in a cohort of 915 workers (534 men, 381 women) in 11 plants in China that produced or used “chloromethylether (CME).” It was not clear whether exposure was to BCME or CMME or both. The concentration of chloromethyl in the air was not measured. Between 1958 and 1981, there were 32 mortalities, 15 from lung cancer. Of the 11 cases evaluated histologically, eight were undifferentiated cell carcinoma and three were squamous cell carcinoma. The average age at death was 49.7 (32-64), and the mean interval from beginning of exposure to diagnosis was 9.86 years (2-20). Calculation of standard mortality ratios using various reference cohorts showed that the excess of deaths from all causes and all cancers were from increased lung cancer mortality. The number of lung cancer cases increased with exposure severity, which was estimated from the degree of irritation, job description, and duration of exposure. Heavy smoking was associated with increased lung cancer. 2.7. Summary No quantitative human studies of BCME were found in which the exposure duration, concentration, and corresponding observed effects were reported. BCME caused severe eye damage and workers developed lung tumors from exposure concentrations that did not produce sensory irritation. The lung cancers had a shorter latency period and histology distinct from tumors from cigarette smoking. BCME is one of the most potent known human (and animal) carcinogens, and is classified as a human carcinogen by EPA, ACGIH, IARC,

bis-Chloromethyl Ether 23 and NIOSH. No human developmental or reproductive toxicity studies of BCME were found. An increased incidence of chromosomal aberrations was found in peripheral lymphocytes of workers exposed to BCME, and BCME induced cell transformation and DNA repair in vitro. A summary of semi- quantitative inhalation exposure studies of BCME is provided in Table 1-4. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Rats In a range-finding study, a 4-h exposure to a nominal concentration of BCME at 7.8 ppm caused death in one of six male albino rats on day 14, and 15.6 ppm caused deaths in all six test rats on days 2, 4, and 7 (Union Carbide 1968; Smyth et al. 1969). The LC50 (lethal concentration, 50% lethality) was reported to be 10.26 ppm. Animals that died had lung hemorrhage and blood in the intestines, and survivors had morphologic lung changes described as “consolidated” or “greatly enlarged” areas. Exposure to “substantially” saturated vapor (~40,000 ppm at saturation) caused irritation and prostration by 3 min, and killed six of six rats within 8 min (Union Carbide 1968). TABLE 1-4 Summary of Human Exposure Data with Defined Concentrations to bis-Chloromethyl Ether Exposure Exposure Concentration Duration Results (Reference) 0.01-3.1 ppb ≤27 years No effects from occupational exposure (Langner 1977) 0.03-15.4 ppb Years No effects reported at three industrial plants (Unwin and Groves 1996) 0.6-4.4 ppb Years No sensory effects reported; workers developed oat-cell carcinoma but were previously exposed to much higher BCME levels (Gowers et al. 1993) <3 ppm Unknown Did not reach the threshold of perception but caused (short-term) severe eye damage several hours after exposure ceased (Travenius 1982) 3 ppm Unknown Distinctly irritating (Flury and Zernik 1931) (short-term) 5 ppm Unknown Highest “tolerable” concentration (Travenius 1982) (momentary) 100 ppm Few seconds Would incapacitate a person (Flury and Zernik 1931) 100 ppm 1-2 min Might produce fatal lung injury (Flury and Zernik 1931)

24 Acute Exposure Guideline Levels In another study, all 12 test rats died after 3 min of inhaling air saturated with BCME (~40,000 ppm) (Zeller and Hoffmann 1973). The animals had mucous membrane irritation, milky opacity of the cornea, narcosis, and dyspnea. Drew et al. (1975) conducted three sets of experiments to evaluate the inhalation toxicity of BCME in male Sprague-Dawley rats. The acute lethality of BCME was determined using ~8-week old rats (10/concentration). Rats were exposed for 7 h to BCME at 0.94-74 ppm and observed for 14 days. BCME vapor was generated by bubbling air through or passing it over liquid BCME before it was introduced into 128-L or 1.3-m3 exposure chambers; air concentrations of BCME were measured every half-hour spectrophotometrically after coupling with 4-(p-nitrobenzyl) pyridine. Lungs were removed from each animal and damage was measured as an increase of three standard deviations in the lung-to-body weight ratio. The ratio for controls was approximately 0.6. A value of 0.9 was considered elevated for rats. (Previous studies with irritants in the same laboratory showed that this ratio was an objective indicator of lung damage.) As shown in Table 1-5, the 14-day LC50 was estimated graphically to be ~7 ppm. All animals given BCME at ≥9 ppm died within 14 days, most on the first post-exposure day. The rats had extensive lung damage, including congestion, edema, and hemorrhage and a dose-related increase in the incidence of lung-to-body weight ratio. In a related experiment, Drew et al. (1975) examined the long-term effects of a single 7-h exposure to BCME at 0.7, 2.1, 6.9, or 9.5 ppm in rats (25/concentration; 50 controls) observed for their lifetimes. Results were reported in terms of percentage of findings per number of observations, as shown in Table 1-6, although it was not clear how the “number of observations” was determined, relative to the original 25 or 50 animals per dose group. At concentrations of 2.1 ppm and greater, rats had severe life shortening (first death during week 2), weight loss, and elevated lung-to-body weight ratios, and as lung edema, congestion, and hemorrhage. Histopathologic findings included increased incidences of tracheal and bronchial hyperplasia (often with nuclear atypia) and squamous metaplasia compared with controls. Animals exposed to BCME at 0.7 ppm had respiratory pathologic changes similar to those of controls, although there was an increase in the incidence of tracheal epithelial hyperplasia (67% vs. 36% in controls) and increased lung-to-body weight ratios. In their third experiment, Drew et al. (1975) subjected groups of 50 rats to 1, 3, 10, or 30 six-hour exposures to BCME at 1 ppm. Results were reported in terms of percentage of findings per number of observations, as shown in Table 1-7. All groups that received 3, 10, or 30 exposures had increased mortality compared with controls and dose-related increases in the incidence of tracheal and bronchial hyperplasia and squamous metaplasia. Additional findings in rats that received 1 or 10 exposures included bronchoalveolar squamous metaplasia (incidences of 1/29 and 5/43, respectively), cuboidal transformation of the alveolar epithelium (4/29 and 7/43, respectively), and alveolar squamous metaplasia (0/29 and 3/43, respectively). One rat that died 570 days after three exposures had an ulcerating squamous skin cell carcinoma. Central nervous

bis-Chloromethyl Ether 25 system effects and extreme irritability were seen after 10 or 30 exposures: subarachnoid hemorrhage was seen microscopically in 24% of the rats given 30 exposures, and in 17% of the rats given 10 exposures. TABLE 1-5 Mortality, Lung-to-Body Weight Ratio, and Estimated LC50 in Rats after Single 7-Hour Exposure to bis-Chloromethyl Ether Rats with increased lung-to-body weight ratio Estimated Concentration (ppm) Mortality at 14 d (%) (%)a LC50b 74 100 100 7 ppm 19 100 100 9 100 100 7.3 60 90 6.2 30 100 4.6 0 100 0.94 0 40 a Relative lung weight is greater than the control mean plus 3 standard deviations. b LC50 value was estimated graphically by the study authors. Source: Adapted from Drew et al. 1975. TABLE 1-6 Median Lifespan, Lung-to-Body Weight Ratio, and Histopathologic Findings in Rats after Single 7-Hour Exposure to bis-Chloromethyl Ether Increased Lung- Concentration Median to-Body Weight Histopathologic Findings in Lung Mucosa (%) (ppm) Lifespan (d) Ratioa (%) (based on number observations [obs])b 9.5 2 93 Specific lesions not quantified; respiratory lesions similar to those at 2.1 ppm but with higher 6.9 2 88 incidence; seen only in rats that survived >2 d 2.1 36 100 Tracheal [obs = 6]: hyperplasia (100), squamous metaplasia (17) Broncheal [obs = 13]: hyperplasia (100), with atypia (28); squamous metaplasia (62) 0.7 420 96 Increased tracheal epithelial hyperplasia (67% vs. 36% in controls;c incidence not stated) Control 462 0 Tracheal [obs = 35]: hyperplasia (31)c, squamous metaplasia (11); Broncheal [obs = 48]: hyperplasia (50), with atypia (6); squamous metaplasia (27) a Relative lung weight is greater than the control mean plus 3 standard deviations. b Report does not state how the “number of observations” was determined, relative to the original 25 animals per dose group and 50 controls. c The incidence of epithelial hyperplasia in controls is reported by Drew et al. (1975) as 36% on page 66 and as 31% on page 64 (see Table 3) of the reference. Source: Adapted from Drew et al. 1975.

26 Acute Exposure Guideline Levels TABLE 1-7 Median Lifespan and Histopathologic Findings in Rats after Multiple 6-Hour Exposures to bis-Chloromethyl Ether at 1 ppm Number Median Histopathologic Findings in the Lung Mucosa (%) Exposures Lifespan (d) (based on number of observations [obs])a 30 23 Tracheal [obs = 35]: hyperplasia (89), with atypia (11); squamous metaplasia (37); Broncheal [obs = 41]: hyperplasia (95), with atypia (27); squamous metaplasia (66), with atypia (7) 10 21 Tracheal [obs = 23]: hyperplasia (70), with atypia (52); squamous metaplasia (13) Broncheal [obs = 45]: hyperplasia (80), with atypia (47); squamous metaplasia (58) 3 168 Tracheal [obs = 23]: hyperplasia (52), with atypia (22) squamous metaplasia (26); Broncheal [obs = 34]: hyperplasia (62), with atypia (26); squamous metaplasia (41), with atypia (3) 1 457 Tracheal [obs = 22]: hyperplasia (27), with atypia (18) Broncheal [obs = 39]: hyperplasia (41), with atypia (5); squamous metaplasia (23) Control 462 Tracheal [obs = 35]: hyperplasia (31), squamous metaplasia (11); Broncheal [obs = 48]: hyperplasia (50), with atypia (6); squamous metaplasia (27) a Report does not state how the “number of observations” was determined, relative to the original 50 animals per dose group. Source: Adapted from Drew et al. 1975. An RD50 (50% decrease in the respiratory rate) value of 145 ppm for BCME was calculated in 8-week old male Crl-CD rats treated head-only for 15 min (Gardner et al. 1985). The BCME exposure concentrations and corresponding mean decreases in respiration rate were 14.4 ppm (14%), 32.5 ppm (16%), 49.8 ppm (37%), 82.8 ppm (55%), 125 ppm (47%), and 233 ppm (62%). The rats (4/dose) were exposed in a body plethysmograph and each rat was its own control. The maximal respiratory inhibition was achieved after 4 min of exposure. During the 5-min post-exposure period, the respiration rate improved but did not return to pretreatment rates. All rats exhibited lacrimation after exposure, and the rats exposed to BCME at 125 and 233 ppm had red nasal discharge. During the 48-h post-treatment observation period, severe weight loss and mortality occurred at ≥82.8 ppm (mortality: 2/4, 2/4, and 1/4 at 82.8, 125, and 233 ppm, respectively). Gardner et al. (1985) also evaluated the respiratory inhibition caused by seven other tumorigens to determine if there was a correlation between sensory irritation potential and nasal tumorigenic potential; no correlation was found.

bis-Chloromethyl Ether 27 3.1.2. Mice Strain A/Heston male mice exposed for 6 h to BCME at 2.7-10.6 ppm had a 14-day LC50 of 5.3 ppm (95% confidence limit: 3.7-7.6 ppm) but no respiratory tract irritation (Leong et al. 1971). No further details of the study were provided. 3.1.3. Hamsters Drew et al. (1975) examined the inhalation toxicity of BCME using male Syrian golden hamsters (~6 weeks old). The generation and measurement of BCME vapor, as well as the evaluation of lung damage was conducted as in the rat studies (see Section 3.1.1.), except that a lung-to-body weight ratio of 0.8 was considered elevated for hamsters. In an acute lethality experiment, hamsters (10/concentration) were exposed for 7 h to BMCE at 0.94-74 ppm and observed for 14 days. Mortality was increased at ≥4.6 ppm, and the 14-day LC50 was 7 ppm. All animals given BCME at ≥9 ppm died within 14 days. Animals had concentration-dependent increases in relative lung weights and damaged lungs (congestion, edema, and hemorrhage). The results are summarized in Table 1-8. TABLE 1-8 Mortality, Lung-to-Body Weight Ratio, and Estimated LC50 in Hamsters Exposed to bis-Chloromethyl Ether for 7 Hours Concentration Mortality at Increased Lung-to-Body (ppm) 14 d (%) Weight Ratioa (%) Estimated LC50b 74 100 100 7 ppm 19 100 100 9 100 100 7.3 60 90 6.2 10 90 4.6 10 100 0.94 0 10 a Relative lung weight is greater than the control mean plus 3 standard deviations. b LC50 values were estimated graphically by the study authors. Source: Adapted from Drew et al. 1975.

28 Acute Exposure Guideline Levels The long-term effect of single 7-h exposures to BCME at 0.7, 2.1, 5.6, or 9.9 ppm was examined in hamsters (25/concentration) by Drew et al. (1975). The animals were observed for their lifetimes. The study results were reported in terms of percentage of findings per number of observations, as shown in Table 1-9. At concentrations of ≥2.1 ppm, animals had severe life shortening (first death during week 4), weight loss, and high lung-to-body weight ratios, as well as lung edema, congestion, and hemorrhage and tracheal and bronchial hyper- plasia (often atypical). The incidence of the mucosal histopathologic changes was tabulated for only the 2.1-ppm exposure group, although the study also re- ported that four of five hamsters exposed at 5.6 ppm had squamous metaplasia of the tracheal epithelium. Animals exposed to BCME at 0.7 ppm had respira- tory pathologic changes similar to those of controls, although there was an in- crease in the incidence of pneumonitis (67% vs. 23% in controls), and a few animals had bronchial hyperplasia (two animals with atypia), alveolar squamous metaplasia, and bronchoalveolar metaplasia. TABLE 1-9 Median Lifespan, Lung-to-Body Weight Ratio, and Histopathoglogic Findings in Hamsters Exposed to bis-Chloromethyl Ether for 7 Hours Increased Lung- Histopathologic Findings in the Lung Concentration Median to-Body Weight Mucosa (%) (as of number of (ppm) Lifespan (d) Ratioa (%) observations [obs])b 9.9 4 68 Not specified 5.6 16 100 Not tabulated; stated 4/5 animals examined had tracheal epithelium squamous metaplasia 2.1 68 100 Tracheal [obs = 17]: hyperplasia (76), with atypia (18) Broncheal [obs = 12]: hyperplasia (58), with atypia (33) 0.7 657 100 Not tabulated; reported increased pneumonitis (67% vs. 23% in controls; incidences not given), and few animals had bronchial hyperplasia (± atypia), alveolar or bronchoalveolar metaplasia. Control 675 0 Tracheal [obs = 23]: hyperplasia (18) Broncheal [obs = 25]: hyperplasia (4) a Relative lung weight is greater than the control mean plus 3 standard deviations. b Report does not state how the “number of observations” was determined, relative to the original 25 animals per dose group. Source: Adapted from Drew et al. 1975.

bis-Chloromethyl Ether 29 Groups of 50 hamsters were exposed 1, 3, 10, or 30 times to BCME for 6 h at 1 ppm (Drew et al., 1975). The study results were reported in terms of percentage of findings per number of observations, but it was not clear how the “number of observations“ was determined relative to the initial 50 animals/group. All groups receiving 3, 10, or 30 exposures had increased mortality compared with controls. Treated hamsters had generally concentration-related increases in the incidence of tracheal and bronchial hyperplasia and squamous metaplasia (with and without atypia), with minor increases evident after a single exposure (see Table 1-10). Several other findings were reported in the 1-, 3-, and 10-exposure groups. Animals given 10 exposures had bronchoalveolar metaplasia (4/26; one atypical), bronchoalveolar squamous metaplasia with atypia (1/26), and atypical alveolar epithelium (4/26). One hamster given three exposures had turbinate mucosa metaplasia, and one hamster that died 756 days after three exposures had an early nasal esthesioneuroepithelioma. Animals exposed once had bronchoal- veolar metaplasia (1/24), atypical alveolar epithelium (1/24), and one animal that died after 1,000 days had an undifferentiated malignant nose tumor. Central nervous system effects and extreme irritability were seen in animals given 10 or 30 exposures; subarachnoid hemorrhage was seen microscopically in 8% of the hamsters given 30 exposures. TABLE 1-10 Median Lifespan and Histopathologic Findings in Hamsters Exposed to bis-Chloromethyl Ether at 1 ppm for 6 Hours Number Median Histopathologic Findings in the Lung Mucosa (%) (as of Exposures Lifespan (d) number of observations [obs])a 30 42 Tracheal [obs = 18]: hyperplasia (67), with atypia (6); squamous metaplasia (44) Broncheal [obs = 10]: hyperplasia (60), with atypia (40) 10 137 Tracheal [obs = 30]: hyperplasia (70), with atypia (33); squamous metaplasia (20) Broncheal [obs = 30]: hyperplasia (50), with atypia (20); squamous metaplasia (7) 3 471 Tracheal [obs = 39]: hyperplasia (21), with atypia (13) Broncheal [obs = 40]: hyperplasia (20), with atypia (8); squamous metaplasia (0), with atypia (0) 1 620 Tracheal [obs = 31]: hyperplasia (16), with atypia (3); squamous metaplasia (3) Broncheal [obs = 40]: hyperplasia (13), with atypia (3) Control 675 Tracheal [obs = 23]: hyperplasia (18) Broncheal [obs = 25]: hyperplasia (4) a Report does not state how the “number of observations” was determined, relative to the original 50 animals per dose group. Source: Adapted from Drew et al. 1975.

30 Acute Exposure Guideline Levels 3.2. Nonlethal Toxicity 3.2.1. Rats Three multiple-exposure rat studies in which carcinogenicity was an end point are detailed in Section 3.5.1. (Kuschner et al. 1975; Leong et al. 1975, 1981; Dulak and Snyder 1980). 3.2.2. Mice In an upper respiratory tract screening assessment (Alarie 1966) with strain A/Heston male mice, 60-sec exposure to BCME was nonirritating at concentrations as high as 10.6 ppm (Leong et al. 1971). No further details of the experiment were given. However, in the screening technique, mice are typically placed in body plethysmographs and a decrease in their breathing rate during the 60-sec exposure or during the ensuing 15-min observation period is considered indicative of irritation. Two multiple-exposure carcinogenicity studies conducted by Leong et al. (1971, 1981) are summarized in Section 3.5.2. 3.2.3. Hamsters A multiple-exposure study of BCME in hamsters (Kuschner et al. 1975) is described in Section 3.5.3. 3.3. Developmental and Reproductive Effects No studies were found assessing developmental or reproductive effects of BCME on animals. 3.4. Genotoxicity BCME was mutagenic in Salmonella typhimurium TA100, but not in TA1535, TA1538, or TA98 in a plate incorporation assay when tested at a con- centration of 20 μg/plate, with activation (Anderson and Styles 1978). Another laboratory found that exposure to BCME at 0.5 μL per 2,000 cm3 in the absence of metabolic activation was weakly mutagenic in S. typhimurium TA1535 (Norpoth et al. 1980). BCME was found to be mutagenic in Escherichia coli and S. typhimurium by Mukai and Hawryluk (1973), but experimental details were not provided. A 6.6-fold increase in the frequency of transformed cells occurred in BHK-21 cells cultured with BCME at 0.008-25 mg/mL in the presence of exogenous activation (Styles 1978).

bis-Chloromethyl Ether 31 Chromosome aberrations were not induced in the bone marrow cells of Sprague-Dawley rats examined 5 days after being exposed by inhalation to BCME at 1-100 ppb for 6 h/day, 5 days/week for 6 months (Leong et al. 1981). DNA synthesis was inhibited in the epidermis of mice for up to 24 h after dermal exposure to BCME at 9 or 18 μmols, as detected by radiolabeled thymidine, cytidine, or leucine administered after treatment. RNA synthesis was increased maximally after 12 h (Slaga et al. 1973). Goldschmidt et al. (1975) showed that BCME binds to DNA at guanine and adenine residues in vitro. However, in other in vitro studies, BCME did not form any isolable discrete base-alkylation products (assessed by thin-layer chromatography) and had no effect on the λ max, Tm, and buoyant density of salmon sperm DNA (Van Duuren et al. 1969, 1972). 3.5. Chronic Toxicity and Carcinogenicity 3.5.1. Rats Male Sprague-Dawley rats (70) were exposed to BCME at 0.1 ppm for 6 h/day, 5 days/week, for their lifetimes (Kuschner et al. 1975). Animals were exposed in a 1.3-m3 chamber, and air concentrations of BCME were measured at 30-min intervals using the coupling agent 4-(p-nitrobenzyl) pyridine. Because mortality was high (43% after 80 exposures [16 weeks]), additional groups of rats were exposed to BCME at 0.1 ppm for a total of 10, 20, 40, 60, 80, or 100 exposures and observed until death (20-50 animals per concentration). A control group of 240 rats was included, but only the mortality results were given for this group. The lungs were examined microscopically, and the nose was also examined once the first nasal tumor was found. Twenty animals from the chronic study were removed after 80 exposures and added to the limited- exposure 80-exposure group to determine cancer incidence. Rats given ≥80 exposures had shortened lifespan and deceased weight gain. In the limited-exposure study, mortality after 80 exposures was about half of that in the initial chronic study, for unknown reasons. Animals given 10-100 exposures had 40 nasal and lung cancers; 17 nasal esthesioneuroepitheliomas, 13 lung squamous-cell carcinomas, four poorly differentiated nasal-epithelial tumors, two nasal adenocarcinomas, and one each of lung adenocarcinoma, malignant olfactory tumor, ganglioneuroepithelioma, and nasal squamous-cell carcinoma. Only one rat (100 exposures) had both cancer types. The median induction time for all tumors was 440 days, and it was determined that there was a probability of ≤1% of developing a tumor before exposure for 210 days. When the survival cutoff of 210 days was used, a clear concentration-response rela- tionship was seen in animals given 10-100 exposures. The shortest number of exposures that resulted in cancer was 10. In that case, a nasal adenocarcinoma was found in one rat that died after 652 days. It is possible that some early nasal tumors were missed because the nose was not dissected in animals that died

32 Acute Exposure Guideline Levels early in the study. Information on controls was not provided by Kuschner et al. (1975), but the incidence of cancer was given as 0/240 in the EPA (2002) Integrated Risk Information System (IRIS) carcinogenicity risk assessment. The limited-exposure study results, summarized in Table 1-11, were used by EPA (2002) to derive a cancer slope factor and unit risk for BCME (see Appendix B). TABLE 1-11 Median Lifespan and Respiratory Cancers in Rats after Limited Exposures to bis-Chloromethyl Ether at 0.1 ppm Number of Rats At Number Median ≥210 d of Lifespan At with Cancer Types Exposures (wk) At start ≥210 d cancer (%) (number of affected animals) 100 50 30 20 12 (60.0) Nose: ENE (3), unclassified malignant tumor (1), PD epithelial tumor (1) Lung: squamous-cell carcinoma (8) 80 43 30 + 20a 34 15 (44.1) Nose: ENE (9), squamous-cell carcinoma (1), ganglioneuroepithelioma (1), PD epithelial tumor (1) Lung: squamous-cell carcinoma (3) 60 61 20 18 4 (22.2) Nose: ENE (2) Lung: squamous-cell carcinoma (2) 40 71 20 18 4 (22.2) Nose: ENE (2), PD epithelial tumor (1) Lung: adenocarcinoma (1) 20 69 50 46 3 (6.5) Nose: ENE (1), PD epithelial tumor (1), adenocarcinoma (1) 10 69 50 41 1 (2.4) Nose: adenocarcinoma (1) 0 66 240 NRb NRb NRb (none) a Twenty animals from the chronic-exposure study were removed after 80 exposures and added to this group to determine cancer incidence. b The incidence of rats with respiratory cancers was not specified in the study, but was reported as 0/240 in EPA (2002). Abbreviations: ENE, esthesioneuroepithelioma; NR, not reported; PD, poorly differ- entiated. Source: Adapted from Kuschner et al. 1975.

bis-Chloromethyl Ether 33 Leong et al. (1975, 1981) attempted to determine whether there is a non- tumorigenic or NOEL for BCME inhalation in rodents. Groups of 120 male rats (Sprague-Dawley Specific Pathogen-free) were exposed to BCME at 0, 1, 10, or 100 ppb for 6 h/day, 5 days/week for 6 months (129 exposures), followed by lifetime observation. Some animals were sacrificed after 6 months for pulmonary exfoliative cytologic examination on day 1 of the post-exposure period, and cytogenetic evaluation of bone marrow chromosomes on day 5 postexposure. Tests were performed in a 3.7-m3 stainless steel chamber where concentrated vapor was delivered via a dual syringe pump and the BCME concentration was measured at least once daily. Parameters assessed included periodic and terminal body weights, gross and microscopic pathology, organ weights, hematology (packed cell volume, mean hemoglobin concentration, red- and white-blood-cell count, and differential white-blood-cell count). No treatment-related non- neoplastic gross or microscopic changes, effects on hematology, organ weights, bone marrow cell chromosome integrity, or pulmonary exfoliated cells were seen in any group of rats. Neither respiratory tumors nor increased mortality occurred in rats or mice exposed to BCME at 1 or 10 ppb. Rats exposed to BCME at 100 ppb, however, had increased (tumor-related) mortality starting at the seventh experimental month (1 month postexposure) and all died or were euthanized by the nineteenth experimental month. Most of the 100-ppb rats developed esthesioneuroepitheliomas (96/111; 86.5%), of which four also had pulmonary adenoma. The tumors were frequently found 2-7 months postexposure, with the first case occurring during the sixth month of exposure. Many of the animals had a distended gastrointestinal-tract lumen secondary to the nasal obstruction and subsequent mouth breathing. Male Sprague-Dawley rats (number not specified) were exposed by inhalation to BCME at 0.1 ppm for 30 exposures (6 h/day, 5 days/week) with lifetime follow-up (Dulak and Snyder 1980). Approximately 35% of the animals died with respiratory tract tumors, which were first observed 350 days after exposure. 3.5.2. Mice A/Heston male mice (47) were exposed to BCME at 1 ppm for 6 h/day, 5 days/week, for 82 times over 27 weeks, after which they were sacrificed (Leong et al. 1971). Testing was performed in 100-L acrylate plastic chambers, and BCME vapor was generated by metering liquid BCME into the airstream entering the exposure chamber; the analytic concentration inside the chamber was not measured. The lungs of all the treated animals, as well as the 49 control males (exposed to filtered room air for 28 weeks) were examined histologically. Compared with untreated controls, the BCME-exposed mice had an increased incidence (55% vs. 41% for controls) and multiplicity (5.2 vs. 2.2 for controls)

34 Acute Exposure Guideline Levels of lung adenomas. These mice had body weight loss, respiratory distress, and 37/50 died during the exposure period. Gross necropsy revealed 27/47 animals with lung tumors and 11/47 with pinpoint hemorrhages or patchy consolidation in the lungs. Leong et al. (1981) exposed groups of 144-157 male Ha/ICR mice to BCME at 0, 1, 10, or 100 ppb for 6 months (129 exposures) followed by lifetime observation to determine whether there is a non-tumorigenic or no-observable- effect level for BCME inhalation. Animals were exposed for 6 h/day, 5 days/week, in a 3.7-m3 stainless steel chamber where concentrated vapor was delivered via a dual syringe pump and the chamber BCME concentration was measured at least once daily. Parameters assessed included periodic body weights and terminal gross and microscopic pathology. All groups had ascending urinary tract infections, which “may have been aggravated by exposure to BCME.” No treatment-related toxic or neoplastic effects were seen in mice exposed at 1 or 10 ppb. However, when mice that died prematurely from urinary tract infections were excluded from analysis, the 100-ppb group had increased mortality and incidence of pulmonary adenomas (8/27 vs. 9/86 for controls). No nasal tumors were seen. Leong et al. (1981) concluded that “10 and 1 ppb appear to be the no-observable-effect-levels for a 6-month exposure period.” 3.5.3. Hamsters Male Syrian golden hamsters (100) were exposed to BCME at 0.1 ppm for 6 h/day, 5 days/week, for their lifetimes (Kuschner et al. 1975). Mortality was increased after 20 weeks and one hamster that received 334 exposures developed an undifferentiated lung carcinoma and died on day 501 (Kuschner et al. 1975). 3.5.4. Carcinogenicity by Other Exposure Routes BCME is also shown to be a carcinogen by other routes of exposure. Application of BCME (2 mg in 0.1 mL benzene) to the skin of female ICR/Ha Swiss mice three times per week for 325 days caused papillomas in 13 of 20 mice, 12 of which became squamous-cell carcinomas (Van Duuren et al. 1968, 1972). A single dermal application of BCME (1 mg in 0.1 mL benzene) had no effect, but when followed by promotion with acetone/phorbol esters, papilloma developed in five of 20 mice, two of which progressed to squamous-cell carcinoma (Van Duuren et al. 1972). Other investigators also showed that BCME (1 mg applied dermally) was a potent tumor initiator in mice (Slaga et al. 1973; Zajdela et al. 1980). Newborn ICR-Swiss mice (50/sex) injected subcutaneously with BCME at 0.0125 mg/kg in peanut oil had a 45% incidence

bis-Chloromethyl Ether 35 and 0.64 multiplicity of pulmonary adenomas at the 6-month sacrifice, and two mice developed papilloma or fibrosarcoma at the injection sites (Gargus et al. 1969). The vehicle control had a 15% incidence and 0.14 multiplicity of lung tumors. Female Sprague-Dawley rats (20) injected with BCME subcutaneously once weekly for 300 days at 1 or 3 mg in Nujol developed local fibromas (2/20) and fibrosarcomas (5/20), but there was no increase in distal tumors or any tumors in rats injected with the solvent only (Van Duuren et al. 1969). ICR/HA Swiss mice (Van Duuren et al. 1975) and XVIInc/Z mice (Zajdela et al. 1980) injected subcutaneously with 0.3 mg of BCME in Nujol once weekly for over a year developed a high incidence (~40%) of sarcomas at the injection site. Van Duuren et al. (1975) also found one sarcoma (1/50 mice) in the Nujol-only controls, and Zajdela et al. (1980) found pulmonary adenomas in 7of 57 mice. Female ICR/HA Swiss mice that received weekly intraperitoneal injections of BCME (0.0.02 mg in 0.05 mL of Nujol) for 537 days developed local sarcomas (4/30) and had a decreased median survival time; no sarcomas were found in the Nujol-treated or untreated controls (Van Duuren et al. 1975). 3.6. Summary Rats and mice had no apparent irritation from exposure to BCME at con- centration greater than those producing carcinogenicity or toxicity. The LC50 of BCME for rats and hamsters, based on a 7-h exposure and 2-week observation period, was about 7 ppm for both species (Drew et al. 1975). An examination of the long-term effects of a single 7-h exposure of BCME at 0.7-9.5 ppm in rats and hamsters showed that some pathologic changes of the respiratory system occurred at even the lowest concentration, although overt treatment-related toxicity and increased mortality occurred at concentration of ≥2.1 ppm (tracheal epithelial hyperplasia in rats and pneumonitis in hamsters) (Drew et al. 1975). Rats and hamsters given 1, 3, 10, or 30 six-hour exposures to BCME at 1 ppm had generally exposure-related increases in the incidence of tracheal and bronchial hyperplasia and squamous metaplasia, and mortality was increased with ≥3 exposures (Drew et al. 1975). Rats, mice, and hamsters exposed by inhalation to BCME at 0.1 ppm for as few as 10 six-hour exposures developed respiratory tumors or had shortened lifetimes (Kuschner et al. 1975; Leong et al. 1975, 1981; Dulak and Snyder 1980). No treatment-related non-neoplastic or neoplastic effects were seen in rats or mice exposed to BCME at 1 or 10 ppb for 6 h/day for 6 months (Leong et al. 1975, 1981). No studies were located assessing developmental or reproductive effects of BCME in animals. BCME was mutagenic in several strains of S. typhimurium, increased the transformation frequency of BHK-21 cells, inhibited DNA synthesis, and was shown to bind DNA, but did not induce chromosome aberrations in rat bone marrow. Summaries of BCME single-exposure and multiple-exposure animal studies are presented in Table 1-12 and Table 1-13, respectively.

36 Acute Exposure Guideline Levels TABLE 1-12 Animal Studies of Single Exposure to bis-Chloromethyl Ether Exposure Concentration Species Duration (ppm) Effects (Reference) Rat 4h 7.8, 15.6 14-d LC50 = 10.26 ppm; 1/6 died at 7.8 ppm (day 14) and 6/6 died at 15.6 ppm (day 2, 4, 7). Decedents had lung hemorrhage and blood in the intestines. Survivors had morphologic lung changes (“consolidated” or “greatly enlarged” areas) (Union Carbide 1968; Smyth et al. 1969). Rat 3 min Saturated Irritation and prostration; 6/6 died (Union Carbide 1968). 8 min (~40,000) Rat 3 min Saturated 12/12 died; mucous membrane irritation, milky opacity (~40,000) of the cornea, narcosis, and dyspnea (Zeller and Hoffmann 1973). Rat 7h 0.94,4.6, 6.2, 14-d LC50 = 7 ppm; 100% mortality at ≥9 ppm (most 7.3, 9, 19, 74 on day 2). Extensive lung congestion, edema, and hemorrhage, and increased lung-to-body weight ratio (Drew et al. 1975). Rat 7h 0.7, 2.1, At 0.7 ppm, increase in tracheal epithelial hyperplasia; 6.9, 9.5 at >2.1 ppm, shortened lifespan, weight loss, increased lung-to-body weight ratio, lung edema, congestion, hemorrhage, tracheal and bronchial hyperplasia (+ nuclear atypia), and squamous metaplasia (Drew et al. 1975). Rat 15 min 14.4, 32.5, Lacrimation at all concentrations; RD50 = 145 ppm 49.8, 82.8, (calculated); red nasal discharge at ≥125 ppm; severe 125, 233 weight loss and increasing mortality at ≥82.8 ppm (48 h after exposure) (Gardner et al. 1985). Mouse 6h 2.7-10.6 14-d LC50 = 5.3 ppm; no respiratory-tract irritation (Leong et al. 1971). Mouse 60 sec ≤10.6 No decrease in breathing rate during exposure or 15-min observation period (Leong et al. 1971). Hamster 7h 0.94, 4.6, 6.2, 14-d LC50 = 7 ppm; mortality increased at ≥4.6 ppm; 7.3, 9, 19, 74 increased relative lung weights and damaged lungs (congestion, edema, and hemorrhage) (Drew et al. 1975). Hamster 7h 0.7, 2.1, At 0.7 ppm, increased pneumonitis and some alveolar 5.6, 9.9 changes; at ≥2.1 ppm, shortened lifespan, weight loss, increased lung-to-body weight ratio, lung edema, congestion, hemorrhage, and tracheal and bronchial hyperplasia (often atypical) (Drew et al. 1975).

bis-Chloromethyl Ether 37 TABLE 1-13 Animal Studies of Multiple Exposures to bis-Chloromethyl Ether Exposure Concentration Species Duration (ppm) Effects (Reference) Rat 1×6h 1 1 exposure: alveolar changes 3×6h 3 or more exposures: increased mortality; 10 × 6 h tracheal and bronchial hyperplasia and squamous 30 × 6 h metaplasia; central nervous system effects; extreme irritability 10 or 30 exposures: subarachnoid hemorrhage (Drew et al. 1975) Rat 6 h/d, 0.001, No effects at 1 or 10 ppb. At 100 ppb, increased 5 d/wk, 0.01, 0.1 death from month 7; all died or were killed by 6 mo month 19; some had pulmonary adenoma; most (129 exp.) had esthesioneuroepitheliomas (Leong et al. 1975, 1981). Rat 6 h/d, 5 d/wk 0.1 High mortality (43% after 80 exposures [16 wk]); for life discontinued after 80 exposures (Kuschner et al. 1975). Rat 10 × 6 h 0.1 ≥80 exposures had shortened lifespan and deceased 20 × 6 h weight gain; using survival cutoff of 210 days, 40 × 6 h concentration-response in tumor incidence 60 × 6 h from 10-100 exposures, primarily nasal 80 × 6 h esthesioneuroepithelioma and lung squamous 100 × 6 h cell carcinoma (Kuschner et al. 1975). Rat 6 h/d, 5 d/wk, 0.1 Approximately 35% mortality from respiratory-tract 6 wk (30 exp.) tumors, first observed 350 days after beginning exposure (Dulak and Snyder 1980). Mouse 6 h/d, 5 d/wk, 0.001, No effects at 1 or 10 ppb. At 100 ppb, increased 6 mo (129 exp.) 0.01, 0.1 mortality and incidence of pulmonary adenoma when mice that died early from urinary tract infections excluded (Leong et al. 1975, 1981). Mouse 6 h/d, 5 d/wk, 1 74% mortality; body weight loss; respiratory distress; 27 wk (82 exp.) lung hemorrhages or patchy consolidation; lung adenomas (Leong et al. 1971). Hamster 1×6h 1 1 exposures: alveolar changes; one undifferentiated 3×6h nasal tumor 10 × 6 h 3 or more exposures: increased mortality; tracheal 30 × 6 h and bronchial hyperplasia; squamous metaplasia 10-30 exposures: central nervous system effects; irritability 30 exposures: subarachnoid hemorrhage (Drew et al. 1975). Hamster 6 h/d, 5 d/wk 0.1 1/100 developed undifferentiated lung carcinoma for life after 334 exposures and died on day 501 (Kuschner et al. 1975).

38 Acute Exposure Guideline Levels 4. SPECIAL CONSIDERATIONS 4.1. Metabolism and Disposition No information was found in the literature regarding BCME metabolism. BCME is hydrolyzed within 10-60 sec in water to form HCl and formaldehyde, with about 20% of the original compound remaining at equilibrium (Van Duuren et al. 1972; Van Duuren 1980). Consistent with its in situ hydrolysis, the respiratory tract is the primary site of BCME toxicity and carcinogenicity after inhalation, and the skin is the target organ after dermal application and subcutaneous injection in humans and animals. Whether BCME or its hydrolysis products are metabolized in vivo, or to what extent any such metabolites contribute to its toxicity and carcinogenicity, is unknown. 4.2. Mechanism of Toxicity The mechanism of BCME toxicity and carcinogenicity has not been de- termined. The chemical structure of BCME predicts that it would be an alkylat- ing agent, which is consistent with its ability to react in vitro with the guanine and adenine of calf thymus DNA (Goldschmidt et al. 1975), its mutagenicity in the Ames test, and its carcinogenicity in animals and humans. This is inconsis- tent, however, with other in vitro studies in which BCME did not form any iso- lable discrete base-alkylation products detected by thin-layer chromatography, or have any effect on the λ max, Tm, and buoyant density of salmon sperm DNA (Van Duuren et al. 1969, 1972). 4.2. Mechanism of Toxicity The mechanism of BCME toxicity and carcinogenicity has not been de- termined. The chemical structure of BCME predicts that it would be an alkylating agent, which is consistent with its ability to react in vitro with the guanine and adenine of calf thymus DNA (Goldschmidt et al. 1975), its mutagenicity in the Ames test, and its carcinogenicity in animals and humans. This is inconsistent, however, with other in vitro studies in which BCME did not form any isolable discrete base-alkylation products detected by thin-layer chromatography, or have any effect on the λ max, Tm, and buoyant density of salmon sperm DNA (Van Duuren et al. 1969, 1972). 4.3. Structure-Activity Relationships The chemical most related to BCME is CMME. BCME was more toxic and carcinogenic than technical grade CMME in all studies, although CMME

bis-Chloromethyl Ether 39 odor was more readily detected (Rohm and Haas, personal communication, Feb. 1998). Comparison of LC50 values for CMME and BCME in rats and hamsters (55-65 ppm for CMME; 7 ppm for BCME) indicates that BCME is more acutely toxic by inhalation than CMME (Drew et al. 1975). Animal carcinogenesis studies indicate that BCME is at least 10-fold more potent a carcinogen than CMME, both by inhalation (Drew et al. 1975; Kuschner et al. 1975; Laskin et al. 1975) and by dermal application and subcutaneous injection (Van Duuren et al. 1968, 1969; Gargus et al. 1969). It has been reported that the higher carcinogenic potency of BCME compared with CMME is not due to the potential of cross-linking DNA strands by BCME (Burchfield and Storrs 1977). The reason is that the reactive groups of a bifunctional alkylating agent should be able to reach across approximately 8Å, and the distance between the reactive halogens in BCME is too short for cross- linking to be likely or possible. When the chlorine and oxygen atoms are separated in structurally- related chloroethers by two or more carbon atoms (e.g., bis(β-chloroethyl) ether), the alkylating power and carcinogenicity are greatly reduced (Burchfield and Storrs 1977), whereas eye irritation seems to be unaffected by chain length (Kirwin and Galvin 1993). 4.4. Other Relevant Information 4.4.1. Species Variability The study by Drew et al. (1975) indicated little variability in the acute tox- icity of BCME between species. The 7-h LC50 for both rats and hamsters was 7 ppm. A similar 6-h LC50 of 5.3 ppm for mice was reported by Leong et al. (1971). 4.4.2. Concentration-Exposure Duration Relationship No data were available from which to determine the concentration-time relationship for BCME-related toxic effects. ten Berge et al. (1986) determined that the concentration-time relationship for many irritant and systemically acting vapors and gases may be described by Cn × t = k, where the exponent n ranges from 0.8 to 3.5. To obtain protective AEGL-2 and AEGL-3 values for durations of 30-480 min (AEGL-1 values were not derived), scaling across time was performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points than the exposure duration in the key study. Extrapolations were not used to determine 10-min values because the National Advisory Committee judged that extrapolation from ≥4 h to 10 min has unacceptably large inherent uncertainty. The 30-min value is adopted for 10-min value to be protective of human health.

40 Acute Exposure Guideline Levels 5. RATIONALE AND PROPOSED AEGL-1 5.1. Human Data Relevant to AEGL-1 No studies were identified that could be used to develop AEGL-1 values. BCME has poor warning properties, and has caused severe eye damage in humans several hours after exposure at concentrations that were not perceived (<3 ppm) (Travenius 1982). 5.2. Animal Data Relevant to AEGL-1 No relevant studies were found because toxicity exceeding the severity of AEGL-1 occurred at concentrations that did not produce sensory irritation. A decrease in the breathing rate of A/Heston male mice, indicative of respiratory irritation, was not observed after inhalation of BCME at concentrations up to 10.6 ppm for 60 sec, although mortality was observed at that concentration after a 6-h exposure (LC50 of 5.3 ppm) (Leong et al. 1971). 5.3. Derivation of AEGL-1 AEGL-1 values are not recommended because no studies were available in which toxicity was limited to AEGL-1 effects. Effects exceeding the severity of AEGL-1 effects occurred at concentrations that did not produce sensory irritation in humans or animals. 6. RATIONALE AND PROPOSED AEGL-2 6.1. Human Data Relevant to AEGL-2 No human data were located that were appropriate for derivation of AEGL-2 values. 6.2. Animal Data Relevant to AEGL-2 The studies considered relevant for derivation of AEGL-2 values included the following:  The 14-day LC50 study of Drew et al. (1975), in which male Sprague- Dawley rats and Syrian golden hamsters were exposed to BCME at 0.94-74 ppm for 7 h and observed for 14 days. At the lowest test concentration of 0.94 ppm, no mortality occurred, and both species had increased lung-to-body weight ratios (40% of rats and 10% of hamsters), lung congestion, edema, and

bis-Chloromethyl Ether 41 hemorrhage. An adjustment factor of 3 was used to estimate an NOAEL of 0.31 ppm for lung lesions, which could be a point-of-departure for developing AEGL-2 values.  The Drew et al. (1975) study which examined the long-term effects of a single 7-h exposure to BCME at 0.7, 2.1, 6.9, and 9.5 ppm in rats and 0.7, 2.1, 5.6, and 9.9 ppm in hamsters. At 0.7 ppm, both species had increased lung-to- body weight ratios (96% rats; 100% hamsters), and there was an increased incidence of tracheal epithelial hyperplasia in rats (67% vs. 36% in controls) and of pneumonitis in hamsters (67% vs. 23% in controls). The respiratory lesions were considered irreversible because they were seen after lifetime observation. At ≥2.1 ppm, both species had increased mortality and lung lesions. The lowest- observed-adverse-effect level (LOAEL) of 0.7 ppm can be divided by an adjustment factor of 3 to estimate a NOAEL of 0.23 ppm for lung lesions as a point-of-departure for developing AEGL-2 values.  The single-exposure scenario of the Drew et al. (1975) study in which rats and hamsters were subjected to 1, 3, 10, or 30 six-hour exposures of BCME at 1 ppm followed by lifetime observation. After one exposure, rats and hamsters had slightly increased incidences of alveolar, tracheal, or bronchial transformation. An adjustment factor of 3 was used to estimate a NOAEL of 0.33 ppm for lung lesions, which could be a point-of-departure for developing AEGL-2 values.  The respiratory inhibition study in which male Crl-CD rats were exposed head-only for 15 min to BCME at 14-233 ppm (Gardner et al. 1985). Lacrimation occurred at all test concentrations and exposure to ≥82.8 ppm caused severe weight loss and mortality during the 48-h observation period. AEGL-2 values could be based on exposure for 15 min to 14.4 ppm, which caused 14% respiratory inhibition and lacrimation, which could impede the ability to escape. However, 14 ppm might cause toxicity exceeding the severity of AEGL-2, on the basis of reports that the highest tolerable BCME air concentration for humans is 5 ppm (Travenius 1982), and that BCME was distinctly irritating at 3 ppm (Flury and Zernik 1931) (no exposure durations were specified in the two references). 6.3. Derivation of AEGL-2 The AEGL-2 values are based on the lowest LOAEL (0.7 ppm) for irreversible respiratory lesions in rats and hamsters (Drew et al. 1975), which was divided by 3 to estimate a NOAEL of 0.23 ppm. This point-of-departure is supported by two other single-exposure experiments by Drew et al. (1975) that had similar LOAELs for irreversible or serious lung lesions. No data were available from which to determine the BCME concentration-time relationship in order 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

42 Acute Exposure Guideline Levels exponent n ranges from 0.8 to 3.5. To obtain protective AEGL-2 values, scaling across time was performed using n = 3 for exposure durations shorter than 7 h and n = 1for exposure durations longer than 7 h. However, such extrapolation was not performed for the 10-min values because of unacceptably large inherent uncertainty; instead, the 30-min AEGL values were adopted for the 10-min val- ues to be protective of human health (see Section 4.2.2.). A total uncertainty factor of 10 was used. An uncertainty factor of 3 was applied for interspecies extrapolation because BCME caused a similar toxic response in two species at the same test concentration in the key study, and is expected to cause toxicity similarly in human lung. An uncertainty factor of 3 was applied for intraspecies variability as recommended by NRC (2001) for chemicals with a steep dose- response relationship (such as BCME), as the effects are unlikely to vary greatly among humans. Using the intraspecies default uncertainty factor of 10 would reduce the 4- and 8-h AEGL-2 values to below 0.010 ppm, which was shown to be a no-effect level after 129 exposures to BCME in rats and mice (6 h/day, 5 days/week) (Leong et al. 1981). The AEGL-2 values are shown in Table 1-14. Analytic methods are able to routinely detect concentrations of BCME below 1 ppb in the air (Collier 1972; Blease et al. 1989). An inhalation cancer slope factor for BCME was derived by EPA (2002). It was used to calculate the concentration of BCME associated with a 1 ×10-4 cancer risk from a single exposure to BCME for 30 min to 8 h, as shown in Appendix B. For exposures of 30 min and 1 h, the BCME concentrations predicted to cause a 1× 10-4 cancer risk are similar to the 30-min and 1-h AEGL- 2 values. For exposures of 4-8 h, BCME concentrations calculated to cause a 1 × 10-4 cancer risk are up to 5-fold lower than the AEGL-2 values. The noncarcinogenic end points were considered more appropriate for AEGL derivation because the data did not show that tumor formation could result from a single exposure. Additionally, a direct comparison of BCME cancer risk and AEGL values is of unknown validity because different methods are used to cal- culate the two sets of numbers (cancer risk calculation uses a linear extrapola- tion from 25,600 days to 0.5 to 8 h whereas AEGL values were extrapolated from a single 7-h exposure using either n = 3 or n = 1, and different uncertainties are addressed by the two methods). 7. RATIONALE AND PROPOSED AEGL-3 7.1. Human Data Relevant to AEGL-3 No appropriate human studies were available. 7.2. Animal Data Relevant to AEGL-3 The following studies were considered relevant for AEGL-3 derivation:

bis-Chloromethyl Ether 43 TABLE 1-14 AEGL-2 Values for bis-Chloromethyl Ether 10 min 30 min 1h 4h 8h 0.055 ppm 0.055 ppm 0.044 ppm 0.028 ppm 0.020 ppm (0.26 mg/m3) (0.26 mg/m3) (0.21 mg/m3) (0.13 mg/m3) (0.095 mg/m3)  The 14-day LC50 study by Drew et al. (1975), in which male Sprague- Dawley rats and Syrian golden hamsters were exposed to BCME at 0.94-74 ppm for 7 h and observed for 14 days. All dose groups of both species had increased lung-to-body weight ratios and extensive lung lesions, including congestion, edema, and hemorrhage. AEGL-3 values could be derived using the BMCL05 (benchmark concentration, 95% lower confidence limit with 5% response) of 3.7 ppm for hamsters and 4.2 for rats. BMC01 [benchmark concentration with 1% response] values were 4.1 and 4.7 ppm, respectively, which were obtained using the log/probit model from EPA’s Benchmark Dose Software, Version 1.3.2 (EPA 2005).  The study by Drew et al. (1975), which examined the long-term effects of a single 7-h exposure to BCME at 0.7, 2.1, 6.9, and 9.5 ppm in rats and 0.7, 2.1, 5.6, and 9.9 ppm in hamsters. At 0.7 ppm, rats had increased incidences of lung lesions but mortality was comparable to controls, whereas at ≥2.1 ppm, both species had increased mortality, weight loss, and lung lesions. The first deaths occurred during week 2 in rats and week 4 in hamsters. Exposure to BCME for 7 h to 0.7 ppm could be considered a NOEL for lethality.  The single-exposure scenario of the study in which rats and hamsters were subjected to 1, 3, 10, or 30 six-hour exposures of BCME at 1 ppm followed by lifetime observation (Drew et al. 1975). Rats and hamsters had slightly increased incidences of lung lesions after one exposure, whereas increased mortality and lung lesions were observed after three exposures. Exposure for 6 h to 1 ppm could be considered a NOEL for lethality.  The respiratory inhibition study in which male Crl-CD rats were exposed head-only for 15 min to BCME at 14.4, 32.5, 49.8, 82.8, 125, or 233 ppm (Gardner et al. 1985). Lacrimation occurred at all test concentrations, and exposure at ≥82.8 ppm caused severe weight loss and mortality during the 48-h observation period. AEGL-3 values could be based on exposure for 15 min to 49.8 ppm, which caused 37% respiratory inhibition and was the NOEL for increased mortality. This study has the drawback of an insufficient observation period, which could have missed treatment-related deaths.  The acute lethality study in which an LC50 of 5.3 ppm was obtained for A/Heston male mice given BCME at 2.7-10.6 ppm for 6 h and observed for 14 days (Leong et al. 1971). Data were not provided to be able determine a BMCL05 or BMC01, although an adjustment factor of 3 could be applied to the LC50 to estimate 1.8 ppm as an estimated NOEL for lethality from a 6-h exposure. However, 1.8 ppm is similar to 2.1 ppm, which caused lethality from a single 7-h exposure in a lifetime observation study (Drew et al. 1975).

44 Acute Exposure Guideline Levels 7.3. Derivation of AEGL-3 AEGL-3 values were derived from the single-exposure scenario of a study in which rats and hamsters were subjected to 1, 3, 10, or 30 six-hour exposures to BCME at 1 ppm followed by lifetime observation (Drew et al. 1975). Rats and hamsters had slightly increased incidences of lung lesions after one expo- sure, whereas increased mortality occurred after three exposures. This study was chosen because it had the highest concentration of BCME that was shown to not cause lethality after lifetime observation. The 7-h BMCL05 of 4.2 ppm for rats and 3.7 ppm for hamsters exceeded a concentration (2.1 ppm) that caused mortality in rats and hamsters from a single 7-h exposure in a lifetime observation study (Drew et al. 1975). Because no data were available from which to determine the BCME concentration-time relationship, scaling across time was performed as for AEGL-2 values, using n = 3 and n = 1 to for durations shorter and longer, respectively, than 6 h. The 10-min AEGL values were set equal to the 30-min values to be protective of human health (see Section 4.4.2.). A total uncertainty factor of 10 was used. An uncertainty factor of 3 was applied for interspecies extrapolation because the NOEL for lethality was the same in two species in the key study, and lethality is expected to occur by a similar mode of action in human and animals. An uncertainty factor of 3 was applied for intraspecies variability as recommended by NRC (2001) for chemicals with a steep dose-response relationship (such as BCME), as the effects are unlikely to vary greatly among humans. The resulting AEGL-3 values are shown in Table 1-15. 8. SUMMARY OF PROPOSED AEGLs 8.1. AEGL Values and Toxicity End Points AEGL-1 values were not recommended because effects exceeding the severity of AEGL-1 effects occurred at concentrations that did not produce sensory irritation in humans or animals. The AEGL-2 values were based on a study in which rats and hamsters were exposed for 7 h to BCME at 0.7-9.5 and 0.7-9.9 ppm, respectively, followed by lifetime observation (Drew et al. 1975). The lowest concentration tested of 0.7 ppm was a LOAEL for irreversible respiratory lesions, and an adjustment factor of 3 was applied to estimate a NOAEL of 0.23 ppm. This point-of-departure is supported by two other experiments by Drew et al. (1975) in which BCME caused irreversible or serious lung lesions. No data were available to determine the BCME concentration-time relationship, and AEGL-2 values for time periods other than 7 h were calculated using the ten Berge et al. (1986) equation Cn × t = k, with n = 3 and n = 1 for exposure durations shorter and longer, respectively, than 7 h. The 30-min values were adopted for the 10-

bis-Chloromethyl Ether 45 TABLE 1-15 AEGL-3 Values for bis-Chloromethyl Ether 10 min 30 min 1h 4h 8h 0.23 ppm 0.23 ppm 0.18 ppm 0.11 ppm 0.075 ppm (1.1 mg/m3) (1.1 mg/m3) (0.86 mg/m3) (0.52 mg/m3) (0.36 mg/m3) min values to be protective of human health (see Section .2.2.). A total uncertainty factor of 10 was used. An uncertainty factor of 3 was applied for interspecies extrapolation because BCME caused a similar toxic response in two species at the same test concentration in the key study, and is expected to cause toxicity similarly in human lung. An uncertainty 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. Using the intraspecies default uncertainty factor of 10 would reduce the 4- and 8-h AEGL-2 values to below 0.010 ppm, which was shown to be a no-effect level in a study of rats and mice exposed to BCME 6 h/day, 5 days/week, for a total of 129 exposures (Leong et al. 1981). AEGL-3 values were derived from the single-exposure scenario of a study in which rats and hamsters were subjected to 1, 3, 10, or 30 six-hour exposures to BCME at 1 ppm, followed by lifetime observation (Drew et al. 1975). After one exposure, rats and hamsters had slightly increased incidences of lung lesions, whereas three exposures caused lung lesions and increased mortality. This study was chosen because it had the highest concentration of BCME that was shown to not cause lethality after lifetime observation. Because no data were available from which to determine the BCME concentration-time relationship, scaling across time was performed as for AEGL-2 values. A total uncertainty factor of 10 was used. An uncertainty factor of 3 was applied for interspecies extrapolation because the NOEL for lethality was 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. An uncertainty 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 inhalation cancer slope factor for BCME was derived by EPA (2002). It was used to calculate the concentration of BCME associated with a 1 × 10-4 cancer risk from a single exposure for 30 min to 8 h, as shown in Appendix B. For exposures of 30 min and 1 h, the BCME concentrations predicted to cause a 1 × 10-4 cancer risk are similar to the 30-min and 1-h AEGL-2 values. For exposures of 4-8 h, BCME concentrations calculated to cause a 1 × 10-4 cancer risk are up to 5-fold lower than the AEGL-2 values. The noncarcinogenic end points were considered more appropriate for AEGL derivation because the data did not show that tumor formation could result from a single exposure. Additionally, the validity of comparing cancer risk and AEGL values is unknown because different methods are used to calculate the two sets of values

46 Acute Exposure Guideline Levels (the cancer-risk calculation involves a linear extrapolation from 25,600 days to 0.5 to 8 h whereas AEGL values were extrapolated from a single 7-h exposure using either n = 3 or n = 1, and different uncertainties are addressed by the two methods). A summary of the AEGL values for BCME is shown in Table 1-16. 8.2. Comparison with Other Standards and Criteria The existing standards and guidelines for BCME are shown in Table 1-17. OSHA, NIOSH, Germany, Austria, and Sweden have no permissible limits for BCME because it is a human carcinogen. A TLV-TWA of 0.001 ppm was adopted by the ACGIH and the Belgium based on the carcinogenic potential of BCME. A large chemical manufacturer in Philadelphia has developed internal Emergency Response Planning Guideline (ERPG) values (1-h exposure) for BCME of 1 ppb for the ERPG-2 and 100 ppb for ERPG-3 (no ERPG-1) (Rohm and Haas, personal communication, Feb. 1998). 8.3. Data Quality and Research Needs No studies of BCME had defined exposures and responses that fell within the scope of AEGL-1 severity. Perhaps a more sensitive, molecular-based assay could be developed to detect subclinical respiratory toxicity. Adequate single-exposure animal studies were available for derivation of AEGL-2 and AEGL-3 values. The AEGL-2 and AEGL-3 values were each supported by several studies with rats and hamsters. However, no relevant human studies were available that adequately documented exposures to BCME (time and concentration). TABLE 1-16 Summary of AEGLs Values for bis-Chloromethyl Ether Classification 10 min 30 min 1h 4h 8h AEGL-1 NRa NR NR NR NR AEGL-2 0.055 ppm 0.055 ppm 0.044 ppmb 0.028 ppmb 0.020 ppmb (0.26 mg/m3) (0.26 mg/m3) (0.21 mg/m3) (0.13 mg/m3) (0.095 mg/m3) AEGL-3 0.23 ppmb 0.23 ppmb 0.18 ppmb 0.11 ppmb 0.075 ppmb (1.1 mg/m3) (1.1 mg/m3) (0.86 mg/m3) (0.52 mg/m3) (0.36 mg/m3) a Not recommended (effects exceeding the severity of AEGL-1 effects occurred at con- centrations that did not produce sensory irritation in humans or animals). b These concentrations are estimated to have a cancer risk greater than 1 × 10-4, on the basis of an inhalation cancer slope factor derived by EPA (2002).

bis-Chloromethyl Ether 47 TABLE 1-17 Extant Standards and Guidelines for bis-Chloromethyl Ether Exposure Duration Guideline 10 min 30 min 1h 4h 8h AEGL-1 NRa NR NR NR NR AEGL-2 0.055 ppm 0.055 ppm 0.044 ppm 0.028 ppm 0.020 ppm AEGL-3 0.23 ppm 0.23 ppm 0.18 ppm 0.11 ppm 0.075 ppm b ERPG-1 (AIHA) Not derived ERPG-2 (AIHA) 0.1 ppm ERPG-3 (AIHA) 0.5 ppm PEL-TWA No valuec (OSHA)c REL-TWA No valued (NIOSH)d TLV-TWA 0.001 ppm (ACGIH)e MAK (Germany)f No valuef OELV-LLV No valueg (Sweden)g VLEP (Belgium)h 0.001 ppm a Not recommended (effects exceeding the severity of AEGL-1 effects occurred at con- centrations that did not produce sensory irritation in humans or animals). b ERPG (Emergency Response Planning Guidelines, American Industrial Hygiene Asso- ciation) (AIHA 2000, documented 9/1/87). ERPG-1 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing effects other than mild, transient adverse health effects or without perceiving a clearly defined objectionable odor. An ERPG-1 was not derived because of insufficient data. ERPG-2 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing irreversi- ble or other serious health effects or symptoms that could impair an individual’s ability to take protective action. The ERPG-2 for BCME is based on animal data, and was intended to be below 0.21 ppm, which was calculated to have a 1 × 10-4 excess cancer risk, and 0.7 ppm, which caused serious respiratory lesions in animals. ERPG-3 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing life- threatening health effects. The ERPG-3 for BCME is based on animal lethality data. c OSHA PEL-TWA (Occupational Safety and Health Administration, Permissible Expo- sure Limits - Time Weighted Average) (54 Fed. Reg. 2931[1989]) is defined analogous to the ACGIH TLV-TWA, but is for exposures of no more than 10 h/day, 40 h/week. A numeric value was not assigned, but OSHA identifies BCME as an occupational carcino- gen and workplace exposure is regulated by law (29 CFR 1910.1006 [1996]).

48 Acute Exposure Guideline Levels d NIOSH REL-TWA (National Institute of Occupational Safety and Health, Recom- mended Exposure Limits - Time Weighted Average) (NIOSH 2005) is defined analogous to the ACGIH TLV-TWA. A numeric value was not assigned, but NIOSH considers BCME to be an occupational carcinogen subject to Federal regulation (29 CFR 1910.1006 [1996]), and recommends that exposure to it be limited to the lowest feasible concentrations. e ACGIH TLV-TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value - Time Weighted Average) (ACGIH 2007) is the time-weighted average concentration for a normal 8-h workday and a 40-h workweek, to which nearly all workers may be repeatedly exposed, day after day, without adverse effect. BCME was classified as carcinogenicity category A1 (“confirmed human carcinogen”). f MAK (Maximale Arbeitsplatzkonzentration [Maximum Workplace Concentration]) (Deutsche Forschungsgemeinschaft -German Research Association (DFG 2002) is de- fined analogous to the ACGIH TLV-TWA. A value was not developed but BCME was classified as a human carcinogen (category 1). g OELV-LLV (Occupational Exposure Limit Value - Level Limit Value) (Swedish Work Environment Authority 2005) is defined analogous to the ACGIH TLV-TWA. A value was not developed but BCME is classified as Group A, a carcinogenic substance that may not be handled. h VLEP [Occupational Exposure Limit (valeurs limites d'exposition professionnelle)] (Ministry of Employment and Work, Belgium 2002) is defined analogous to the ACGIH TLV-TWA. BCME was classified as a carcinogenic substance. 9. REFERENCES ACGIH (American Conference of Government Industrial Hygienists). 1991. Bis(chloromethyl) ether. Pp. 292-293 in Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th Ed. American Conference of Government Industrial Hygienists, Cincinnati, OH. ACGIH (American Conference of Government Industrial Hygienists). 2007. Bis (chloromethyl) ether. In Documentation of TLVs and BEIs, 7th Ed. American Conference of Government Industrial Hygienists, Cincinnati, OH. Agrelo, C.E., and B.J. Severn. 1981. A simplified method for measuring scheduled and unscheduled DNA synthesis in human fibroblasts. Toxicology 21(2):151-158. AIHA (American Industrial Hygiene Association). 2000. Emergency Response Planning Guidelines: Bis(chloromethyl) ether. American Industrial Hygiene Association: Fairfax, VA. Alarie, Y. 1966. Irritating properties of airborne materials to the upper respiratory tract. Arch. Environ. Health 13(4):433-449. Albert, R.E., A.R. Sellakumar, S. Laskin, M. Kuschner, N. Nelson, and C.A. Snyder. 1982. Gaseous formaldehyde and hydrogen chloride induction of nasal cancer in the rat. J. Natl. Cancer Inst. 68(4):597-603. Anderson, D., and J.A. Styles. 1978. An evaluation of 6 short-term tests for detecting organic chemical carcinogens. Appendix 2. The bacterial mutation test. Br. J. Cancer 37(6):924-930. Blease, T.G., J.H. Scrivens, and W.E. Morden. 1989. The determination of atmospheric bis (chloromethyl) ether by gas chromatography/tandem mass spectrometry. Biol. Mass Spectrom. 18(9):775-779.

bis-Chloromethyl Ether 49 Burchfield, H.P., and E.E. Storrs. 1977. Organohalogen carcinogens. Pp. 319-371 in Advances in Modern Toxicology, Vol. 3. Environmental Cancer, H.F. Kraybill, and H.A. Mehlman, eds. New York: John Wiley and Sons. ChemSources. 2005. Chemical Sources International, Inc. [online]. Available: http:// www.chemsources.com [accessed March 2005]. Collier, L. 1972. Determination of bischloromethyl ether at the ppb level in air samples by high-resolution mass spectroscopy. Environ. Sci. Technol. 6(10):930-932. Collingwood, K.W., B.S. Pasternack, and R.E. Shore. 1987. An industry-wide study of respiratory cancer in chemical workers exposed to chloromethyl ethers. J. Natl. Cancer Inst. 78(6):1127-1136. Crump, K.S., and R.B. Howe. 1984. The multistage model with a time-dependent dose pattern: Applications to carcinogenic risk assessment. Risk Anal. 4(3):163-176. DFG (Deutsche Forschungsgemeinschaft). 2002. List of MAK and BAT Values 2002. Maximum Concentrations and Biological Tolerance Values at the Workplace Re- port No. 38. Weinheim, Federal Republic of Germany: Wiley VCH. Donaldson, H.M., and W.N. Johnson. 1972. Field Survey of Diamond Shamrock Chemical Company, NOPCO Chemical Division, Redwood City, California. NIOSH Report No. IWS 33.10. U.S. Department of Health, Education and Welfare, Public Health Service, Center for Disease Control, Cincinnati, OH. 7pp. 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. Dulak, N.C., and C.A. Snyder. 1980. The relationship between the chemical reactivity and the inhalation carcinogenic potency of direct-acting chemical agents. Proc. Am. Assoc. Cancer Res. 21:106 [Abstract No. 426]. EPA (U.S. Environmental Protection Agency). 2002. Bis(chloromethyl) Ether (BCME). Integrated Risk Information System, U.S. Environmental Protection Agency [online]. Available: http://www.epa.gov/iris/subst/0375.htm [accessed Oct. 20, 2011]. EPA (U.S. Environmental Protection Agency). 2005. Benchmark Dose Software. Version 1.3.2 U.S. Environmental Protection Agency, National Center for Environmental Assessment, Office of Research and Development: Washington, DC [online]. Available: http://www.epa.gov/ncea/bmds.htm [accessed March 2005]. Fishbein, G. ed. 1972. Chemical suspected in 6 cases of lung cancer. Occup. Health Saf. Lett. 2:1. Flury, F., and F. Zernik. 1931. Dichlordimethyläther. Pp. 360-361 in Schädliche Gase Dämpfe, Nebel, Rauch-, und Stauberten. Berlin, Germany: Verlag von Julius Springer. Frankel, L.S., K.S. McCallum, and L. Collier. 1974. Formation of bis(chloromethyl) ether from formaldehyde and hydrogen chloride. Environ. Sci. Technol. 8(4):356-359. Fujio, A., M. Kitano, T. Matsui, S. Asakura,and A. Tatsumi. 1986. Lung cancer due to exposure to bis (chloromethyl) ether [in Japanese]. Nihon Kyobu Shikkan Gakkai Zasshi 24(1):79-82. Gardner, R.J., B.A. Burgess, and G.L. Kennedy, Jr. 1985. Sensory irritation potential of selected nasal tumorigens in the rat. Food Chem. Toxicol. 23(1):87-92. Gargus, J.L., W.H. Reese, Jr., and H.A. Rutter. 1969. Induction of lung adenomas in newborn mice by bis(chloromethyl) ether. Toxicol. Appl. Pharmacol. 15:92-96. Goldschmidt, B.M., B.L. Van Duuren, and K. Frenkel. 1975. The reaction of 14C-labelled bis(chloromethyl)ether with DNA. Proc. Am. Assoc. Cancer Res. 16(1):66 [Abstract No. 263].

50 Acute Exposure Guideline Levels Gowers, D.S., L.R. DeFonso, P. Schaffer, A. Karli, C.B. Monroe, L. Bernabeu, and F.M. Renshaw. 1993. Incidence of respiratory cancer among workers exposed to chloromethyl-ethers. Am. J. Epidemiol. 137(1):31-42. HSDB (Hazardous Substances Data Bank). 2005. bis-Chloromethyl ether (CASRN 542- 88-1). TOXNET Specialized Information Services, U.S. National Library of Medicine: Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/ sis/htmlgen?HSDB [accessed Oct. 19, 2011]. IARC (International Agency for the Research on Cancer). 1974. bis(chloromethyl)ether. Pp. 231-238 in Some Aromatic Amines, Hydrazine and Related Substances, N- Nitroso Compounds and Miscellaneous Alkylating Agents. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans Vol. 4. Lyon, France: IARC. IARC (International Agency for the Research on Cancer). 1987. Pp. 119-120, 159-160 in Genetic and Related Effects: An Updating of Selected IARC Monographs from Volumes 1 to 42. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, Suppl. 6. Lyon, France: IARC. Kallos, G.J., and R.A. Solomon. 1973. Investigations of the formation of bis-chloromethyl ether in simulated hydrogen chloride-formaldehyde atmospheric environments. Am. Ind. Hyg. Assoc. J. 34(11):469-473. Kirwin, C.J., and J.B. Galvin. 1993. Ethers. Pp. 445-525 in Patty’s Industrial Hygiene and Toxicology, 4th Ed., Vol. 2A. G.D. Clayton, and F.E. Clayton, eds. New York: John Wiley & Sons. Kurian, P., S. Nesnow, and G.E. Milo. 1990. Quantitative evaluation of the effects of human carcinogens and related chemicals on human foreskin fibroblasts. Cell Biol. Toxicol. 6(2):171-184. Kuschner, R.T., S. Laskin, R.T. Drew, V. Cappiello,,and N. Nelson. 1975. Inhalation carcinogenicity of alpha halo ethers. III. Lifetime and limited period inhalation studies with bis(chloromethyl)ether at 0.1 ppm. Arch. Environ. Health 30(2):73- 77. Langner, R.R. 1977. How to control carcinogens in chemical production. Occup. Health Saf. (March/April):33-39. Laskin, S., R.T. Drew, V. Cappiello, M. Kuschner, and N. Nelson. 1975. Inhalation carcinogenicity of alpha halo ethers. II. Chronic inhalation studies with chloromethyl methyl ether. Arch. Environ. Health 30(2):70-72. Lemen, R.A., W.M. Johnson, J.K. Wagoner, V.E. Archer, and G. Saccomanno. 1976. Cytologic observations and cancer incidence following exposure to BCME. Ann. N.Y. Acad. Sci. 271:71-80. Leong, B.K., H.N. Macfarland, and W.H. Reese, Jr. 1971. Induction of lung adenomas by chronic inhalation of bis(chloromethyl)ether. Arch. Environ. Health 22(6):663-666. Leong, B.K., R.J. Kociba, G.C. Jersey, and P.J. Gehring. 1975. Effects from repeated inhalation of parts per billion of bis(chloromethyl)ether in rats [Abstract]. Toxicol. Appl. Pharmacol. 33(1):175. Leong, B.K., R.J. Kociba, and G.C. Jersey. 1981. A lifetime study of rats and mice exposed to vapors of bis(chloromethyl)ether. Toxicol. Appl. Pharmacol. 58(2): 269-281. Ministry of Employment and Work (Belgium) 2002. Liste de valeurs limites d’expositions professionnelle aux agents chimiques, Annexe 1 A: Oxyde de bis(chlorométhyle). [online]. Available: http://www.ilo.org/safework/areasofwork/ lang--en/WCMS_118291/index.htm [accessed Oct. 21, 2011].

bis-Chloromethyl Ether 51 Mukai, F.H., and I. Hawryluk. 1973. The mutagenicity of some halo-ethers and halo- ketones. [Abstract]. Mutat. Res. 21:228. NIOSH (National Institute for Occupational Safety and Health). 2005. NIOSH Pocket Guide to Chemical Hazards: bis-Chloromethyl ether. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Cincinnati, OH. September 2005 [online]. Available: http://www.cdc.gov/niosh/npg/npgd0128.html [accessed Nov. 4, 2011]. Nishimura, K., K. Miyashita, Y. Yoshida, M. Kuroda, M. Matsumoto, K. Matsumoto, S. Takeda, and I. Hara. 1990. An epidemiological study of lung cancer among workers exposed to bis(chloromethyl)ether [in Japanese]. Sangyo Igaku 32(6):448- 453. Norpoth, K.H., A. Reisch, and A. Heinecke. 1980. Biostatistics of Ames-test data. Pp. 312-322 in: Short Term Test Systems for Detecting Carcinogens, K.H. Norpoth, and R.C. Garner, eds. Berlin: Springer. NRC (National Research Council). 1985. Hydrazine. Pp. 5-21 in Emergency and Continuous Exposure Guidance Levels for Selected Airborne Contaminants, Vol. 5. Washington, DC: National Academy Press. NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na- tional Academy Press. NTP (National Toxicology Program). 2011. Substance Profiles: bis(chloromethyl) Ether and Technical Grade Chloromethyl Methyl Ether. CASRN. 542-88-1 and 107-30- 2. Pp. 71-73 in Report on Carcinogens, 12th Ed. U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program [online]. Available: http://ntp.niehs.nih.gov/ntp/roc/twelfth/roc12.pdf [accessed Oct. 19, 2011]. O’Neil, M.J., A. Smith, and P.E. Heckelman, eds. 2001. P. 357 in The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 13th Ed. Whitehouse Station, NJ: Merck. Reznik, G., H.H. Wagner, and Z. Atay. 1977. Lung cancer following exposure to bis(chloromethyl)ether: A case report. J. Environ. Pathol. Toxicol. 1(1):105-111. Roe, F.J. 1985. Chloromethylation: Three lung cancer deaths in young men. Lancet 2(8447):268. Sakabe, H. 1973. Lung cancer due to exposure to bis(chloromethyl) ether. Ind. Health 11(3):145-148. Sellakumar, A.R., C.A. Snyder, J.J. Solomon, and R.E. Albert. 1985. Carcinogenicity of formaldehyde and hydrogen chloride in rats. Toxicol. Appl. Pharmacol. 81(3 Part 1):401-406. Slaga, T.J., G.T. Bowden, B.G. Shapas, and R.K. Boutwell. 1973. Macromolecular synthesis following a single application of alkylating agents used as initiators of mouse skin tumorigenesis. Cancer Res. 33(4):769-776. Smyth, H.F., C.P. Carpenter, C.S. Weil, U.C. Pozzani, J.A. Striegel, and J.S. Nycum. 1969. Range-finding toxicity data: List VII. Am. Ind. Hyg. Assoc. J. 30(5):470- 476.

52 Acute Exposure Guideline Levels Sram, R.J., I. Samkova, and N. Hola. 1983. High-dose ascorbic acid prophylaxis in workers occupationally exposed to halogenated ethers. J. Hyg. Epidemiol. Microbiol. Immunol. 27(3):305-318. Sram, R.J., K. Landa, N. Hola, and I. Roznickova. 1985. The use of cytogenetic analysis of peripheral lymphocytes as a method for checking the level of MAC in Czechoslovakia. Mutat. Res. 147:322. Styles, J.A. 1978. Mammalian cell transformation in vitro. Six tests for carcinogenicity. Br. J. Cancer. 37(6):931-936. Swedish Work Environment Authority. 2005. bis(chloromethyl) ether. In Occupational Exposure Limit Values and Measures Against Air Contaminants. AFS 2005:17 [online]. Available: http://www.av.se/dokument/inenglish/legislations/eng0517.pdf [accessed Oct. 20, 2011]. ten Berge, W.F., A. Zwart, and L.M. Appleman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Haz- ard. Mater. 13(3):301-309. Thiess, A.M., W. Hey, and H. Zeller. 1973. Toxicology of dichlorodimethylether- suspected cancerogenic effect in man [in German]. Zentralbl. Arbeitsmed. 23(4):97-102. 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. Union Carbide. 1968. Summary of Acute Toxicity and Irritancy Studies of BCME. Report 31-85. Union Carbide Co, Danbury CT. Unwin, J., and J.A. Groves. 1996. Measurement of bis(chloromethyl) ether at the parts per billion level in air. Anal. Chem. 68(24):4489-4493. 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. 1980. Prediction of carcinogenicity based on structure, chemical reactivity and possible metabolic pathways. J. Environ. Pathol. Toxicol. 3(4):11-34. 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. Van Duuren, B.L., B.M. Goldschmidt, and I. Seidman. 1975. Carcinogenic activity of di- and trifunctional α-chloro ethers and of 1,4-dichlorobutene-2 in ICR/HA Swiss mice. Cancer Res. 35(9):2553-2557. Xue, S.Z., C. Qian, G.F. Tang, Z.Q. Wang, D.H. Zhou, J. Deng, J.Z. Zhao, and Y.P. He. 1988. Epidemiological investigation on the lung cancer among chloro-methyl- ether exposures. Pp. 75-80 in Occupational Health in Industrialization and Modernization, S. Xue, and Y. Liang. eds. Shanghai, People’s Republic of China: Shanghai Medical University Press. Zajdela, F., A. Croisy, A. Barbin, C. Malaveille, L. Tomatis, and H. Bartsch. 1980. Carcinogenicity of chloroethylene oxide, an ultimate reactive metabolite of vinyl

bis-Chloromethyl Ether 53 chloride, and bis(chloromethyl)ether after subcutaneous administration and in initiation-promotion experiments in mice. Cancer Res. 40(2):352-356. Zeller, H., and H. Hoffmann. 1973. Unpublished Experiments of BASF Medical- Biological Research Laboratories (as cited in Thiess et al. 1973).

54 Acute Exposure Guideline Levels APPENDIX A DERIVATION OF AEGL VALUES FOR bis-CHLOROMETHYL ETHER Derivation of AEGL-1 Values AEGL-1 values were not recommended because effects exceeding the severity of AEGL-1 occurred at concentrations that did not produce sensory irritation in humans or animals. Derivation of AEGL-2 Values Key study: Drew et al. 1975 Toxicity end point: 0.23 ppm was NOAEL for irreversible respiratory lesions in rats and hamsters Time scaling: Cn × t = k (n = 3 for longer to shorter exposure periods; n = 1 for shorter to longer exposure periods); extrapolation not performed for 10-min (0.23 ppm/10) 3 × 7 h = 8.52 x 10-5 ppm3-h (0.23 ppm/10) 1 × 7 hr 0.16 ppm-h Uncertainty factors: 3 for interspecies variability 3 for intraspecies variability Combined uncertainty factor of 10 Modifying factor: None Calculations: 10-min AEGL-2: Set equal to 30-min value because of uncertainty in extrpolating a 7-h exposure to 10 min 30-min AEGL-2: C3 × 0.5 h = 8.52 × 10-5 ppm3-h C = 0.055 ppm [0.26 mg/m3] 60-min AEGL-2: C3 × 1 h = 8.52 × 10-5 ppm3-h C = 0.044 ppm [0.21 mg/m3] 4-h AEGL-2: C3 × 4 h = 8.52 × 10-5 ppm3-h

bis-Chloromethyl Ether 55 C = 0.028 ppm [0.13 mg/m3] 8-h AEGL-2: C1 × 8 hr = 0.16 ppm-h C = 0.020 ppm [0.095 mg/m3] Derivation AEGL-3 Values Key study: Drew et al. (1975) Toxicity end point: NOEL of 1 ppm for lethality from lung lesions. Time scaling: Cn × t = k (n = 3 for longer to shorter exposure periods; n = 1 for shorter to longer exposure periods); extrapolation not performed for 10-min values (1.0 ppm/10)3 × 6 h = 6.0 × 10-3 ppm3-h (1.0 ppm/10)1 × 6 h = 0.60 ppm-h Uncertainty factors: 3 for interspecies variability 3 for intraspecies variability Combined uncertainty factor of 10 Calculations: 10-min AEGL-2: Set equal to 30-min value because of uncertainty in extrapolating a 6-h exposure to 10 min 30-min AEGL-3: C3 × 0.5 h = 6.0 × 10-3 ppm3-h C = 0.23 ppm [1.1 mg/m3] 60-min AEGL-3: C3 × 1 h = 6.0 × 10-3 ppm3-h C = 0.18 ppm [0.86 mg/m3] 4-h AEGL-3: C3 × 4 hr = 6.0 × 10-3 ppm3-h C = 0.11 ppm [0.52 mg/m3] 8-h AEGL-3: C1 × 8 h = 0.60 ppm-h C = 0.075 ppm [0.36 mg/m3]

56 Acute Exposure Guideline Levels APPENDIX B CARCINOGENICITY ASSESSMENT FOR BIS-CHLOROMETHYL ETHER Cancer Assessment A cancer assessment of BCME was performed by EPA (2002) on the basis of data from Kuschner et al. (1975). That study is summarized in Section 3.5.1. The inhalation unit risk for BCME was calculated to be 6.2 ×10-2 per 3 μg/m , using the linearized multistage procedure, extra risk (EPA 2002). 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 days). 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 in the exposure concentrations is made to account for interspecies variability. A comparison of the AEGL-2 and AEGL-3 values for BCME with the estimated concentration associated with a cancer risk of 1 × 10-4 is shown below. For risks of 1 × 10-5 and 1 × 10-6, the 1 × 10-4 values are reduced 10-fold or 100- fold, respectively. Also shown are the estimated cancer risks for the AEGL-2 and AEGL-3 values, obtained by assuming a linear relationship between ex- posure concentration and cancer risk.

bis-Chloromethyl Ether 57 TABLE B-1 Estimated Cancer Risks Associated with a Single Exposure to bis-Chloromethyl Ether Exposure Duration 10 min 30 min 1h 4h 8h BCME Not 0.069 ppm 0.035 ppm 0.0086 ppm 0.0043 ppm concentration: calculated 1.0 × 10-4 1.0 × 10-4 1.0 × 10-4 1.0 × 10-4 Estimated cancer risk: AEGL-2 value: 0.055 ppm 0.055 ppm 0.044 ppm 0.028 ppm 0.020 ppm Estimated Not 8.0 × 10-5 1.3 × 10-4 3.3 × 10-4 4.7 × 10-4 cancer risk: calculated AEGL-3 value: 0.23 ppm 0.23 ppm 0.18 ppm 0.11 ppm 0.075 ppm Estimated Not 3.3 × 10-4 5.1 × 10-4 1.3 × 10-3 1.7×x 10-3 cancer risk: calculated

58 Acute Exposure Guideline Levels APPENDIX C ACUTE EXPOSURE GUIDELINE LEVELS FOR bis-CHLOROMETHYL ETHER Derivation Summary AEGL-1 VALUES 30 min 30 min 1h 4h 8h Not Recommended (effects exceeding the severity of AEGL-1 effects occurred at concentrations that did not produce sensory irritation in humans or animals) 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 quality and support for AEGL-1 values: Values were not derived because no studies were available in which toxicity was limited to AEGL-1 effects. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 0.055 ppm 0.055 ppm 0.044 ppm 0.028 ppm 0.020 ppm (0.26 mg/m3) (0.26 mg/m3) (0.21 mg/m3) (0.13 mg/m3) (0.095 mg/m3) 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; 25/test concentration/species Exposure route/Concentrations/Durations: Inhaled BCME at 0.7, 2.1, 6.9, or 9.5 ppm (rats) or 0.7, 2.1, 5.6, or 9.9 ppm (hamsters) for 7 h. Lifetime observation. Effects: At 0.7 ppm, both species had increased lung-to-body weight ratios; rats had increased incidence of tracheal epithelial hyperplasia, and hamsters had increased incidence of pneumonitis. Respiratory lesions were considered irreversible because they were found after lifetime observation. At ≥2.1 ppm, both species had increased mortality and lung lesions. (Continued)

bis-Chloromethyl Ether 59 AEGL-2 VALUES Continued 10 min 30 min 1h 4h 8h 0.055 ppm 0.055 ppm 0.044 ppm 0.028 ppm 0.020 ppm (0.26 mg/m3) (0.26 mg/m3) (0.21 mg/m3) (0.13 mg/m3) (0.095 mg/m3) End point/Concentration/Rationale: A NOAEL of 0.23 ppm for irreversible respiratory lesions in rats and hamsters was estimated by applying an adjustment factor of 3 to LOAEL of 0.7 ppm. Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 applied because BCME caused a similar toxic response in two species at the same test concentration in the key study, and is expected to cause toxicity similarly in human lungs. Intraspecies: 3 recommended in the Standard Operating Procedures (NRC 2001) for deriving AEGLs for chemicals with a steep dose-response relationship, because effects are unlikely to vary greatly among humans. Using the intraspecies default uncertainty factor of 10 would reduce the 4- and 8-h AEGL-2 values below 0.010 ppm, the NOEL in a study of rats and mice exposed to BCME for 6 h/day, 5 days/week, for a total of 129 exposures (Leong et al. 1981). Modifying factor: None Animal-to-human dosimetric adjustment: Not applied Time saling: 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 4.4.2.). Data quality and support for AEGL-2 values: Adequate data were available to develop values. The estimated NOAEL of 0.23 ppm was supported by two other single-exposure experiments by Drew et al. (1975) that had similar LOAELs for irreversible or serious lung lesions. AEGL-3 VALUES 10 min 30 min 1h 4h 8h 0.23 ppm 0.23 ppm 0.18 ppm 0.11 ppm 0.075 ppm (1.1 mg/m3) (1.1 mg/m3) (0.86 mg/m3) (0.52 mg/m3) (0.36 mg/m3) 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; 50/test concentration/species Exposure route/Concentrations/Durations: Inhalation of BCME at 1 ppm for 6 h/day for 1, 3, 10, or 30 days. Lifetime observation. (Continued)

60 Acute Exposure Guideline Levels AEGL-3 VALUES Continued 10 min 30 min 1h 4h 8h 0.23 ppm 0.23 ppm 0.18 ppm 0.11 ppm 0.075 ppm (1.1 mg/m3) (1.1 mg/m3) (0.86 mg/m3) (0.52 mg/m3) (0.36 mg/m3) Effects: Slightly increased incidences of lung lesions in rats and hamsters after single exposure; lung lesions and increased mortality with ≥3 exposures. End point/Concentration/Rationale: A single exposure of 1 ppm for 6 h was the NOEL for lethality from lung lesions. Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 applied because NOEL for lethality was 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 deriving AEGLs for chemicals with a steep dose-response relationship, because effects are unlikely to vary greatly among humans. Modifying factor: None 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 4.4.2.). Data quality and support for AEGL-3 values: The database was sufficient to develop AEGL-3 values. The key study was chosen because it had the highest concentration of BCME that did not cause lethality after lifetime observation; another study by the same authors found a lethality NOEL of 0.7 ppm (7 h) for rats and hamsters after lifetime observation. A 7-h LC50 study using rats and hamsters (Drew et al. 1975) was not used because it yielded a BMCL05 of 4.2 ppm for rats and 3.7 ppm for hamsters, which exceed 2.1 ppm, the concentration that caused mortality in rats and hamsters after a single 7-h exposure to BCME in a lifetime observation study (Drew et al. 1975).

bis-Chloromethyl Ether 61 APPENDIX D 1E3 Human - No Effect 1E2 Human - Discomfort Human - Disabling 1E1 Animal - No Effect ppm 1E0 Animal - Discomfort AEGL-3 1E-1 Animal - Disabling AEGL-2 1E-2 Animal - Some Lethality 1E-3 Animal - Lethal AEGL 1E-4 0 60 120 180 240 300 360 420 480 Minutes FIGURE D-1 Category plot for bis-chloromethyl ether. Multiple-exposure studies were not included in the plot except for Leong et al. (1975, 1981).

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At the request of the Department of Defense and the Environmental Protection Agency, the National Research Council has reviewed the relevant scientific literature compiled by an expert panel and established Acute Exposure Guideline Levels (AEGLs) for several chemicals. AEGLs represent exposure levels below which adverse health effects are not likely to occur and are useful in responding to emergencies, such as accidental or intentional chemical releases in community, workplace, transportation, and military settings, and for the remediation of contaminated sites. Three AEGLs are approved for each chemical, representing exposure levels that result in: 1) notable but reversible discomfort; 2) long-lasting health effects; and 3) life-threatening health impacts. This volume in the series includes AEGLs for bis-chloromethyl ether, chloromethyl methyl ether, chlorosilanes, nitrogen oxides, and vinyl chloride.

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