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1 bis-Chloromethyl Ether: Acute Exposure Guideline Levels
Pages 13-61

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From page 13...
... Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels.
From page 14...
... 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
From page 15...
... . After one exposure, rats and hamsters had slightly increased incidences of lung lesions, whereas three exposures produced lung lesions and increased mortality.
From page 16...
... 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)
From page 17...
... . 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.
From page 18...
... 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)
From page 19...
... (1971) stated that BCME is a health risk at concentrations that do not produce sensory irritation.
From page 20...
... 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)
From page 21...
... with 100-200 workers exposed to BCME from anionexchange resin production died from lung cancer, and two more workers developed lung cancer (Donaldson and Johnson 1972; Fishbein 1972)
From page 22...
... 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.
From page 23...
... . TABLE 1-4 Summary of Human Exposure Data with Defined Concentrations to bis-Chloromethyl Ether Exposure Exposure Concentration Duration Results (Reference)
From page 24...
... Histopathologic findings included increased incidences of tracheal and bronchial hyperplasia (often with nuclear atypia) and squamous metaplasia compared with controls.
From page 25...
... 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 LungConcentration Median to-Body Weight Histopathologic Findings in Lung Mucosa (%)
From page 26...
... 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)
From page 27...
... 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)
From page 28...
... 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)
From page 29...
... 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)
From page 30...
... 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.
From page 31...
... 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.
From page 32...
... . 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)
From page 33...
... 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)
From page 34...
... followed by lifetime observation to determine whether there is a non-tumorigenic or no-observableeffect 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.
From page 35...
... . 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)
From page 36...
... . 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)
From page 37...
... . 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.
From page 38...
... 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.
From page 39...
... 1975) and by dermal application and subcutaneous injection (Van Duuren et al.
From page 40...
... 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.
From page 41...
... 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.
From page 42...
... 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 calculate the two sets of numbers (cancer risk calculation uses 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)
From page 43...
... . Rats and hamsters had slightly increased incidences of lung lesions after one exposure, whereas increased mortality and lung lesions were observed after three exposures.
From page 44...
... . Rats and hamsters had slightly increased incidences of lung lesions after one exposure, whereas increased mortality occurred after three exposures.
From page 45...
... . After one exposure, rats and hamsters had slightly increased incidences of lung lesions, whereas three exposures caused lung lesions and increased mortality.
From page 46...
... (0.36 mg/m3) a Not recommended (effects exceeding the severity of AEGL-1 effects occurred at concentrations that did not produce sensory irritation in humans or animals)
From page 47...
... 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 lifethreatening health effects.
From page 48...
... e ACGIH TLV-TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value - Time Weighted Average)
From page 49...
... I The acute inhalation toxicity of chloromethyl methyl ether and bis(chloromethyl)
From page 50...
... II. Chronic inhalation studies with chloromethyl methyl ether.
From page 51...
... 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals.
From page 52...
... 1988. Epidemiological investigation on the lung cancer among chloro-methyl ether exposures.
From page 53...
... bis-Chloromethyl Ether 53 chloride, and bis(chloromethyl) ether after subcutaneous administration and in initiation-promotion experiments in mice.
From page 54...
... 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)
From page 55...
... (1975) Toxicity end point: NOEL of 1 ppm for lethality from lung lesions.
From page 56...
... 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.
From page 57...
... 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
From page 58...
... 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.
From page 59...
... 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)
From page 60...
... (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.
From page 61...
... 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.


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