Registration Dossier
Registration Dossier
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EC number: 203-870-1 | CAS number: 111-44-4
Toxicological Summary
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DMEL (Derived Minimum Effect Level)
- Value:
- 0.92 µg/m³
- Most sensitive endpoint:
- carcinogenicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Dose descriptor starting point:
- T25
- Value:
- 13.9 mg/kg bw/day
- Modified dose descriptor starting point:
- T25
- Value:
- 161 mg/m³
- Explanation for the modification of the dose descriptor starting point:
For the calculation of derived minimal effect levels (DMELs) for workers, the study of Innes et al. (1969) (mice, oral route (feed), 18 months duration, dose level: 43.1 mg/kg bw/day) was used. Two hybrid strains of mice (C57BL/6 x C3H/Anf)F1 and (C57BL/6 x AKR)F1) were exposed to Bis(2-chloroethyl) ether (BCEE). Hepatomas were found in 87.5 and 53% of males treated with BCEE from strain (C57BL/6 x C3H/Anf)F1 and strain (C57BL/6 x AKR)F1, respectively. In females treated with BCEE, no hepatomas were found in animals from strain (C57BL/6 x AKR)F1, while they were found in 22% of females from strain (C57BL/6 x C3H/Anf)F1.
In male mice of the strain (C57BL/6 x C3H/Anf)F1 (the test group showing the highest increase in the incidence of hepatomas following exposure to BCEE), incidence of hepatomas was 8/79 (10%) in the control group and 14/16 (87.5%) in the treated group (at 43.1 mg/kg bw/day), which is equivalent to a 77.5 % increase in hepatomas incidence. For the calculation of the DMELs, T25 value was used as starting point. T25 value indicates the dose, at which 25 % of the test animals show occurrence of hepatomas. As the dose for 77.5 % incidence hepatomas in male mice was experimentally determined as 43.1 mg/kg bw/day, T25 value for developing hepatomas in male mice was calculated as 13.9 mg/kg bw/day. DMELs were derived according to the REACH Guidance chapter R.8 (ECHA 2012a). As there is no conclusive evidence supporting that the substance acts as a threshold carcinogen, BCEE was assessed using the more conservative default approach of assuming no threshold.
Derivation of the modified dose descriptor:
The modified dose descriptor starting point was derived using the "Modified sequence of extrapolation" (10 m3 approach). The following correcting factors were taken into account in order to derive the modified dose descriptor:
-Deviation from standard test duration: The standard lifespan is considered to be 2 years in mice. However, the study was conducted for c.a. 18 months. More precisely, the male mice from strain
(C57BL/6 x C3H/Anf)F1 were necropsied at 80 weeks. They were given BCEE in feed during the entire course of the experiment. Accordingly, the lifetime daily dose giving rise to a 25% tumour incidence was corrected by (80/104)2(= 0.591) (according to Appendix R8-6 of ECHA guidance).
- Route-specific bioavailability: The absorption rate via the oral route was found to be 98 % based on experimental data (Lingg et al., 1982). The absorption rate via inhalation is > 95 % based on experimental data (Gwinner et al., 1983). Both adsorption rates were set to 100%.
-Body weight (kg): 70 (according to the REACH guidance R.8)
-Breathing volume workers (m3): 10 (according to the REACH guidance R.8)
-Occupational vs. lifetime exposure: For non-threshold carcinogens, lifetime risks for consumers and for humans exposed indirectly via the environment is associated with daily exposure of 24 hours (7 days a week) for 75 years. This exposure duration is considered equivalent to the life-time exposure in experimental studies of 2 years. For workers, however, the exposure time is 8 hours per day, 5 days per week, 48 weeks per year for 40 years. This implies that for workers, a correction factor should be applied to the dose descriptor based on animal life-time exposure data. The default value of 2.8 (7/5 x 52/48 x 75/40) proposed in REACH guidance R.8 was applied.
Based on the above, the modified dose descriptor was set to:
13.9 * 0.591 * 100/100 * 70/10 * 2.8 = 161 mg/m3
Acute/short term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
DNEL related information
Workers - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DMEL (Derived Minimum Effect Level)
- Value:
- 0.13 µg/kg bw/day
- Most sensitive endpoint:
- carcinogenicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Dose descriptor starting point:
- T25
- Value:
- 13.9 mg/kg bw/day
- Modified dose descriptor starting point:
- T25
- Value:
- 23 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
For the calculation of derived minimal effect levels (DMELs) for workers, the study of Innes et al. (1969) (mice, oral route (feed), 18 months duration, dose level: 43.1 mg/kg bw/day) was used. Two hybrid strains of mice (C57BL/6 x C3H/Anf)F1 and (C57BL/6 x AKR)F1) were exposed to Bis(2-chloroethyl) ether (BCEE). Hepatomas were found in 87.5 and 53% of males treated with BCEE from strain (C57BL/6 x C3H/Anf)F1 and strain (C57BL/6 x AKR)F1, respectively. In females treated with BCEE, no hepatomas were found in animals from strain (C57BL/6 x AKR)F1, while they were found in 22% of females from strain (C57BL/6 x C3H/Anf)F1.
In male mice of the strain (C57BL/6 x C3H/Anf)F1 (the test group showing the highest increase in the incidence of hepatomas following exposure to BCEE), incidence of hepatomas was 8/79 (10%) in the control group and 14/16 (87.5%) in the treated group (at 43.1 mg/kg bw/day), which is equivalent to a 77.5 % increase in hepatomas incidence. For the calculation of the DMELs, T25 value was used as starting point. T25 value indicates the dose, at which 25 % of the test animals show occurrence of hepatomas. As the dose for 77.5 % incidence hepatomas in male mice was experimentally determined as 43.1 mg/kg bw/day, T25 value for developing hepatomas in male mice was calculated as 13.9 mg/kg bw/day. DMELs were derived according to the REACH Guidance chapter R.8 (ECHA 2012a). As there is no conclusive evidence supporting that the substance acts as a threshold carcinogen, BCEE was assessed using the more conservative default approach of assuming no threshold.
Derivation of the modified dose descriptor:
The following correcting factors were taken into account in order to derive the modified dose descriptor:
- Deviation from standard test duration: The standard lifespan is considered to be 2 years in mice. However, the study was conducted for c.a. 18 months. More precisely, the male mice from strain (C57BL/6 x C3H/Anf)F1 were necropsied at 80 weeks. They were given BCEE in feed during the entire course of the experiment. Accordingly, the lifetime daily dose giving rise to a 25% tumour incidence was corrected by (80/104)2(= 0.591) (according to Appendix R8-6 of Echa guidance).
-Route-specific bioavailability: The absorption rate via the oral route was found to be 98 % based on experimental data (Lingg et al., 1982). No data on the absorption rate via the dermal route is available. Therefore, both adsorption rates were set to 100%.
- Occupational vs. lifetime exposure:For non-threshold carcinogens, lifetime risks for consumers and for humans exposed indirectly via the environment is associated with daily exposure of 24 hours (7 days a week) for 75 years. This exposure duration is considered equivalent to the life-time exposure in experimental studies of 2 years. For workers, however, the exposure time is 8 hours per day, 5 days per week, 48 weeks per year for 40 years. This implies that for workers, a correction factor should be applied to the dose descriptor based on animal life-time exposure data. The default value of 2.8 (7/5 x 52/48 x 75/40) proposed in REACH guidance R.8 was applied.
Based on the above, the modified dose descriptor was set to:
13.9 * 0.591 * 100/100 * 2.8 =23 mg/kg bw/day
Acute/short term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
Workers - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- no hazard identified
Additional information - workers
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
General Population - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
General Population - Hazard via oral route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
General Population - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- no hazard identified
Additional information - General Population
No hazard assessment is performed for the general population as the use of the substance is restricted to workers.
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