Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 11 (2012) / Chapter Skim
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2 Chloromethyl Methyl Ether: Acute Exposure Guideline Levels
2 Chloromethyl Methyl Ether: Acute Exposure Guideline Levels
Pages 62-105
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From page 62... ...
Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels.
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From page 63... ...
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 corresponding AEGL. SUMMARY Chloromethyl methyl ether (CMME)
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A modifying factor of 1.7 was also applied because the content of BCME in technical-grade CMME in the key study was unknown. The AEGL values are summarized in Table 2-1.
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Because of this uncertainty and the large differences in methods used to derive the AEGL values as compared with extrapolating the carcinogenic potency from a lifetime study to a single exposure, the noncarcinogenic end points were considered to be more appropriate for deriving AEGLs for CMME.
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From page 66... ...
Technical-grade CMME contains 1-10% BCME as a contaminant, which is a more potent human carcinogen than CMME and is believed to be responsible for most or all of the carcinogenic activity of technical-grade CMME (Travenius 1982; HSDB 2010)
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HUMAN TOXICITY DATA 2.1. Acute Lethality No quantitative information was located regarding acute exposure to CMME in humans.
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2.2.2. Accidents Accidental industrial exposure to "rather high" concentrations of CMME caused sore throat, fever, and chills, and the person was not able to work for 8 days, at which time recovery appeared complete (Hake and Rowe 1963)
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. The American Conference of Industrial Hygienists has classified CMME as a "suspected human carcinogen" (Class A2)
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No excess respiratory-tract cancer or oat-cell lung cancer was found in workers during the plant's 27 years of operation. Industrial workers exposed for months to years to CMME (containing BCME)
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Technical-grade CMME (unspecified BCME content) was used in the production of anion exchange resins in a factory (Rohm & Haas)
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The three cases of lung cancer (men aged 33-39) among about 45 workers who worked in the production of CMME (0.5-4% BCME)
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of lung cancer were small-cell carcinomas (one was large-cell) ; the two laryngeal cancers were squamous cell carcinomas.
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at a factory in South Wales between 1948 and 1980 showed an increased incidence of lung cancer but not other cancers compared with a local unexposed population of 295 men (McCallum et al.
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have described occupational exposure to CMME and BCME that was associated with an increased incidence of lung cancer. The lung cancer occurred approximately 10 years earlier than in the general population (who would most likely get it from cigarette smoking)
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Congestion, edema, hemorrhage, and acute necrotizing bronchitis were evident in lungs of animals that died and to a lesser degree in surviving animals. No statements were made about the incidence of lung lesions in the 12.5-ppm group, so this possibility cannot be ruled out even though no significant changes in lung-to-body weight ratio were found.
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Damage was measured as an increase of 3 standard deviations in the lung-tobody weight ratio. Animals given CMME had concentration-related increases in their relative lung weights.
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TABLE 2-4 Mortality, Lung-to-Body Weight Ratio, and Estimated LC50 in Hamsters after Single 7-Hour Exposure to Chloromethyl Methyl Ether Hamsters with Increased Concentration (ppm) Mortality at 14 d (%)
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Technical grade CMME (12.5 or 25 μmols) did not induce DNA, RNA, or protein synthesis in the epidermis of mice treated dermally with CMME, as measured by radiolabeled thymidine, cytidine, and leucine (Slaga et al.
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There was no effect on mortality or body weight gain in either species. Histologic examination of the respiratory-tract mucosa of the rats showed a marked increase in the incidence of tracheal squamous metaplasia and bronchial hyperplasia compared with controls (74 sham exposed)
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From page 81... ...
Consistent with its in situ hydrolysis, the respiratory tract is the primary site of technical grade CMME toxicity and carcinogenicity in humans and animals. It is unknown to what extent the CMME hydrolysis products, metabolites, or any potentially-formed BCME are responsible for the toxicity and carcinogenicity of CMME.
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From page 82... ...
To obtain protective AEGL-2 and AEGL-3 values for 30-480 minutes, n = 3 and n = 1 were used to extrapolate to shorter and longer durations, respectively, than the exposure duration in the key study. The 10-min values were not extrapolated because the National Advisory Committee determined that extrapolating from ≥4 h to 10 min has unacceptably large inherent uncertainty, so the 30-min value was adopted for 10-min value to be protective of human health.
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. Treated mice were killed after 6 months, and necropsy showed a slightly increased incidence and multiplicity of pulmonary adenomas (incidence of 17% for treated and 14% for controls; multiplicity of 0.21 for treated and 0.14 for controls)
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. Toxic effects were not attributed to specific concentrations, but it was stated that animals that died had increased relative lung weights, pulmonary congestion, edema, hemorrhage, and acute necrotizing bronchitis.
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A modifying factor of 1.7 was also applied because the BCME content in technical grade CMME in the key study was unknown. The modifying factor was obtained by assuming contamination with 10% BCME (the maximum reported)
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Concentration-related increases in relative lung weights, congestion, edema, hemorrhage, and acute necrotizing bronchitis were found in all groups of treated animals that died and were found to a lesser degree in surviving animals. Study of male Sprague-Dawley rats exposed for 30 consecutive days to technical grade CMME at 10.0 ppm for 6 h/day (Drew et al.
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From page 87... ...
An intraspecies uncertainty factor of 3 was also used in the derivation of AEGL-3 values for BCME. As for AEGL-2, a modifying factor of 1.7 was also applied because the content of BCME in technical grade CMME in the key study was unknown.
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From page 88... ...
, a modifying factor of 1.7 was applied because the BCME content in technical grade CMME in the key study was unknown, and scaling across time was performed using the ten Berge et al (1986) equation Cn × t = k, with n = 1 or n = 3.
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From page 89... ...
Germany and Sweden also consider CMME a human carcinogen in their workplace exposure guidelines. The American Industrial Hygiene Association (AIHA 2000)
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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 irreversible or other serious health effects or symptoms that could impair an individual's ability to take protection action. 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 lifethreatening health effects.
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1987. An industry-wide study of respiratory cancer in chemical workers exposed to chloromethyl ethers.
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1976. Lung cancer following exposure to chloromethyl methyl ether: An epidemiological study.
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1984. Lung cancer and exposure to chloromethyl ether: An occupational epidemiological survey.
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2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals.
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1980. The cigarette factor in lung cancer due to chloromethyl ethers.
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3 × 7 h = 0.106 ppm3-h (4.2 ppm/17) 1 × 7 h = 1.73 ppm3-h Uncertainty factors: 3 for interspecies variability 3 for intraspecies variability Combined uncertainty factor of 10 Modifying factor: 1.7 because BCME content in technical grade CMME in the key study was unknown.
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From page 97... ...
3 ×7 h = 8.31 ppm3-h (18 ppm/17) 1 × 7 h = 7.41 ppm-h Uncertainty factors: 3 for interspecies variability 3 for intraspecies variability Combined uncertainty factor of 10 Modifying factor: 1.7 because BCME content in technical grade CMME in the key study was unknown.
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98 Acute Exposure Guideline Levels Calculations: 10-min AEGL-3: Set equal to 30-min value because of uncertainty in extrapolating a 7-h exposure to 10 min.
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I The acute inhalation toxicity of chloromethyl methyl ether and bis(chloromethyl)
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From page 100... ...
for chemicals with a steep dose-response relationship, because effects are unlikely to vary greatly among humans. Modifying factor: 1.7 used because the BCME content in technical grade CMME in the key study was unknown; obtained by assuming 10% BCME (the maximum reported)
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I The acute inhalation toxicity of chloromethyl methyl ether and bis(chloromethyl)
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. Data adequacy: The key study was adequate and the two test species had similar results.
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From page 103... ...
Chloromethyl Methyl Ether 103 APPENDIX C CMME Toxicity 1000.0 Human - No Effect Human - Discomfort 100.0 Human - Disabling Animal - No Effect ppm 10.0 Animal - Discomfort Animal - Disabling AEGL-3 1.0 Animal - Some Lethality AEGL-2 Animal - Lethal 0.1 AEGL 0 60 120 180 240 300 360 420 480 Minutes FIGURE C-1 Category plot of animal toxicity data compared with AEGL values. Multiple-exposure studies are not included in the plot.
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From page 104... ...
Because the animal dose was converted to an air concentration that results in an equivalent human inhaled dose for the derivation of the cancer slope factor, no reduction of exposure concentrations is made to account for interspecies variability. The calculated concentration of BCME associated with a 1 ×10-4 cancer risk is shown in Table D-1 for a single exposure of 10 min to 8 h.
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From page 105... ...
TABLE D-1 Estimated Cancer Risks Associated with a Single Exposure Chloromethyl Methyl Ether or bis-Chloromethyl Ether Exposure 10 min 30 min 1h 4h 8h BCME Concentration Not 0.069 ppm 0.035 ppm 0.0086 ppm 0.0043 ppm calculated Estimated 1 × 10-4 1 × 10-4 1 × 10-4 1 × 10-4 cancer risk CMME, containing 10% BCMEa Concentration Not 0.36 ppm 0.18 ppm 0.045 ppm 0.023 ppm calculated Estimated 1 × 10-4 1 × 10-4 1 × 10-4 1 × 10-4 cancer risk AEGL-2 value 0.60 ppm 0.60 ppm 0.47 ppm 0.30 ppm 0.22 ppm Estimated Not 1.7 × 10-4 2.6 × 10-4 6.7 ×10-4 9.6 × 10-4 cancer risk calculated AEGL-3 value 2.6 ppm 2.6 ppm 2.0 ppm 1.3 ppm 0.93 ppm Estimated Not 7.4 × 10-4 1.1 × 10-3 2.9 × 10-3 4.1 × 10-3 cancer risk calculated a Assumes BCME is a 10-fold more potent carcinogen than CMME.
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