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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Study period:
Received for publication 1946
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Peer-reviewed publication but is an old study not conducted in accordance with any official guidelines. Also the dermal exposure was not occlusive.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1947
Report Date:
1946

Materials and methods

Principles of method if other than guideline:
No guidelines followed
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Diethylene glycol monoethyl ether (DEGM)
- Molecular formula (if other than submission substance): C6H14O3
- Molecular weight (if other than submission substance): 134
- Smiles notation (if other than submission substance): OCCOCCOCC
- InChl (if other than submission substance):
- Structural formula attached as image file (if other than submission substance): see Fig.
- Substance type: organic
- Physical state: Liquid
- Analytical purity: Specially purified compound practically free from ethylene glycol
- Impurities (identity and concentrations): no data
- Composition of test material, percentage of components: No data

Test animals

Species:
rabbit
Strain:
not specified
Sex:
male

Administration / exposure

Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: 100 cm2
- % coverage: No data
- Type of wrap if used:
- Time intervals for shavings or clippings: One day before application

REMOVAL OF TEST SUBSTANCE
- Washing (if done):
- Time after start of exposure:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.02,0.04,0.08, 0.16, 0.32, 1.25, 1.5, 2.5, 5.0 cm3 per kg body weight
- Concentration (if solution):
- Constant volume or concentration used: no


USE OF RESTRAINERS FOR PREVENTING INGESTION: no
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
30 days
Frequency of treatment:
Once daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0.02,0.04,0.08, 0.16, 0.32, 1.25, 1.5, 2.5, 5.0
Basis:
other: mL/kg bw
No. of animals per sex per dose:
Variable - see table below
Control animals:
yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No

DETAILED CLINICAL OBSERVATIONS: No


DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations:

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION:
Records kept of food consumed

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION: No data
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations:
- Dose groups that were examined:

HAEMATOLOGY: No data
- Time schedule for collection of blood:
- Anaesthetic used for blood collection: Yes (identity) / No / No data
- Animals fasted: Yes / No / No data
- How many animals:
- Parameters checked in table [No.?] were examined.

CLINICAL CHEMISTRY: No data
- Time schedule for collection of blood:
- Animals fasted: Yes / No / No data
- How many animals:
- Parameters checked in table [No.?] were examined.

URINALYSIS: No data
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.

NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:

OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
lungs, heart, gonads

HISTOPATHOLOGY: Yes
Skin, kidneys, liver
Other examinations:
Renal and hepatic efficiency. For testing renal function, phenol red and blood urea were used. After DEGM, these renal function tests were made
periodically during the life of the rabbits, but for not longer than sixty days. For testing hepatic functional
efficiency, rose bengal, 3.0 mg per Kg, was injected intravenously before, and periodically after, DEGM, samples of plasma being estimated
at end of two, fifteen and thirty minutes after injection of the dye.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
21% decrease in weight gain for surviving animals
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Kidney
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
From lowest to highest dose respectively 0.02, 0.04,0.08, 0.16, 0.32, 0.63, 1.25, 1.5, 2.5 and 5.0 mL/kg mortality was as follows: 0, 16.67, 30, 62.5, 47,89, 100, 100, 100, 100%

GROSS PATHOLOGY:
all organs appeared normal

HISTOPATHOLOGY: NON-NEOPLASTIC
The lungs, heart, and gonads showed no abnormal treatment-related changes. The skin showed a mild, lymphocytic infiltration of the corium in the majority of the animals. The majority of animals receiving 0.63 ml/kg DGEE or more showed hydropic degeneration of the tubular epithelial cells of the kidneys . Occasional animals receiving lower doses of diethylene glycol monoethyl ether had focal areas of degeneration. One of six rabbits receiving 0.04 ml/kg DEGM had evidence of mild tubular damage.

Effect levels

Dose descriptor:
NOAEL
Remarks on result:
not determinable
Remarks:
no NOAEL identified

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

The great majority (83 and 1/3 per cent) of rabbits tested, or 15 of 18, showed reductions in renal functional efficiency observed as changes in urinary phenol red and/or blood urea tests.

According to the test results, renal function is definitely impaired as mortality increased after repeated epidermal application of diethylene glycol monoethyl ether. Renal function was unchanged or decreased to a comparatively minor degree where there was no or minor mortality as after 30 daily applications at doses of 0.02 to 0.04 mL and perhaps 0.08 mL per Kg.

Applicant's summary and conclusion

Conclusions:
Repeated daily dermal applications of DEGM at doses of 0.02 to 5.0mL/kg resulted in cumulative effects with manifestations of ill health,
renal damage and death in the vast majority of animals.
Executive summary:

DEGDEE and DEGEE, which is in the above study tested for its repeated dose toxicity in rabbits, 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 DEGEE is scientifically justified