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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
repeated dose toxicity: oral
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Non GLP but peer reviewed publication. The restriction is also due to the use of read across approach: the study was performed not with DEGDEE but with DEGDME, a substance which like DEGDEE is part of the diethylene glycol monoalkyl and dialkyl ethers category. These substances have been demonstrated to be similar in structure, physical/chemical properties and toxicological profile.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1989

Materials and methods

Principles of method if other than guideline:
No information on whether or not a guideline was followed.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Test material form:
other: liquid
Details on test material:
- Name of test material (as cited in study report): Bis(2-methoxyethyl) ether - (diglyme)
- Molecular formula (if other than submission substance):
- Physical state: liquid
- Analytical purity: 99.8%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 190 to 210g (after the acclimation period)
- Housing: 5 animals per cage
- Diet (e.g. ad libitum): NIH-07 rat and mouse diet
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 to 24
- Humidity (%):45 to 51
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
A dosing solution of diglyme at 1.02 M (136.8 mgt mL) in distilled water was prepared.
For the analysis of LDH-X, an isoenzyme-specific substrate solution was prepared to contain 60 mmol/L of DL-alpha-hydroxycaproic acid in
106 mmol/L Tris buffer with 0.05% sodium azide and was adjusted to pH 9.0 at 30°C. A similar solution without the DL-alphahydroxycaproic
acid was prepared as a reagent blank.

Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
20 days plus an 8 week recovery period
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
5.1 mmol/kg bw (684 mg/kg bw) of diglyme
Basis:
nominal in water
Remarks:
Doses / Concentrations:
5 mL/kg bw of distilled water
Basis:

No. of animals per sex per dose:
90
Control animals:
yes

Examinations

Observations and examinations performed and frequency:
Primary and secondary spermatocyte degeneration and spermatidic giant cells were observed after six to eight treatments. In addition, the testes to body weight ratio was significantly reduced by the tenth day of treatment and continued to be depressed eight weeks after discontinuation of the
treatment. Testicular LDH-X activity, a pachytene spermatocyte marker enzyme, was significantly decreased in animals by the eighteenth
day of treatment with diglyme.
Sacrifice and pathology:
Animals were killed in groups of 5 at 2-day intervals during the dosing period for evaluation of any histopathological or biochemical changes and at weekly intervals for 8 weeks after cessation of dosing. At necropsy, animals were weighed, anesthetized with secobarbital sodium and killed by exsanguination. Testes,as well as epididymides, thymus glands, and brains, were excised, and organ weights were determined.
The right testes were stored at-20°C until time of analysis for LDH-X enzyme activity, and the remaining tissues were prepared for histology.
Other examinations:
Histology and enzyme analysis
Statistics:
Statistical differences between group means were determined using one-way analysis of variance. The level of significance chosen was p <0.05.
Supplied by

Results and discussion

Results of examinations

Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
reduced body weight gain and reduced weights of certain organs
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
some degenerative changes occured in the test
Details on results:
In the current study, signs of toxicity observed after repeated daily administration of diglyme, an aprotic solvent, included testes pathology, significant decreases in body and organ weights, and decreased testes LDH -X activity. Such effects are consistent with those reported for certain other glycol ethers.
The toxicity of diglyme, resulting from enzymatic cleavage of the central ether linkage and subsequent production of methoxyacetic acid, suggests
that other related aprotic glycol ethers should be considered for evaluation of testicular toxicity.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The results of this study indicate that the continued daily administration of diglyme to the male rat results in pathologic changes to the testes.
Executive summary:

DEGDEE and DEGDME, which is in the above study tested for its repeated dose toxicity in rats, are both part of the diethylene glycol monoalkyl and dialkyl ethers category described and evaluated in the document titled "Category Approach-Read across Bis(2 -ethoxyethyl)ether" (2013).

These substances have been demonstrated to be very similar in structure, physical/chemical properties and toxicological profile . Therefore, a read-across from DEGDEE to data obtained with DEGDME is scientifically justified.