Registration Dossier

Administrative data

Description of key information

Oral:
- female rats, LD50: 3850 mg/kg bw
- female mice, LD50: 5140 mg/kg bw (supporting data)
- female rats, LD50 (triglyme): 5390 mg/kg bw (supporting data)
- female rats, LD50 (diglyme): 4760 mg/kg bw (supporting data)
- female rats, LD50 (monoglyme): 5370 mg/kg bw (supporting data)
- male rats, LD50 (2-ME): 2460 mg/kg bw (supporting data)
- rats, LD50 (EMDE): ca.6500 mg/kg bw (supporting data)
Inhalation:
- male/female rats, LC0 (diglyme; 7h exposure): 11 mg/L -> 19.3 mg/L (4h calculated exposure)
- male/female rats, LC0 (monoglyme; 1h exposure): 240 mg/L -> 60 mg/L (4h calculated exposure)
- rats, LC50 (monoglymer; 6h exposure): > 20 mg/L
Dermal:
- male rats, LD50 (triglyme): > 6900 mg/kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1982-06-23 to 1982-07-20
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non GLP; Scientifically well performed study.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Route of administration:
oral: gavage
Vehicle:
water
Doses:
2500, 3150, 3550, 3750, 4000, 5000 mg/kg bw
No. of animals per sex per dose:
10
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes/
- Other examinations performed: clinical signs, body weight
Sex:
female
Dose descriptor:
LD50
Effect level:
3 850 mg/kg bw
Based on:
act. ingr.
95% CL:
> 3 640 - < 4 160
Mortality:
Dose (mg/kg bw) number of dead animals/total animals
2500, 0/10
3150, 0/10
3550, 1/10
3750, 5/10
4000, 9/10
5000 , 9/10

animal died on day 2-4 after administration
Clinical signs:
hyperactivity, then passivity, dizziness, deep anesthesia, balance disturbance, ataxia, squatting position, prone position, dorsal position, lateral position, twitching, orthotonus hyporeflexia, negative miosis pupil, muco serous nasal discharge, skin redness, snapping breathable, and noisy breathing
Body weight:
normal in survived animals
Gross pathology:
in dead animals: intestinal tract filled with black pulpy mass and diffuse redness, red diffuse pancreas, adrenal colored red-brown bubble, bladder steeply filled, orange to pink to red lung, skin redness.

no

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The median lethal dose of Tetraethylenglycodimethylether (LD50) was 3850 mg per kg body weight. Based on the result of this study Tetraethylenglycodimethylether is not subject for labelling and classification requirements according to regulatory requirements.
Executive summary:

The acute toxicity was tested using female Wista rats. The animal received a single dose of the test item by gavage and were observed for 14 days.

The median lethal dose of Tetraethylenglycodimethylether (LD50) after single oral administration was 3850 mg per kg body weight. Based on the result of this study Tetraethylenglycodimethylether is not subject for labelling and classification requirements according to regulatory requirements.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
3 850 mg/kg bw
Quality of whole database:
reliable and robust; total 5 studies/reports are available on target or source chemicals; the results are in line indicating low oral toxicity.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
10 July - 14 July 1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The target chemical belongs to the homologues series of glymes, where there is an incremental increase in the number of CH2CH2O units. Therefore, it can be assumed that target and other glyme members (mono-, di-, and triglyme) share the same toxic mode action.
Qualifier:
according to
Guideline:
other: OECD 403, 5. Annex: Inhalation Hazard Test
Deviations:
yes
Remarks:
nose-only exposure
GLP compliance:
no
Remarks:
study performed before GLP guidelines
Test type:
other: Inhalation Hazard Test
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: males 234-250g, females 200-220g

- Housing:
- Diet (e.g. ad libitum): 1324, ad libitum
- Water (e.g. ad libitum): community tap water, ad libitum

ENVIRONMENTAL CONDITIONS
- Housing: Macrolon cages with softwood bedding
- Temperature (°C): 22°C


IN-LIFE DATES: From: To: 10. july - 24. July 1979
Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose only
Vehicle:
clean air
Details on inhalation exposure:
Each rat was placed in a plastic tube, which were connected to the inhalation chamber (20 L volume). Exposure was by nose exclusively. Diethylene glycol dimethyl ether was applied to a vaporizer and continuously evaporated. The resulting test substance/air mixture was carried to the inhalation chambers using an air stream of 600 L/h. Diethylene glycol dimethyl ether consupmtion was determined by weighing before study start and at study termination.

Temperature: 21.9 - 22.0°C
Pressure: 1010 mbar
Exposure duration: 7 h
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
7 h
Concentrations:
11.1 mg/L (7 hours), 6 males, 6 females
No. of animals per sex per dose:
6
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: clinical - daily, weighing - weekly
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, macroscopy
Statistics:
none
Preliminary study:
None
Sex:
male/female
Dose descriptor:
LC0
Effect level:
11 mg/L air
Exp. duration:
7 h
Remarks on result:
other: test substance saturated atmosphere
Mortality:
0/12 animals (7 h, 11 mg/L)
Clinical signs:
other: No effects
Body weight:
No effects
Gross pathology:
No effects
Other findings:
None

Analogue approach justification:

The analogue approach using glymes as source chemical is justified:

a.   The target chemical belongs to the homologues series of glymes, where there is an incremental increase in the number of CH2CH2O units. Therefore, it can be assumed that target and other glyme members (mono-, di-, and triglyme) share the same toxic mode action.

b.   The findings in repeated dose toxicity studies are comparable for target and source chemicals: the target is the male reproductive organ. Further, findings in thymus and altered hematological values are indicative of altered blood system.

c.    The findings in reproductive performance are comparable: No live pubs and/or reduced number of pubs were the common finding.

d.   The findings in developmental toxicity studies are comparable: the most notable findings were paw skeletal malformations. These findings were observed also at dose levels not associated with apparent maternal toxicity.

Interpretation of results:
not classified
Remarks:
Migrated information LC0: 11 mg/L for 7 h Criteria used for interpretation of results: expert judgment
Conclusions:
No classification is warranted for tetraglyme based on the read-across approach using diglyme as read-across supporting substance. Diglyme did not induce any effect in rats exposed to the saturated concentration of 11 mg/L for 7h.
Executive summary:

The acute inhalation toxicity of tetraglyme was assessed based on the read-across approach using diglyme as read-across supporting substance.

One group of 6 male and 6 female Wistar rats were exposed to a saturated diglyme atmosphere at a concentrations of 11.1 mg/L for 7 hours. All animals survived without irreversible clinical signs or macroscopic findings.

Due to the higher molecular mass and lesser volutility the acute inhalation toxicity of tetraglyme is likely to be less potent than diglyme.

No classification is warranted for tetraglyme.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
reliable and robust; total 3 studies/reports are available on source chemicals; the results are in line indicating low inhalation toxicity.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1984
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The target chemical belongs to the homologues series of glymes, where there is an incremental increase in the number of CH2CH2O units. Therefore, it can be assumed that target and other glyme members (mono-, di-, and triglyme) share the same toxic mode action.
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
only one sex tested, only 2 animals per dose tested, limitations in study reporting
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
-Strain: COBS/Wistar rats
- Age at study initiation: no data
- Weight at study initiation: 225-306 g (male animals)
- Animalsa caged singly
Type of coverage:
other: non-occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: shaved, ca. 20 - 25% of the body surface on the backs and the flanks of the animals

Duration of exposure:
no data
Doses:
1.7 g/kg body weight
3.5 g/kg body weight
6.9 g/kg body weight
No. of animals per sex per dose:
2 males
Control animals:
no
Details on study design:
The tests used a non-occluded technique.
Volumes of the compound (0.1 ml to 2.0 ml maximum) were applied to shaved areas (approximately 20-25% of the body surface) on the backs and the flanks of the animals. "Toby" collars prevented grooming and the contaminated areas were not covered.
Animals were caged singely under normal conditions.
Statistics:
not required
Preliminary study:
no preliminary study performed
Sex:
male
Dose descriptor:
LD50
Effect level:
> 6 900 mg/kg bw
Mortality:
No mortality
Clinical signs:
no effects observed
Body weight:
no data
Gross pathology:
no data
Other findings:
No further findings

Analog Approach Justification:

The analogue approach using glymes as source chemical is justified:

a.   The target chemical belongs to the homologues series of glymes, where there is an incremental increase in the number of CH2CH2O units. Therefore, it can be assumed that target and other glyme members (mono-, di-, and triglyme) share the same toxic mode action.

b.   The findings in repeated dose toxicity studies are comparable for target and source chemicals: the target is the male reproductive organ. Further, findings in thymus and altered hematological values are indicative of altered blood system.

c.    The findings in reproductive performance are comparable: No live pubs and/or reduced number of pubs were the common finding.

d.   The findings in developmental toxicity studies are comparable: the most notable findings were paw skeletal malformations. These findings were observed also at dose levels not associated with apparent maternal toxicity.

Interpretation of results:
not classified
Remarks:
Migrated information LD50 > 6900 mg/kg Criteria used for interpretation of results: expert judgment
Conclusions:
No classification is warranted for tetraglyme based on the read-across approach using triglyme as read-across supporting substance. The median lethal dose (LD50) of triglyme for the dermal route of application is greater 6900 mg/kg body weight in male rats.
Executive summary:

The acute dermal toxicity of tetraglyme was assessed based on the read-across appoach using triglyme as read-across supporting substance.

Three groups of male wistar rats (2 animals per group) were exposed to triglyme on the shaved areas on the backs and flanks of the animals. The median lethal dose (LD50) of triglyme for the dermal route of application is greater 6900 mg/kg body weight in male rats.

No classification is warranted for tetraethylene glycol dimethyl ether based on the analogue approach.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
reliable and robust; the result obtained in the available study is in line with observed low (no) toxicity in oral and inhalation studies.

Additional information

The acute toxicity of tetraglyme can reasonably be derived based on the experimental data and on the read-across approach using low molecular glymes as source chemicals.

The underlying scientific rationale is that target chemical belongs to the homologues series of glymes and thus to a “chain length category”, where there is an incremental increase in the number of CH2CH2O units. Based on the basic concept of “chain length category”, the same toxic mode of action can be assigned for each category members and the use of toxicity data of other glyme members (mono-, di-, triglymes) for read-across purpose to tetraglyme is justified (see for more information “Assessment of the validity of the analogue approach”).

Total five oral studies, three inhalation studies and one dermal studies were used for the assessment of acute toxicity of tetraglyme. Based on the study results no acute toxicity could be derived.


Justification for selection of acute toxicity – oral endpoint
Scientifically well performed study

Justification for selection of acute toxicity – inhalation endpoint
Scientifically well performed study

Justification for selection of acute toxicity – dermal endpoint
Scientifically well performed study

Justification for classification or non-classification

Based on the available data no classification is warranted according to the criteria laid down in the EU Dangerous Substances Directive (67/548/EEC) and in the EU Classification Labelling and Packaging Regulation (1272/2008/EC).