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 Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals.

AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows:

AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory

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



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 13
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

OCR for page 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

OCR for page 13
15 bis-Chloromethyl Ether 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,

OCR for page 13
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) NRa AEGL-1 NR NR NR NR (nondisabling) 0.055 ppm 0.055 ppm 0.044 ppmb 0.028 ppmb 0.020 ppmb NOAEL for AEGL-2 (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) 0.23 ppmb 0.23 ppmb 0.18 ppmb 0.11 ppmb 0.075 ppmb Lethality NOEL for AEGL-3 (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 1.0 × 10-4 1.0 × 10-4 1.0 × 10-4 1.0 × 10-4 concentration: Estimated cancer risk: AEGL-2 value: 0.055 ppm 0.055 ppm 0.044 ppm 0.028 ppm 0.020 ppm Not calculated 8.0 × 10-5 1.3 × 10-4 3.3 × 10-4 4.7 × 10-4 Estimated cancer risk: AEGL-3 value: 0.23 ppm 0.23 ppm 0.18 ppm 0.11 ppm 0.075 ppm Not calculated 3.3 × 10-4 5.1 × 10-4 1.3 × 10-3 1.7 × 10-3 Estimated cancer risk:

OCR for page 13
17 bis-Chloromethyl Ether 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

OCR for page 13
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% 1 mg/m3 = 0.21 ppm; 1 ppm = 4.75 mg/m3 Conversion factors HSDB 2005

OCR for page 13
19 bis-Chloromethyl Ether 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.

OCR for page 13
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.

OCR for page 13
21 bis-Chloromethyl Ether 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

OCR for page 13
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,

OCR for page 13
23 bis-Chloromethyl Ether 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)

OCR for page 13
51 bis-Chloromethyl Ether 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.

OCR for page 13
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

OCR for page 13
53 bis-Chloromethyl Ether 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).

OCR for page 13
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 Cn × t = k (n = 3 for longer to shorter Time scaling: exposure periods; n = 1 for shorter to longer exposure periods); extrapolation not performed for 10-min (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 C3 × 0.5 h = 8.52 × 10-5 ppm3-h 30-min AEGL-2: C = 0.055 ppm [0.26 mg/m3] C3 × 1 h = 8.52 × 10-5 ppm3-h 60-min AEGL-2: C = 0.044 ppm [0.21 mg/m3] C3 × 4 h = 8.52 × 10-5 ppm3-h 4-h AEGL-2:

OCR for page 13
55 bis-Chloromethyl Ether C = 0.028 ppm [0.13 mg/m3] C1 × 8 hr = 0.16 ppm-h 8-h AEGL-2: 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. Cn × t = k (n = 3 for longer to shorter Time scaling: exposure periods; n = 1 for shorter to longer exposure periods); extrapolation not performed for 10-min 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 C3 × 0.5 h = 6.0 × 10-3 ppm3-h 30-min AEGL-3: C = 0.23 ppm [1.1 mg/m3] C3 × 1 h = 6.0 × 10-3 ppm3-h 60-min AEGL-3: C = 0.18 ppm [0.86 mg/m3] C3 × 4 hr = 6.0 × 10-3 ppm3-h 4-h AEGL-3: C = 0.11 ppm [0.52 mg/m3] C1 × 8 h = 0.60 ppm-h 8-h AEGL-3: C = 0.075 ppm [0.36 mg/m3]

OCR for page 13
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.

OCR for page 13
57 bis-Chloromethyl Ether 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 1.0 × 10-4 1.0 × 10-4 1.0 × 10-4 1.0 × 10-4 concentration: calculated Estimated cancer risk: AEGL-2 value: 0.055 ppm 0.055 ppm 0.044 ppm 0.028 ppm 0.020 ppm 8.0 × 10-5 1.3 × 10-4 3.3 × 10-4 4.7 × 10-4 Estimated Not cancer risk: calculated AEGL-3 value: 0.23 ppm 0.23 ppm 0.18 ppm 0.11 ppm 0.075 ppm 3.3 × 10-4 5.1 × 10-4 1.3 × 10-3 1.7×x 10-3 Estimated Not cancer risk: calculated

OCR for page 13
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)

OCR for page 13
59 bis-Chloromethyl Ether 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)

OCR for page 13
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).

OCR for page 13
61 bis-Chloromethyl Ether 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 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).