Bis(Chloromethyl) Ether and Chloromethyl Methyl Ether - PSL1

2.0 Summary of Information Critical to Assessment of "Toxic"

2.1 Identity, Properties, Production, and Uses

Bis(Chloromethyl) Ether - Bis(chloromethyl) ether (BCME) is an a-chloroalkyl ether with the Chemical Abstracts Service (CAS) registry number 542-88-1; the molecular formula C₂H₄C1₂0; and the structural formula CICH₂OCH₂Cl (Sittig, 1981; U.S.EPA, 1980). Synonyms for BCME include: chloro(chloromethoxy) methane, sym-dichloro-dimethyl ether, dimethyl-1, 1'-dichloroether, oxybis(chloromethane), dichloromethyl ether, and bichloromethyl ether (Sax, 1984; Verschueren, 1983).

Bis(chloromethyl) ether is a colourless, volatile liquid with a "suffocating" odour (Sittig, 1981; Verschueren, 1983). No experimental values for the vapour pressure of BCME were found in the literature. There are no experimental values for water solubility and Henry's Law Constant for BCME, as this substance hydrolyses very rapidly in water (see Subsection 2.3.1). This substance is miscible with most organic solvents (Weast, 1984). Analytical methods used to quantify BCME involve gas chromatography/mass spectrometry or gas chromatography with electron capture detection (Collier, 1972; Evans et al., 1975; Frankel and Black, 1976).

Chloromethyl Methyl Ether - Chloromethyl methyl ether (CMME) is an a-chloroalkyl ether with the CAS registry number 107-30-2; the molecular formula C₂H₅ClO; and the structural formula CH₃OCH₂C1 (Sittig, 1981; U.S. EPA, 1980). Synonyms for CMME include: chloromethoxymethane, dimethylchloro ether, monochlorodimethyl ether, and methoxymethyl chloride (Sax, 1984; Verschueren, 1983; Sittig, 1981). Technical grade CMME contains from 1 to 8% BCME (Travenius, 1982). Available data for CMME permit evaluation only of the technical grade material (referred to as "CMME", unless otherwise specified).

Chloromethyl methyl ether is a colourless liquid with an "irritating" odour (Verschueren, 1983). No experimental values for the vapour pressure of CMME were found in the literature. There are no experimental values for water solubility and Henry's Law Constant for CMME as this substance is hydrolyzed very rapidly in water (Radding et al., 1977; Verschueren, 1983). This substance is soluble in most organic solvents (Weast, 1984). Analytical methods used to quantify CMME include gas chromatography with electron-capture detection (Kallos et al., 1977; Langhorst et al., 1981; Sittig, 1981).

Information provided in response to a Notice published under Section 16(1) of CEPA indicated that there was no commercial activity involving more than one kilogram of either BCME or CMME in Canada during 1990 or 1991 (Environment Canada, 1992). However, each of these compounds was reported to be used in Canada between 1984 and 1986 (Canada Gazette, 1991).

Since the early 1980s, industrial use of both BCME and CMME in the United States has been restricted to specific intermediate chemical reactions (Travenius, 1982).

2.2 Entry into the Environment

Neither BCME or CMME occurs naturally in the environment. However, BCME can be formed as a by-product when formaldehyde reacts with chloride ions in an acidic medium (Travenius, 1982). Moderate to high concentrations (mg/L or mg/m³) of the reactants are required to produce low concentrations (µg/L) of BCME (Tou and Kallos, 1974; Travenius, 1982; Kallos and Tou, 1977).

Information showing that CMME may be formed as a by-product during the production of other industrial chemicals was not found.

It was reported in the Toxic Release Inventory (U.S. EPA, 1990) that less than 1 kg of BCME and 50 kg of CMME were released to the atmosphere in the United States from industrial producers and users during 1989. No releases were reported in other media (water, soil, underground injection).

2.3 Exposure-related Information

2.3.1 Fate

Bis(chloromethyl) ether and CMME hydrolysis rapidly in water. At 20°C, half-lives in water of 38 seconds for BCME and <1 second for CMME have been reported (U.S. EPA, 1980; Tou et al., 1974; Radding et al., 1977). Although BCME may be degraded by oxidation, the extremely rapid hydrolysis of BCME in an aqueous medium precludes any oxidative degradation of this substance from taking place in aquatic systems (Callahan et al., 1979). Bis(chloromethyl) ether is hydrolyzed to formaldehyde and hydrogen chloride (ASTDR, 1989). Chloromethyl methyl ether is hydrolyzed to hydrogen chloride, methanol, and formaldehyde (Travenius, 1982).

Owing to their rapid hydrolysis in an aqueous medium, the volatilization of BCME and CMME from surface water is likely to be insignificant. Callahan et al. (1979) suggested that BCME could volatilize rapidly from an aquatic system only if it were discharged in a water-immiscible solvent that had a high vapour pressure. Once in the atmosphere, these substances would be degraded by photo-oxidation or hydrolysis. Cupitt (1980) reported atmospheric half-lives of <2.9 days for BCME and <3.9 days for CMME. Tou and Kallos (1974) reported half-lives for atmospheric hydrolysis as >1 day for BCME and between 0.0024 (Nichols and Merritt, 1973) and 0.27 days for CMME, in humid air. At low humidity levels, however, BCME may be degraded by oxidative as well as hydrolytic pathways (Callahan et al., 1979).

In air, the decomposition products for BCME include hydrogen chloride, formaldehyde, and chloromethylformate, while those for CMME include chloromethyl and methyl formate (Cupitt, 1980).

Very little information was found concerning the behaviour of BCME or CMME in soil. For BCME, Mabey et al. (1982) calculated a log organic carbon partition coefficient (log K_??) of 1.2. On the basis of this value, BCME appears to have minimal potential to adsorb to soil. However, it is also unlikely that BCME and CMME are mobile in soil as both compounds are hydrolyzed rapidly in an aqueous environment. No information on the biodegradation of either BCME or CMME in soil was identified.

The high rates of hydrolysis preclude any possibility of BCME or CMME bioaccumulating in organisms.

2.3.2 Concentrations

No data on levels of BCME or CMME in the ambient Canadian environment or in industrial effluents were identified.

2.4 Effects-related Information

2.4.1 Experimental Animals and In Vitro

Bis(chloromethyl) ether and CMME are acutely toxic following inhalation, oral, or dermal exposure. The LC₅₀ for the exposure (by inhalation) of experimental animals to BCME ranges from 5.3 ppm (25 mg/m³) to 10.3 ppm (48 mg/m³) (Drew et al., 1975; Union Carbide, 1968; Leong et al., 1971). The LD₅₀ for the oral administration of BCME to rats was 0.21 mL/kg body weight (b.w.) (278 mg/kg b.w.) (Union Carbide, 1968). The LC₅₀ for the exposure (by inhalation) of rats and hamsters to CMME was 55 ppm (182 mg/m³) and 65 ppm (215 mg/m³), respectively (Drew et al., 1975). It should be noted that since CMME contains between 1 to 8% BCME, the toxic effects produced by CMME may be due, at least in part, to BCME.

Information is limited on the toxicological effects produced following short-term exposure of experimental animals to BCME or CMME. The repeated exposure by inhalation of male rats or hamsters to 1 ppm (4.7 mg/m³) BCME over periods of up to 30 days, produced a marked reduction in survival, hyperplastic changes within the trachea and bronchus, and subarachnoid haemorrhage, compared to unexposed controls (Drew et al., 1975). In male rats exposed (duration not specified) by inhalation to 10 ppm (33 mg/m³) CMME, there was a reduction in survival in addition to alterations in lung/body weight ratios, and regenerative hyperplasia of the bronchial epithelium, compared to unexposed controls (Drew et al., 1975).

Studies on the toxicological effects produced following long-term inhalation exposure to BCME and CMME have been restricted primarily to limited carcinogenesis bioassays in mice, rats, and hamsters. Following exposure (inhalation) of male mice to 5 mg/m³ BCME over a period of 82 days, there was a marked reduction in survival, and increased incidence of pulmonary tumors (adenomas) compared to unexposed controls (26/47 versus 20/49, respectively). The statistical significance of this increase, however, was not specified (Leong et al., 1971). The number of lung tumors per animal in the BCME-exposed mice was slightly higher than in unexposed controls (5.2 versus 2.2, respectively). In male mice exposed to 1, 10, or 100 ppb (0.0047, 0.047, or 0.47 mg/m³) BCME over a period of 6 months, there was a reduction in survival (compared to unexposed controls), although after 6 months, a significant increase in the incidence of pulmonary adenomas was observed only in surviving mice exposed to the highest concentration (Leong et al., 1981).

In male rats exposed (by inhalation) to 1, 10, or 100 ppb (0.0047, 0.047, or 0.47 mg/m³) BCME over a period of 6 months, there was an increase in the incidence of "tumors of the respiratory tract" at the highest concentration (102/111 in BCME-exposed group versus 0/112 in unexposed controls); 94% of which were tumors of the olfactory neural tissue (esthesioneuroepitheliomas)(Leong et al., 1981). In male rats exposed to 0.1 ppm (0.47 mg/m³) BCME for periods ranging up to 20 weeks, there was an increase in the incidence of nasal esthesioneuroepitheliomas and squamous cell carcinomas of the lung with increasing periods of exposure; the incidence of carcinomas of the lung in animals exposed over a 20-week period was 8/30. Survival was reduced by approximately 24% in animals exposed to BCME over periods of 16 and 20 weeks (Kuschner et al., 1975).

In male mice exposed (by inhalation) to 2 ppm (6.6 mg/m³) CMME over a period of 101 days, the incidence of "pulmonary tumors" was not greater than in unexposed controls, although the number of lung tumors per animal in the CMME-exposed group was slightly higher than in the controls (3.1 versus 2.2, respectively) (Leong et al., 1971). In male rats exposed to 1 ppm (3.3 mg/m³) CMME for virtually their entire lives, the incidence of tracheal metaplasia and bronchial hyperplasia was greater than in unexposed controls; two tumors of the respiratory tract (an esthesioneuroepithelioma and lung squamous cell carcinoma) were observed in CMME-exposed animals, while none was reported in unexposed controls (Laskin et al., 1975). In male hamsters exposed to 1 ppm (3.3 mg/m³) CMME for virtually their entire lives, the incidence of tracheal metaplasia and bronchial hyperplasia was increased compared to unexposed controls. One lung adenocarcinoma and a tracheal squamous papilloma were observed in two animals exposed to CMME (information on tumor incidence in controls was not presented) (Laskin et al., 1975).

The incidence of pulmonary adenomas was greater in mice observed for six months after receiving a single subcutaneous injection of 12.5 µL/kg b.w. (16.6 mg/kg b.w.) BCME, or 125 µL/kg b.w. (132.5 mg/kg b.w.) CMME than in mice that received vehicle alone. There were, however, no effects on growth or survival of the animals (Gargus et al., 1969). In female rats administered BCME (3 mg) or "laboratory purified" CMME (3 mg) subcutaneously once a week for approximately 300 days (though the dose and schedule of administration were modified owing to the corrosive effects of BCME around the site of injection), there was an increase in the incidence of tumors (though the statistical significance was not specified) at the site of injection for BCME but not for "laboratory purified" CMME, compared to that in the control group administered vehicle alone (van Duuren et al., 1969). However, in a subsequent study (van Duuren et al., 1972) in which "laboratory purified" CMME (300 µg/animal) was administered once a week to female mice for their entire lives, the number of mice with sarcomas at the site of injection was 0/30 in the (vehicle) control and 10/30 in the (laboratory-purified) CMME-exposed groups. In mice, the incidence of tumors (mainly fibrosarcomas) at the site of injection was increased following 32 subcutaneous injections of 0.3 mg BCME compared to that in a control group administered vehicle alone (Zajdela et al., 1980). The incidence of squamous cell carcinomas of the skin in female mice that received 2 mg of BCME (applied dermally) or solvent, i.e., benzene, alone (controls) three times a week for 325 days was 12/20 and 0/20, respectively. "Laboratory purified" CMME (2 mg), however, was not carcinogenic in this skin tumor bioassay. In two-stage skin tumor carcinogenesis bioassays in which several substances were examined, BCME and CMME had "weak" tumor-initiating activity (van Duuren et al., 1969; Zajdela et al., 1980).

The genotoxicity of BCME and CMME has been examined in a variety of limited in vitro bioassays (Anderson and Styles, 1978; Mukai and Hawryluk, 1973; Agrelo and Severn, 1981; Styles, 1978; Kurian et al., 1990; Goldschmidt et al., 1975; Shooter, 1975; Perocco et al., 1983). The weight of evidence from these investigations in which a range of endpoints was examined indicates that both BCME and CMME are genotoxic. Available studies, however, are limited and generally, poorly documented.

No other relevant information was identified concerning the reproductive, developmental, immunological, or neurological toxicity of BCME or CMME in experimental animals or in humans.

2.4.2 Humans

In several case reports and series, the occurrence of lung cancer, several of which were small (oat) cell cancers, has been reported in workers exposed to BCME (Roe, 1985; Sakabe, 1973) or both compounds (Reznick et al., 1977). In addition, there have been a number of epidemiological studies of populations occupationally exposed to BCME or CMME.

In 136 workers employed at a chemical plant in California where BCME was used in the production of ion-exchange resins (Lemen et al., 1976) and in a population of 35 BCME-exposed workers employed at two dye stuff factories in Japan (Nishimura et al., 1990), the standardized mortality ratios for lung cancer were 9.3 and 21, respectively. The average age of appearance of or death due to a lung cancer was 47 and 46 years, respectively, and the average latency period was 10 years and 13.5 years, respectively.

For CMME, in prospective (cohort) studies of 125 employees of a chemical plant in the United States (Weiss, 1976; 1982), 737 "exposed" and 2120 "unexposed" workers at a chemical plant in Philadelphia (Maher and DeFonso, 1987) and 2460 "exposed" and 3692 "unexposed" workers at seven industrial facilities (Collingwood et al., 1987), the standardized mortality ratios for lung cancer were 20, 2.8, and 3, respectively. In the study reported by Weiss (1982), the standardized mortality ratios for deaths due to lung cancer peaked 15 to 19 years from the onset of exposure; similarly, Maher and DeFonso (1987) reported that the greatest increase in deaths due to cancer of the respiratory tract occurred approximately 10 to 20 years after first exposure.

For BCME, exposure was not assessed in any of the available epidemiological studies; however, a relationship between qualitative measures of exposure to CMME and lung cancer was observed in the only two studies in which it was examined (Collingwood et al., 1987; Maher and DeFonso, 1987).

Sram et al. (1983) reported that the proportion of peripheral lymphocytes with chromosomal aberrations (breaks, exchanges) isolated from 77 workers exposed to BCME and CMME was approximately twofold higher than that observed in lymphocytes isolated from 25 non-exposed controls. Except for information on whether the workers were smokers, which did not influence the results, no other relevant information was provided in this published account.

2.4.3 Ecotoxicology

No studies were found that investigated the toxicity of either BCME or CMME to aquatic or terrestrial organisms.

No information on the effects of BCME or CMME on the ozone layer or global warming was found. In view of their relatively short atmospheric lifetime, however, effects of these substances on the ozone layer or global warming are not anticipated.