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Diss Factsheets

Administrative data

Description of key information

1. Acute toxicity via the oral route:

Acute toxicity data following administration by the orale route were identified in three publications. Most data originate from pre-GLP studies and data on post-exposure observations are limited. The lowest mammalian LD50 was reported by Smyth (J. Ind Hyg. Toxicol., 1948, 30(1):63-8). In this studies, the rat LD50 was found to be 75 mg/kg bw. In Drake & Myer (1990), a synthetic summary of an acute oral toxicity study on mice and rats is reported. The rat LD50 (male/female) was found to be 144 mg/kg bw, while a mice LD50 (male/female) of 211 mg/kg bw is reported. In both cases, deaths occurred in the first days following exposure (by day 3 for rats and day 5 for mice). Exposure to Bis(2-chloroethyl) ether did not induce any remarkable changes in body weight nor any visible abnormalities in any surviving rats at study termination. Pharmacotoxic signs observed in rats included ptosis, increased salivation, mucoid diarrhea, soft stool, anogenital staining and decreased activity. In mice, low carriage, decreased activity, ataxia, tremors and anogenital staining was observed. No details on organ necropsy of histological examionation were reported. Other mammalian LD50 data were published in Spector (1956). These data originate from unpublished studies by Smyth. Rat, mice and rabbit LD50 were found to be 105, 136 and 126 mg/kg bw. Taken together, these data suggest that their is no marked differences in the sensitivity of these species towards the toxicity of Bis(2-chloroethyl) ether after oral administration.

2. Acute toxicity via the inhalation route:

All available data related to the acute toxicity through the inhalation route of bis(2-chloroethyl) ether were generated in published pre-GLP studies. The lowest reliable LD50 values were published in a data book from the USSR State Committee for Science and Technology and republished in English by UNEP (Izmerov, 1982). The methodology used to acquire these data is not detailed. In rats, the LC50 following a 4 hour exposure to mist of Bis(2-chloroethyl) ether was 0.330 mg/L. The LC50 following a 2 hour exposure of mice to mist of Bis(2-chloroethyl) ether was 0.650 mg/L. Based on modified Haber's law as detailed in the Guidance on IR&CSA Section R.7.4.4.1, the mice LC50 is 0.325 mg/L when exposure duration is extrapolated to 4h. Both rats and mice LD50 data classify Bis(2-chloroethyl) ether in the Acute Category II according to the CLP criteria. In addition, Izmerov (1982) report the fact that LOEL based on irritation of mucous membranes of upper airways estimated using vital staining of lung tissue was 0.017 mg/L in rats (unspecified exposure length) and 0.019 mg/L in rabbits (5 min exposure length). In carpenter et al. (J. Ind. Hyg. Toxicol., 1948, 31(6):343-6), 96 compounds were graded on the basis of the response of rats (6 test animals) to a 4-hour vapor exposure in a 14-day observation period. In the conditions of this test, exposure to vapour of Bis(2-chloroethyl) ether at 250 ppm led to the death of 2 to 4 animals (out of 6). No results regarding clinical signs or gross pathology are reported. Based on these observation, the LC50 is thus approximatively 250 ppm or 1.464 mg/L. In Schrenk et al. (Public Health Rep., 1933, 48(46):1389-98), the authors report that following a 4.5h exposure period to Bis(2-chloroethyl) ether, no Guinea pigs died at a vapour concentration of 0.618 mg/L while most guinea pigs died within 24h at 1.550 mg/L. In the conditions of this experiment, Bis(2 -chloroethyl) ether LC50 lies between 0.168 and 1.550 mg/L. In this study, Bis(2-chloroethyl) ether was found to be an intense irritant to the respiratory passages and lungs, causing congestion, edema, and hemorrhage of the lung, which progresses with time to, in some instances, complete consolidation, often giving rise to a delayed death 1 to 8 days after exposure. The authors concluded that the pathology of Bis(2-chloroethyl) ether was similar to that produced by other respiratory irritants, such as the acid gases.

3. Acute toxicity via the dermal route:

All available data related to the acute toxicity of bis(2-chloroethyl) ether through the dermal route were generated in published pre-GLP studies. The lowest LD50 is reported by Clayton & Clayton (Patty's Indutsrial Hygiene and Toxicology, Vol. IIA (3rd revised edition), 1981, p. 2518). The data originates an internal toxicity test from Dow Chemical Co. Following exposure by skin contact to a 10 % Bis(2-chloroethyl) ether solution in propylene glycol for 24 hours, the rabbit LD50 was found to be 90 mg/kg bw. It is not stated if the reported LD50 of 90 mg/kg bw is based on the applied substance or the Bis(2-chloroethyl) ether content. As worst case scenario, it is assumed that the LD50 is based on the total applied material. Other LD50 data obtained on rabbits and guinea pigs (see "Additional information" for details) range between 366 and 870 mg/kg, which question the representativity and reliability of the data selected by Clayton & Clayton (1981).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
according to guideline
Guideline:
other: Range Finding Test of Smyth and Carpenter (1944)
Principles of method if other than guideline:
- Principle of test: standard acute test discribed in Smyth & Carpenter (1944), The place of the range finding test in the industrial toxicology laboratory. J. Ind. Hyg. Toxicol. 26, 269-273 and subsequent updates
GLP compliance:
no
Remarks:
pre-GLP
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
TEST MATERIAL
Name of test material (as cited): Dichloroethyl ether
Purity: not specified
Species:
rat
Strain:
Sherman
Sex:
male
Route of administration:
oral: gavage
Vehicle:
water
Doses:
10, 100, 1000, 10000 mg/kg bw etc.
No. of animals per sex per dose:
6
Details on study design:
Details on study design
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: No data available
- Necropsy of survivors performed: No data available
- Other examinations performed: Mortality
Other details:
6 male Sherman strain rats are given a single dose by stomach tube of 10, 1, 0.1, etc. g/kg body weight. One week later six more animals are given some other dosage and this procedure is repeated until two dosages differing by a multiple of ten are found, one of which within fourteen days kills some or all animals and the other of which kills some or no animals. An LD50 is then estimated on the assumption that the slope of a probit mortality vs. log dosage curve is the same as that of some structurally similar material which has been studied in more details previously.
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
75 mg/kg bw
Based on:
test mat.
Clinical signs:
other: No data
Gross pathology:
No data
Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
Following the oral (gavage) exposure of groups of 6 Sherman rats at 10, 100, 1000, 10000 mg/kg bw, the LD50 value obtained for Bis(2-chloroethyl) ether in rat by oral route is 75 mg/kg. This data classifies the substance in the Acute Category III according to GHS criteria.
Executive summary:

In this pre-GLP study, groups of 6 Sherman rats were exposed to Bis(2-chloroethyl) ether through the orale route (gavage) at 10, 100, 1000, 10000 mg/kg bw. The methodology used is derived from the Range Finding method of Smyth and Carpenter (1944). Mortality of test animals was monitored for 14 days post-exposure. No clinical observations, body weight measurements or necropsy data are reported in the original publication.

The rat LD50 of Bis(2-chloroethyl) ether following single exposure by the oral route was found to be 75 mg/kg bw. Despite the lack of detailed observation following exposure to the substance, the data were generated based on a standardised method and has been peer-reviewed.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Guideline:
other: standard acute test
GLP compliance:
no
Remarks:
pre-GLP
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
TEST MATERIAL
Name (as cited): 2,2'-dichloroethyl ether
Purity: not specified
Species:
mouse
Strain:
not specified
Sex:
not specified
Route of administration:
oral: unspecified
Vehicle:
not specified
Doses:
No data
No. of animals per sex per dose:
No data
Sex:
not specified
Dose descriptor:
LD50
Effect level:
136 mg/kg bw
Based on:
test mat.
95% CL:
112 - 165
Clinical signs:
other: No data
Gross pathology:
No data
Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The LD50 value obtained for Bis(2-chloroethyl) ether in mice by the oral route is 136 mg/kg. This data classifies the substance in the Acute category III according to GHS criteria.
Executive summary:

This handbook reports unpublished acute oral toxicity data by Smyth H.F. Jr. (Mellon Insitute, Pittsburgh University). The LD50 value obtained for Bis(2-chloroethyl) ether in mice by the oral route is 136 mg/kg. This data classifies the substance in the Acute category III according to GHS criteria.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Qualifier:
according to guideline
Guideline:
other: standard acute test
GLP compliance:
no
Remarks:
pre-GLP
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
TEST MATERIAL
Name (as cited): 2,2'-dichloroethyl ether
Purity: not specified
Species:
rat
Strain:
not specified
Sex:
not specified
Route of administration:
oral: unspecified
Vehicle:
not specified
Doses:
No data
No. of animals per sex per dose:
No data
Sex:
not specified
Dose descriptor:
LD50
Effect level:
105 mg/kg bw
Based on:
test mat.
95% CL:
95 - 116
Clinical signs:
other: No data
Gross pathology:
No data
Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The LD50 value obtained for Bis(2-chloroethyl) ether in rats by the oral route is 105 mg/kg. This data classifies the substance in the Acute Category III according to GHS criteria.
Executive summary:

This handbook reports unpublished acute oral toxicity data by Smyth H.F. Jr. (Mellon Insitute, Pittsburgh University). The LD50 value obtained for Bis(2-chloroethyl) ether in rats following exposure by the oral route is 105 mg/kg. This data classifies the substance in the Acute Category III according to GHS criteria.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Qualifier:
according to guideline
Guideline:
other: standard acute test
GLP compliance:
no
Remarks:
pre-GLP
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
TEST MATERIAL
Name (as cited): 2,2'-dichloroethyl ether
Purity: not specified
Species:
rabbit
Strain:
not specified
Sex:
not specified
Route of administration:
oral: unspecified
Vehicle:
not specified
Doses:
No data
No. of animals per sex per dose:
No data
Sex:
not specified
Dose descriptor:
LD50
Effect level:
126 mg/kg bw
Based on:
test mat.
95% CL:
117 - 135
Clinical signs:
other: No data
Gross pathology:
No data
Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The LD50 value obtained for Bis(2-chloroethyl) ether in rabbits by the oral route is 126 mg/kg. This data classifies the substance in the Acute category III according to GHS criteria.
Executive summary:

This handbook reports unpublished acute oral toxicity data by Smyth H.F. Jr. (Mellon Insitute, Pittsburgh University). The LD50 value obtained for Bis(2-chloroethyl) ether in rabbits following exposure by the oral route is 126 mg/kg. This data classifies the substance in the Acute category III according to GHS criteria.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Qualifier:
according to guideline
Guideline:
other: standard acute test
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
TEST MATERIAL
- Name (as cited): DCEE
- CAS registry number: 111-44-4
- Synonyms: Bis(2-chloroethyl) ether, BCEE, dichloroethyl ether
- Purity: not specified
Species:
mouse
Strain:
CD-1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 20-30g
Route of administration:
oral: unspecified
Vehicle:
cotton seed oil
Doses:
Doses: 140, 200, 240, 290 mg/kg bw. Oral doses of DCEE were diluted with cottonseed oil (dose volume = 10 ml/kg).
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily clinical observation; body weights on days 1,8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: A gross necropsy was performed on dead animal at the time of death
Statistics:
LD50 and 95% confindence intervals were determined according to:
- Bliss, CI (1938). Quarterly Journal Pharm Pharmacol 11, 192-216.
- Rosiello, AP et al. (1977). Journal Toxicology and Environmental Health, 3, 797-809.
Sex:
female
Dose descriptor:
LD50
Effect level:
209 mg/kg bw
Based on:
test mat.
95% CL:
186 - 236
Sex:
male
Dose descriptor:
LD50
Effect level:
215 mg/kg bw
Based on:
test mat.
95% CL:
173 - 266
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
211 mg/kg bw
Based on:
test mat.
95% CL:
187 - 237
Mortality:
see "Any other information on results incl. tables"
Clinical signs:
other: Clinical signs included low carriage, decreased activity, ataxia, tremors and anogenital staining.
Gross pathology:
In animals that died, findings included congestion and black foci of the gastric mucosa. There were no visible abnormalities in any mice sacrificed at study termination.

All deaths occurred by day 5. The mortality occurred as follows:

   140 mg/kg bw   200 mg/kg bw   240 mg/kg bw   290 mg/kg bw
 Males  0/5  3/5  4/5  3/5
 Females  0/5  2/5  4/5  5/5
 Total  0/10  5/10  8/10  8/10
Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The LD50 value obtained for Bis(2-chloroethyl) ether in mice (male/female) by the oral route is 211 mg/kg. This data classifies the substance in the Acute Category III according to GHS criteria.
Executive summary:

This report from Buckman Laboratories International Inc. present a synthetic summary of an acute oral toxicity study on mice. Bis(2-chloroethyl) ether was administered to 5 male and 5 female CD-1 mice in doses ranging from 140 to 290 mg/kg bw. The mice were monitored for 15 days after dosing. The LD50 was 215 mg/kg bw (CI 95%: 173 -266 mg/kg bw) in males, 209 mg/kg bw (CI 95%: 186 -236) in females and 211 mg/kg bw (CI 95%: 187 -237 mg/kg bw) for males and females combined.

All deaths occurred by day 5. Pharmacotoxic signs observed included low carriage, decreased activity, ataxia, tremors and anogenital staining. There were no remarkable changes in body weights. In animals that died, findings included congestion and black foci of the gastric mucosa. There were no visible abnormalities in any mice sacrificed at study termination.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Qualifier:
according to guideline
Guideline:
other: standard acute test
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
TEST MATERIAL
- Names (as cited): DCEE
- CAS registry number: 111-44-4
- Synonyms: Bis(2-chloroethyl) ether, BCEE, dichloroethyl ether
- Purity: not specified
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 150-300g
Route of administration:
oral: unspecified
Vehicle:
cotton seed oil
Doses:
Doses: 70, 100, 150, 210 mg/kg bw. Oral doses of DCEE were diluted with cottonseed oil (dose volume = 10 ml/kg).
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily clinical observation; body weights on days 1,8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: A gross necropsy was performed on dead animal at the time of death
Statistics:
LD50 and 95% confindence intervals were determined according to:
- Bliss, CI (1938). Quarterly Journal Pharm Pharmacol 11, 192-216.
- Rosiello, AP et al. (1977). Journal Toxicology and Environmental Health, 3, 797-809.
Sex:
female
Dose descriptor:
LD50
Effect level:
122 mg/kg bw
Based on:
test mat.
95% CL:
101 - 148
Sex:
male
Dose descriptor:
LD50
Effect level:
175 mg/kg bw
Based on:
test mat.
95% CL:
119 - 259
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
144 mg/kg bw
Based on:
test mat.
95% CL:
120 - 172
Mortality:
see "Any other information on results incl. tables"
Clinical signs:
other: Clinical signs included ptosis, increased salivation, mucoid diarrhea, soft stool, anogenital staining and decreased activity.
Gross pathology:
In animals that died, findings included congestion of the lung/thymus. There were no visible abnormalities in any rats at study termination.
Other findings:
All survivors appeared normal by day 5.

All deaths occurred by day 3. The mortality occurred as follows:

   70 mg/kg bw   100 mg/kg bw   150 mg/kg bw   210 mg/kg bw
 Males  0/5  1/5  2/5  3/5
 Females  0/5  1/5  4/5  5/5
 Total  0/10  2/10  6/10  8/10
Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The LD50 value obtained for Bis(2-chloroethyl) ether in rats (male/female) by the oral route is 144 mg/kg. This data classifies the substance in the Acute category III according to GHS criteria.
Executive summary:

This report from Buckman Laboratories International Inc. presents a synthetic summary of an acute oral toxicity study on rats. Bis(2-chloroethyl) ether was administered to 5 male and 5 female Sprague-Dawley rats in doses ranging from 70 to 210 mg/kg bw. The rats were monitored for 14 days after dosing. The LD50 was 175 mg/kg bw (CI 95%: 119-259 mg/kg bw) in males, 122 mg/kg bw (CI 95%: 101-148) in females and 144 mg/kg bw (CI 95%: 120-172 mg/kg bw) for males and females combined.

All deaths occurred by day 3. Pharmacotoxic signs observed included ptosis, increased salivation, mucoid diarrhea, soft stool, anogenital staining and decreased activity. All survivors appeared normal by day 5. There were no remarkable changes in body weights. In animals that died, findings included congestion of the lung/thymus. There were no visible abnormalities in any rats at study termination.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
75 mg/kg bw
Quality of whole database:
The assessment rely mostly on pre-GLP studies. None of the studies reported were explicitely conducted according to guidelines. The organ toxicity of BCEE following a single orale exposure has not been thoroughly investigated.

Acute toxicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
Age of test animals not specified. Weight variation among test animals not specified. Acclimation period not specified. Unclear if negative control animals were used. No analytical check of the concentration of the prepared vapour.
GLP compliance:
no
Remarks:
pre-GLP
Test type:
traditional method
Limit test:
no
Specific details on test material used for the study:
TEST MATERIA
- Name (as cited): 2, 2' -dichloroethyl ether
- Purity: not specified
Species:
rat
Strain:
Sherman
Sex:
not specified
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Mellon institute in-house breeding
- Age at study initiation: not specified
- Weight at study initiation: 100-150 g
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
air
Analytical verification of test atmosphere concentrations:
no
Duration of exposure:
4 h
Concentrations:
Not specified
No. of animals per sex per dose:
6
Control animals:
not specified
Sex:
not specified
Dose descriptor:
LC50
Effect level:
ca. 250 ppm
Based on:
test mat.
Remarks:
nominal concentration
Exp. duration:
4 h
Remarks on result:
other: equivalent to 1.464 mg/L
Mortality:
No detailed mortality data are reported
Clinical signs:
other: The data are not reported
Body weight:
The data are not reported
Gross pathology:
The data are not reported
Interpretation of results:
Category 2 based on GHS criteria
Conclusions:
In the conditions of this test, exposure to vapour of Bis(2-chloroethyl) ether at 250 ppm led to the death of 2 to 4 animals (out of 6). The LC50 is thus approximatively 250 ppm or 1.464 mg/L. This data classifies the substance in the Acute Category II according to the CLP criteria.
Executive summary:

In this publication, 96 compounds were graded on the basis of the response of rats to a 4-hour vapor exposure followed by a 14-day observation period. The methodological aspects of the study are described in sufficient details and, despite detailed results are not reported, the data are judged reliable.

In the conditions of this test, exposure to vapour of Bis(2-chloroethyl) ether at 250 ppm led to the death of 2 to 4 animals (out of 6). No results regarding clinical signs or gross pathology are reported. Based on these observation, the LC50 in Sherman rats is thus approximatively 250 ppm or 1.464 mg/L Bis(2 -chloroethyl) ether. This data classifies the substance in the Acute Category II according to the CLP criteria.

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
TEST MATERIAL
- Name (as cited): β,β'-dichloroethyl ether (chlorex)
- Purity: not specified
Species:
rat
Strain:
not specified
Sex:
not specified
Route of administration:
inhalation: mist
Type of inhalation exposure:
not specified
Vehicle:
not specified
Analytical verification of test atmosphere concentrations:
yes
Remarks:
by photometry (detection limit 5µg in analytical volume)
Duration of exposure:
4 h
Concentrations:
No data
No. of animals per sex per dose:
No data
Control animals:
not specified
Key result
Sex:
not specified
Dose descriptor:
LC50
Effect level:
0.33 mg/L air
Based on:
test mat.
95% CL:
>= 0.135 - <= 0.528
Exp. duration:
4 h
Sex:
not specified
Dose descriptor:
other: LOEC
Remarks:
Based on behavior
Effect level:
0.08 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Sex:
not specified
Dose descriptor:
other: LOEC
Remarks:
Based on based on irritation of mucous membranes of upper airways
Effect level:
0.017 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Mortality:
Not data
Clinical signs:
other: Not data
Body weight:
Not data
Gross pathology:
Not data
Interpretation of results:
Category 2 based on GHS criteria
Conclusions:
The LC50 following a 4 hour exposure of rats to mist of Bis(2-chloroethyl) ether was 0.330 mg/L. Based on behavior, the LOEL was found to be 0.080 mg/L. Based on irritation of mucous membranes of upper airways estimated using vital staining of lung tissue, the LOEL was 0.017 mg/L. This data classifies Bis(2-chloroethyl) ether in the Acute Category II according to the CLP criteria.
Executive summary:

This data book originally published by the USSR State Committee for Science and Technology and republished in English by UNEP. As the data originate from leading international organizations, they are judged reliable. The LC50 following a 4 hour exposure of rats to mist of Bis(2-chloroethyl) ether was 0.330 mg/L. Based on behavior, the LOEC was found to be 0.080 mg/L. Based on irritation of mucous membranes of upper airways estimated using vital staining of lung tissue, the LOEC was 0.017 mg/L. This data classifies Bis(2-chloroethyl) ether in the Acute Category II according to the CLP criteria.

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
TEST MATERIAL
- Name (as cited): β,β'-dichloroethyl ether (chlorex)
- Purity: not specified
Species:
rat
Strain:
not specified
Sex:
not specified
Route of administration:
inhalation: mist
Type of inhalation exposure:
not specified
Vehicle:
not specified
Analytical verification of test atmosphere concentrations:
yes
Remarks:
by photometry (detection limit 5 µg in analytical volume)
Duration of exposure:
2 h
Concentrations:
No data
No. of animals per sex per dose:
No data
Control animals:
not specified
Sex:
not specified
Dose descriptor:
LC50
Effect level:
0.65 mg/L air
Based on:
test mat.
95% CL:
>= 0.54 - <= 0.78
Exp. duration:
2 h
Mortality:
No data
Clinical signs:
other: No data
Body weight:
No data
Gross pathology:
No data
Interpretation of results:
Category 2 based on GHS criteria
Conclusions:
The LC50 following a 2 hour exposure of mice (sex not specified) to mist of Bis(2-chloroethyl) ether was 0.650 mg/L. Based on modified Haber's law as detailed in the Guidance on IR&CSA Section R.7.4.4.1, the mice LC50 is 0.325 mg/L when exposure duration is extrapolated to 4h. This data classifies Bis(2-chloroethyl) ether in the Acute Category II according to the CLP criteria.
Executive summary:

This data book originally published by the USSR State Committee for Science and Technology and republished in English by UNEP. As the data originate from leading international organizations, they are judged reliable. The LC50 following a 2 hour exposure of mice (sex not specified) to mist of Bis(2-chloroethyl) ether was 0.650 mg/L. Based on modified Haber's law as detailed in the Guidance on IR&CSA Section R.7.4.4.1, the mice LC50 is 0.325 mg/L when exposure duration is extrapolated to 4h. This data classifies Bis(2-chloroethyl) ether in the Acute Category II according to the CLP criteria.

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
TEST MATERIAL
- Name (as cited): β,β'-dichloroethyl ether (chlorex)
- Purity: not specified
Species:
rabbit
Strain:
not specified
Sex:
not specified
Route of administration:
inhalation: mist
Type of inhalation exposure:
not specified
Vehicle:
not specified
Analytical verification of test atmosphere concentrations:
yes
Remarks:
by photometry (detection limit 5 µg in analytical volume)
Duration of exposure:
5 min
Concentrations:
No data
No. of animals per sex per dose:
No data
Control animals:
not specified
Sex:
not specified
Dose descriptor:
other: LOEC
Remarks:
Based on based on irritation of mucous membranes of upper airways
Effect level:
0.019 mg/L air
Based on:
test mat.
Exp. duration:
5 min
Mortality:
No data
Clinical signs:
other: No data
Body weight:
No data
Gross pathology:
No data
Conclusions:
Based on irritation of mucous membranes of upper airways estimated using vital staining of lung tissue, the LOEC in rabbits was 0.019 mg/L following a 5 min exposure period.
Executive summary:

This data book originally published by the USSR State Committee for Science and Technology and republished in English by UNEP. As the data originate from leading international organizations, they are judged reliable. Based on irritation of mucous membranes of upper airways estimated using vital staining of lung tissue, the LOEC in rabbits was 0.019 mg/L following a 5 min exposure period.

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
Method decribed in Yant et al. (1931) Ind. Eng. Chem., 1931, 23 (5), pp 551–555 with modifications.
GLP compliance:
no
Remarks:
pre-GLP
Test type:
other: acute standard test
Specific details on test material used for the study:
TEST MATERIAL
- Name (as cited): BB' dichloroethyl ether
- Purity: not specified
Species:
guinea pig
Strain:
not specified
Sex:
not specified
Details on test animals or test system and environmental conditions:
Pre-acclimation period: yes
Test chambers: gas tight; 288 cubic feet capacity; made of metal-covered framework and wire-embedded plate glass; fitted with all-metal cages for housing the animals
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
Vapor-air mixtures:
To reach vapour saturation (approximately 0.1 % vapor in air by volume), air was blown by means of a fan across a series of wicks suspended in a reservoir of dichloroethyl ether three hours before the guinea pigs were placed in the chamber. For concentrations below saturation, vapor-air mixture was maintained by continuously vaporizing a measured quantity of the liquid in a measured volume of air.

Test atmosphere:
The atmosphere of the test chamber is replaced at a constant rate of 8 air changes per hour.

Analytical verification of test atmosphere concentrations:
yes
Remarks:
Hydrolysis of a known volume of test atmopshere and inorganic chlorides determination by the Volhard method
Duration of exposure:
13.5 h
Concentrations:
0, 0.205, 0.618, 1.550, 3.349, 6.062 mg/L (measured)
No. of animals per sex per dose:
Not specified
Control animals:
yes
Details on study design:
No data available
Dose descriptor:
LC50
Effect level:
> 0.618 - < 1.55 mg/L air (nominal)
Based on:
test mat.
Exp. duration:
4.5 h
Mortality:
No detailed data preported
Clinical signs:
other: - At high concentrations (3.349 and 6.062 mg/L): immediate intense irritation of the conjunctiva and nasal mucous membrane (lacrimation and squinting of the eyes, scratching at the nose with the forepaws), decreasing motility, slight retching and slow lab
Gross pathology:
- Control animals: no significant gross pathology findings

- Exposed animals that died: moderate to marked congestion of the brain, severe congestion of the lungs and nasal passages, including trachea and bronchi, with emphysema, edema, and hemorrhages of lungs and occasional complete consolidation

- Exposed animals tthat survived: similar symptoms but delayed response. Animals exposed for shorter period of time showed recovery.

The table below presents the average time required to observed the symptoms following exposure to various Bis(2-chloroethyl ether concentrations):

          Type of symptom     Period of exposure causing symptom (min) as a function of vapour concentration (mg/L)
 6.062  3.349

 1.550

  0.618  0.205

 Nasal irritation

(scratchning of nose)

 Immediately Immediately 1 2 3-10

 Eye irritation

(Squinting)

 Immediately Immediately 1 20 Not observed

Eye irritation

(Lacrimation)

 1-2 1-2 3 Not observed Not observed
Disturbance in respiration 90 180 310 450 Not observed
Disturbance of motility 180-300 240-480 445-600 525-810 Not observed
Death 230-330 360-500 450-470 Unclear Not observed
Interpretation of results:
Category 2 based on GHS criteria
Conclusions:
Following a 4.5h exposure period to Bis(2-chloroethyl) ether, no Guinea pigs died at a vapour concentration of 0.618 mg/L while most guinea pigs died within 24h at 1.550 mg/L. In the conditions of this experiment, Bis(2 -chloroethyl) ether LC50 lies between 0.618 and 1.550 mg/L. These experimental data classifies the substance in the Acute Category II according to GHS criteria.
Executive summary:

In guinea pigs, Bis(2-chloroethyl) ether was found to be an intense irritant to the respiratory passages and lungs, causing congestion, edema, and hemorrhage of the lung, which progresses with time to, in some instances, complete consolidation, often giving rise to a delayed death 1 to 8 days after exposure. The brain shows moderate to marked congestion. Congestion of the liver and kidneys was evident in varying degree. The authors concluded that the pathology of Bis(2-chloroethyl) ether was similar to that produced by other respiratory irritants, such as the acid gases.

No precise LC50 was estimated from the experimental data. However, it is reported that following a 4.5h exposure period to Bis(2-chloroethyl) ether, no Guinea pigs died at a vapour concentration of 0.618 mg/L while most guinea pigs died within 24h at 1.550 mg/L. In the conditions of this experiment, Bis(2 -chloroethyl) ether LC50 lies between 0.618 and 1.550 mg/L. The experimental data classifies the substance in the Acute Category II according to GHS criteria.

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
Justification for type of information:
Unsufficient methodological details and results are reported for assessment of data quality
Qualifier:
no guideline required
Principles of method if other than guideline:
Smyth HF Jr, Carpenter CP (1944): The place of the range finding test in the industrial toxicology laboratory. J. Ind. Hyg. Toxicol. 26, 269-273 and subsequent updates
GLP compliance:
no
Remarks:
pre-GLP
Specific details on test material used for the study:
TEST MATERIAL
- Name (as cited): Dichlorethyl ether
- Purity: not specified
Species:
rat
Strain:
not specified
Sex:
not specified
Details on test animals or test system and environmental conditions:
No data
Route of administration:
inhalation: vapour
Type of inhalation exposure:
not specified
Vehicle:
air
Analytical verification of test atmosphere concentrations:
no
Remarks:
Concentrations estimated from the settings of a proportioning pump and flowmeter
Duration of exposure:
0.75 h
Concentrations:
No specified
No. of animals per sex per dose:
6
Control animals:
not specified
Sex:
not specified
Dose descriptor:
LC50
Effect level:
1 000 ppm
Based on:
test mat.
Remarks:
nominal
Exp. duration:
0.75 h
Mortality:
No detailed data reported
Clinical signs:
other: No data
Body weight:
No data
Gross pathology:
No data
Interpretation of results:
Category 2 based on GHS criteria
Conclusions:
In the conditions of this test, exposure to vapour of Bis(2-chloroethyl) ether at 1000 ppm during 3/4 h led to the death of 3/6 animals over the 14 day observation period. Based on modified Haber's law as detailed in the Guidance on IR&CSA Section R.7.4.4.1, the rat LC50 is 187.5 ppm when the exposure duration is extrapolated to 4h (equivalent to 1.092 mg/L). This data classifies the substance in the Acute Category II according to GHS criteria.
Executive summary:

In the conditions of this test, exposure to vapour of Bis(2-chloroethyl) ether at 1000 ppm during 3/4 h led to the death of 3/6 animals over the 14 day observation period. No results regarding clinical signs or gross pathology are reported. Based on modified Haber's law as detailed in the Guidance on IR&CSA Section R.7.4.4.1, the rat LC50 is 187.5 ppm when the exposure duration is extrapolated to 4h (equivalent to 1.092 mg/L). This data classifies the substance in the Acute Category II according to GHS criteria.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
325 mg/m³ air
Quality of whole database:
Acute toxicity data via the inhalation route were identified in 4 publication. The assessment rely exclusively on pre-GLP studies with limited observation beyong mortality of test animals. Only one study (Schrenk et al. 1933) provides dose-response data for other endpoints of toxicity than mortality (lung irritation and edema).Further inhalation studies using modern analytical and histological techniques would be valuable in confirming and refining the limited data available on lung injury, and in determining whether other tissues are injured as well.

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
It is not clear if the administered dose refers to the 10 % solution prepared or to BCEE. This causes uncertainty in the interpretation of the results
Principles of method if other than guideline:
No information provided
GLP compliance:
not specified
Species:
rabbit
Strain:
not specified
Sex:
not specified
Type of coverage:
not specified
Vehicle:
propylene glycol
Duration of exposure:
24 h
Sex:
not specified
Dose descriptor:
LD50
Effect level:
90 mg/kg bw
95% CL:
>= 55 - <= 145
Remarks on result:
other: It is not stated if the reported LD50 of 90 mg/kg bw is based on the applied substance or the BCEE content.
Key result
Sex:
not specified
Dose descriptor:
LD50
Effect level:
9 mg/kg bw
95% CL:
>= 5.5 - <= 14.5
Remarks on result:
other: It is not stated if the reported LD50 of 90 mg/kg bw is based on the applied substance or the ai content. As worst case scenario, it is assumed that the LD50 is based on the total applied material. Hence, the LD50 based on ai is 10% of the applied amount
Interpretation of results:
Category 1 based on GHS criteria
Conclusions:
Following exposure by skin contact to a 10 % Bis(2-chloroethyl) ether solution in propylene glycol for 24 hours, the rabbit LD50 was found to be 90 mg/kg bw. Assuming that the LD50 is based on the total applied material, the LD50 based on Bis(2-chloroethyl) ether is 10% of the applied amount, i.e., 9 mg/kg bw. This data classifies the substance in the Acute Catgeory I according to GHS criteria.
Executive summary:

This handbook reports the results of an internal toxicity test from Dow Chemical Co. Following exposure by skin contact to a 10 % Bis(2-chloroethyl) ether solution in propylene glycol for 24 hours, the rabbit LD50 was found to be 90 mg/kg bw. It is not stated if the reported LD50 of 90 mg/kg bw is based on the applied substance or the Bis(2-chloroethyl) ether content. As worst case scenario, it is assumed that the LD50 is based on the total applied material. Hence, the LD50 based on Bis(2-chloroethyl) ether is 10% of the applied amount, i.e., 9 mg/kg bw. This data classifies the substance in the Acute Category I according to GHS criteria.

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
significant methodological deficiencies
Remarks:
4 days exposure; poultice data are regarded as obsolete because the saturated pad prevents complete contact of the dose with the skin
Principles of method if other than guideline:
Method described in Smyth & Carpenter (1944), The place of the range finding test in the industrial toxicology laboratory. J. Ind. Hyg. Toxicol., 26:269.
GLP compliance:
no
Remarks:
pre-GLP
Specific details on test material used for the study:
TEST MATERIAL
- Name (as cited): Dichloroethyl ether
- Purity: not specified
Species:
guinea pig
Strain:
not specified
Sex:
not specified
Type of coverage:
other: poultice
Vehicle:
unchanged (no vehicle)
Duration of exposure:
4 days
Control animals:
not specified
Dose descriptor:
LD50
Effect level:
366 mg/kg bw
Based on:
test mat.
Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
In the conditions of this test, the guinea pigs LD50 following dermal exposure to Bis(2-chloroethyl) ether for 4 days was 366 mg/kg bw. This result classifies the substance in the Acute Category III according to GHS criteria.
Executive summary:

In the conditions of this test, the guinea pigs LD50 following dermal exposure to Bis(2-chloroethyl) ether for 4 days was 366 mg/kg bw. No results regarding clinical signs or gross pathology are reported. This data is judge to have limited reliability as poultice data are regarded as obsolete because the saturated pad prevents complete contact of the dose with the skin. In addition, the exposure duration (4 days) is non standard.

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Principles of method if other than guideline:
No information available
GLP compliance:
no
Remarks:
pre-GLP
Specific details on test material used for the study:
TEST MATERIAL
- Name (as cited): 2,2'-dichloroethyl ether
- Purity: not specified
Species:
rabbit
Strain:
not specified
Sex:
not specified
Type of coverage:
not specified
Vehicle:
not specified
Duration of exposure:
Not specified
Control animals:
not specified
Sex:
not specified
Dose descriptor:
LD50
Effect level:
410 mg/kg bw
95% CL:
>= 360 - <= 460
Mortality:
No data available
Clinical signs:
other: No data available
Gross pathology:
No data available
Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The LD50 value obtained for Bis(2-chloroethyl) ether in rabbits following exposure by the dermal route is 410 mg/kg. This data classifies the substance in the Acute Category III according to GHS criteria.
Executive summary:

This handbook reports unpublished acute dermal toxicity data by Smyth H.F. Jr. (Mellon Insitute, Pittsburgh University). The LD50 value obtained for Bis(2-chloroethyl) ether in rabbits following exposure by the dermal route is 410 mg/kg. This data classifies the substance in the Acute Category III according to GHS criteria.

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Principles of method if other than guideline:
No information available
GLP compliance:
not specified
Species:
rabbit
Strain:
not specified
Sex:
not specified
Type of coverage:
not specified
Vehicle:
not specified
Duration of exposure:
Not specified
Control animals:
not specified
Dose descriptor:
LD50
Effect level:
870 mg/kg bw
Mortality:
No data available
Clinical signs:
other: No data available
Gross pathology:
No data available
Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
Bis(2-chloroethyl) ether was found to have a LD50 equal to 870 mg/kg in rabbits. This data classifies the substance in the Acute Category III according to GHS criteria.
Executive summary:

In this review on the toxicology of Bis(2-chloroethl) ether, the author cites an unpublished study from Union Carbide (1948), where Bis(2-chloroethyl) ether was found to have a LD50 equal to 870 mg/kg in rabbits. This data classifies the substance in the Acute Category III according to GHS criteria.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
9 mg/kg bw
Quality of whole database:
Four publications reports acute dermal toxicity data originating from pre-GLP studies. The data selected as key information is doubtful as it is unclear if the data is expressed in terms of active substance or diluted substance. All other available data support the classification of the substance in Acute Category III according to GHS criteria. Additional studies based on current guideline would be helpful in better characterizing the toxicity of the substance.

Additional information

1. Acute toxicity via the oral route:

Three published studies report the results of acute toxicity studies following single exposure to Bis(2-chloroethyl) ether by the oral route. All pre-GLP data were generated by Smyth (Mellon Institute). In his 1948 publication, groups of 6 Sherman rats were exposed to Bis(2-chloroethyl) ether through the orale route (gavage) at 10, 100, 1000, 10000 mg/kg bw. The methodology used is derived from the Range Finding method of Smyth and Carpenter (1944). Mortality of test animals was monitored for 14 days post-exposure. No clinical observations, body weight measurements or necropsy data are reported in the original publication. Other data from the same author are reported in Spector (1956). While no methodological details are reported, it can reasonnably be assumed that a very similar methodology was used. Rat, mice and rabbit LD50 were found to be 105, 136 and 126 mg/kg bw. More recently, Drake & Myer (Buckman Laboratories International, Inc. & International Research and Development Corp., 1990) conducted acute toxicity experiments in Sprague-Dawley rats and in CD-1 mice. Groups of 5 males and 5 females were exposed to Bis(2-chloroethyl) ether doses ranging from 70 to 210 mg/kg bw and from 140 to 290 mg/kg bw, in rats and mice, respecitevely. Animales were monitored for 2 weeks after dosing. The rat LD50 was 175 mg/kg bw (CI 95%: 119-259 mg/kg bw) in males, 122 mg/kg bw (CI 95%: 101-148) in females and 144 mg/kg bw (CI 95%: 120-172 mg/kg bw) for males and females combined. The mice LD50 was 215 mg/kg bw (CI 95%: 173 -266 mg/kg bw) in males, 209 mg/kg bw (CI 95%: 186 -236) in females and 211 mg/kg bw (CI 95%: 187 -237 mg/kg bw) for males and females combined. In both cases, deaths occurred in the first days following dosing (in the first 3 days for rats and in the first 5 days for mice). Exposur to the substance did not induce any remarkable chnage in body weight and surviving animals recovered by the end of the observation period. No visible abnormalities in any rats or mice at study termination. The published report does not include a detailed description of necropsy or histological observations. Organ toxicity of Bis(2 -chloroethyl) ether following single oral exposure remains understudied.

2. Acute toxicity via the inhalation route:

All data on the acute toxicity of Bis(2-chloroethyl) ether through the inhalation route orignate from pre-GLP studies. In a data book published by the USSR State Committee for Science and Technology and republished in English by UNEP, Izmerov (1982) reports 4h exposure LD50 estimates on rats and mice. The methodology in these experiments is unknown. Data originating from handbook and data books are considered reliable as it is assumed that a variety of data sources have been consulted, that the test methodology and identity of the test substance has been evaluated, and that a reliable and representative value for the endpoint has been selected. They were thus judged acceptable for this assessment. The LC50 following a 4 hour exposure of rats to mist of Bis(2-chloroethyl) ether was 0.330 mg/L. Based on behavior, the LOEL was found to be 0.080 mg/L. Based on irritation of mucous membranes of upper airways estimated using vital staining of lung tissue, the LOEL was 0.017 mg/L. In mice, The LC50 following a 2 hour exposure to mist of Bis(2-chloroethyl) ether was 0.650 mg/L. Based on modified Haber's law as detailed in the Guidance on IR&CSA Section R.7.4.4.1, the mice LC50 is 0.325 mg/L when exposure duration is extrapolated to 4h. This data classifies Bis(2-chloroethyl) ether in the Acute Category II according to the CLP criteria. Based on irritation of mucous membranes of upper airways estimated using vital staining of lung tissue, the LOEL in rabbits was 0.019 mg/L following a 5 min exposure period. In Carpenter et al. (1948), 96 compounds were graded on the basis of the response of rats to a 4-hour vapor exposure in a 14-day observation period. The methodological aspects of the study are described in sufficient details and, despite detailed results are not reported, the data are judged reliable.In the conditions of this test, exposure to vapour of Bis(2-chloroethyl) ether at 250 ppm led to the death of 2 to 4 animals (out of 6). No results regarding clinical signs or gross pathology are reported. Based on these observation, the LC50 is thus approximatively 250 ppm or 1.464 mg/L Bis(2 -chloroethyl) ether. This data classifies the substance in the Acute Category II according to the CLP criteria. In Schrenk et al. (1933), Bis(2-chloroethyl) ether was found to be an intense irritant to the respiratory passages and lungs of Guinea pigs, causing congestion, edema, and hemorrhage of the lung, which progresses with time to, in some instances, complete consolidation, often giving rise to a delayed death 1 to 8 days after exposure. The brain shows moderate to marked congestion. Congestion of the liver and kidneys was evident in varying degree. The authors concluded that the pathology of Bis(2-chloroethyl) ether was similar to that produced by other respiratory irritants, such as the acid gases. No precise LC50 was estimated from the experimental data. However, it is reported that following a 4.5h exposure period to Bis(2-chloroethyl) ether, no Guinea pigs died at a vapour concentration of 0.618 mg/L while most guinea pigs died within 24h at 1.550 mg/L. In the conditions of this experiment, Bis(2 -chloroethyl) ether LC50 lies between 0.168 and 1.550 mg/L. Finally, in Smyth and Carpenter (1948), rats were exposed to a single dose of Bis(2 -chloroethyl) ether. Unsufficient methodological details and results are reported for assessment of data quality. In the conditions of this test, exposure to vapour of Bis(2-chloroethyl) ether at 1000 ppm during 3/4 h led to the death of 3/6 animals over the 14 day observation period. No results regarding clinical signs or gross pathology are reported. Based on modified Haber's law as detailed in the Guidance on IR&CSA Section R.7.4.4.1, the rat LC50 is 187.5 ppm when the exposure duration is extrapolated to 4h (equivalent to 1.092 mg/L).

3. Acute toxicity via the dermal route:

All available data related to the acute toxicity of bis(2-chloroethyl) ether through the dermal route were generated in published pre-GLP studies. The lowest LD50 is reported by Clayton & Clayton (Patty's Indutsrial Hygiene and Toxicology, Vol. IIA (3rd revised edition), 1981, p. 2518). The data originates from an internal toxicity test from Dow Chemical Co. Following exposure by skin contact to a 10 % Bis(2-chloroethyl) ether solution in propylene glycol for 24 hours, the rabbit LD50 was found to be 90 mg/kg bw. It is not stated if the reported LD50 of 90 mg/kg bw is based on the applied substance or the Bis(2-chloroethyl) ether content. As worst case scenario, it is assumed that the LD50 is based on the total applied material. Hence, the LD50 based on Bis(2-chloroethyl) ether is 10% of the applied amount, i.e., 9 mg/kg bw. Spector (1956) reports an unpublisheddermal toxicity study by Smyth (Mellon Insitute, Pittsburgh University). The LD50 value obtained for Bis(2-chloroethyl) ether in rabbits following exposure by the dermal route was 410 mg/kg. In Smyth (1948) a similar estimate was obtained in Guinea pigs. In the conditions of this test, the guinea pigs LD50 following dermal exposure to Bis(2-chloroethyl) ether for 4 days was 366 mg/kg bw. No results regarding clinical signs or gross pathology are reported. This data is judge to have limited reliability as poultice data are regarded as obsolete because the saturated pad prevents complete contact of the dose with the skin. In addition, the exposure duration (4 days) is non standard. Finally, in a review on the toxicology of Bis(2-chloroethl) ether by USEPA (1989), the author cites an unpublished study from Union Carbide (1948), where Bis(2-chloroethyl) ether was found to have a LD50 equal to 870 mg/kg in rabbits.

Justification for classification or non-classification

1. Acute toxicity via the oral route:

All available data on the acute toxicity of Bis(2 -chlorethyl) ether support classification of the substance in Acute Category III according to GHS criteria (LD50 within 50-300 mg/kg bw). However, in Table 3.1. to Annex VI of the Regulation (EC) No 1271/2008 on the classification, labelling and packaging of substances and mixtures (CLP) a harmonized classification for Bis(2-chloroethyl) ether is provided and classifies the substance as Acute Category (oral) II.

2. Acute toxicity via the inhalation route:

Based on the data from Izmerov (1982), the rats and mice LD50 following a 4h exposure to mist of Bis(2-chloroethyl) ether was 0.330 and 0.325 mg/l, respectively. In cerpenter et al. (1948), therat LD50 following a 4h exposure to mist of Bis(2-chloroethyl) ether was 1.464 mg/L. These data are in line with Table 3.1. to Annex VI of the Regulation (EC) No 1271/2008 on the classification, labelling and packaging of substances and mixtures (CLP), which classifies the substance as Acute Category (inhalation) II.

3. Acute toxicity via the dermal route:

The lowest LD50 is reported by Clayton & Clayton (Patty's Indutsrial Hygiene and Toxicology, Vol. IIA (3rd revised edition), 1981, p. 2518). The data originates from an internal toxicity test from Dow Chemical Co. Following exposure by skin contact to a 10 % Bis(2-chloroethyl) ether solution in propylene glycol for 24 hours, the rabbit LD50 was found to be 90 mg/kg bw. It is not stated if the reported LD50 of 90 mg/kg bw is based on the applied substance or the Bis(2-chloroethyl) ether content. As worst case scenario, it is assumed that the LD50 is based on the total applied material. Hence, the LD50 based on Bis(2-chloroethyl) ether is 10% of the applied amount, i.e., 9 mg/kg bw.

This data is in line withTable 3.1. to Annex VI of the Regulation (EC) No 1271/2008 on the classification, labelling and packaging of substances and mixtures (CLP), which classifies the substance as Acute Catgerory (dermal) I. However, due to a lack of methodological details, the data is doubtful. In addition, classification in Category I is not supported by other experimental evidences.