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Toxicological information

Toxicity to reproduction: other studies

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Administrative data

Endpoint:
toxicity to reproduction: other studies
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
1984
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Scientifically sound non-guideline study with restrictions.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1984

Materials and methods

Test guideline
Qualifier:
no guideline followed
Deviations:
not applicable
Principles of method if other than guideline:
Study a:
Male mice were orally treated with Ethylene glycol dimethyl ether for 5 weeks and examined for testicular effects.
Study b:
Pregnant mice were dosed with Ethylene glycol dimethyl ether from gestation days 7 to 10. Litters were examined for abnormalities.
GLP compliance:
not specified
Type of method:
in vivo

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Obtained from Wako Chemical Co.

Test animals

Species:
mouse
Strain:
other: males: JCL-ICR, females: CRJ:CD-1
Sex:
male/female
Details on test animals and environmental conditions:
Study a:
TEST ANIMALS
- Source: Japan CLEA Co.
- Age at study initiation:6 weeks

Study b:
TEST ANIMALS
- Source: Charles River Japan Inc.
- Age at study initiation:12 weeks

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Study a:
Ethylene glycol dimethyl ether was given orally by gavage 5 days per week for 5 weeks. The daily doses were 250, 500 and 1000 mg/kg bw/d. The control mice were given water. On the following day of the final administration, animals were necropsied under pentobarbital sodium anesthesia. The testis were weighed and the combined weight of seminal vesicles and coagulating gland was also measured. Tissue specimens for histopathological examination were fixed 10% buffered formalin solution, embedded in paraffin, sectioned, and stained with hematoxylin and eosin. Blood for hematological studies was taken from posterior vena cava at the time of necropsy.

Study b:
Female CRJ:CD-1 mice were housed overnight with the same stock males, and the day on which a vaginal plug was observed was designated day 0 of gestation. On days 7 to 10 of gestation, Ethylene glycol dimethyl ether at various daliy doses (250, 350 and 490 mg/kg bw/d) dissolved in water was given by gavage. The group administered vehicle only served as the control. On day 18 of gestation, mice were sacrificed. Litter values and gross abnormalities were examined. Fetuses wereexamined for their skeletal abnormalities and the degree of ossification.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
Study a: 5 weeks
Study b: gestation days 7 to 10
Frequency of treatment:
Study a: 5 days per week
Study b: daily
Duration of test:
Study a : 5 weeks
Study b: 18 days
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
250 mg/kg bw/d (studies a and b)
Basis:
actual ingested
Remarks:
Doses / Concentrations:
350 mg/kg bw/d (study b)
Basis:
actual ingested
Remarks:
Doses / Concentrations:
490 mg/kg bw/d (study b)
Basis:
actual ingested
Remarks:
Doses / Concentrations:
500 mg/kg bw/d (study a)
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000 mg/kg bw/d (study a)
Basis:
actual ingested
No. of animals per sex per dose:
Study a: 5 males/dose
Study b: no data
Control animals:
yes, concurrent vehicle
Details on study design:
Please refer to "Details on exposure"
Statistics:
no data

Results and discussion

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
< 250 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: based on decreased testis/body weight ratio
Dose descriptor:
NOAEL
Effect level:
< 250 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: based on fetal body weight loss, skeletal malformations and variations, retardation of ossification

Observed effects

Please refer to "Remarks on results"

Any other information on results incl. tables

Study a: testicular effects

In animals given Ethylene glycol dimethyl ether, dose-dependent decreases in testicular weight were observed. A slight decrease in the combined weight of seminal vesicles and the coagulating gland was seen in groups receiving higher doses of the test item. Histopathological examinations of the testis revealed dose-related atrophy of the seminiferous epithelium at various degrees. Sertoli cells remianed normal up to later stage. Leydig cells were normal in appearance, though infrequently proliferative. In the hematological examination, the decrease in white blood cell was the most prominent change. Ethylene glycol dimethyl ether caused a significant decrease in the white blood cell count, and the order of toxic effect on leukocyte by this chemical resembled that on testis weight. The change in red blood cells was slighter than leukocyte changes, and red cell count, packed cell volume and/or hemoglobin content decreased at the higher dose levels.

Study b: teratogenic effects

Ethylene glycol dimethyl ether induced marked and dose-related embryotoxic effects. There was an increase in the incidence of dead fetuses in the 490 mg/kg bw/d group. An increase in number of gross abnormalities, such as exencephaly, caudal effect and umbilical hernia, were observed in the 350 mg/kg bw/d and higher dose groups. In all treated groups, increased incidence of skeletal malformations such as fused ribs and vertebrae, skeletal variations such as extra ribs and retardation of skeletal ossification was noted.

Applicant's summary and conclusion

Conclusions:
Ethylene glycol dimethyl ether caused reduction of testicular weight and malformations when given to male and pregnant female mice at a concentration of 250 mg/kg bw/d.
Executive summary:

Diethylene glycol dimethyl ether and Ethylene glycol dimethyl ether, which is tested for its reproducitve effetcs, belong to the glycol ether family. These substances have been demonstrated to be very similar in structure, physical/chemical properties and the toxicological profile. Due to the fact that Diethylene glycol dimethyl ether and Ethylene glycol dimethyl ether have nearly the same chemical structure (especialy with reference to the functional groups):

1. Ethylene glycol dimethyl ether:H3C-O-CH2-CH2-O-CH3

2. Diethylene glycol dimethyl ether:H3C-O-CH2-CH2-O-CH2-CH2-O-CH3

the same mode of interaction with bio-macromolecules, living cells and tissue and metabolic pathway is expected. Therefore, a read-across from Diethylene glycol dimethyl ether to data obtained with Ethylene glycol dimethyl ether is scientifically justified.

Ethylene glycol dimethyl ether was given orally to male mice 5 days per week for 5 weeks. The daily doses were 250, 500 and 1000 mg/kg bw/d. The control mice were given water.

Dose-dependent decreases in testicular weight were observed. A slight decrease in the combined weight of seminal vesicles and the coagulating gland was seen in groups receiving higher doses of the test item. Histopathological examinations of the testis revealed dose-related atrophy of the seminiferous epithelium at various degrees. Sertoli cells remianed normal up to later stage. Leydig cells were normal in appearance, though infrequently proliferative. In the hematological examination, the decrease in white blood cell was the most prominent change. Ethylene glycol dimethyl ether caused a significant decrease in the white blood cell count, and the order of toxic effect on leukocyte by this chemical resembled that on testis weight. The change in red blood cells was slighter than leukocyte changes, and red cell count, packed cell volume and/or hemoglobin content decreased at the higher dose levels.

Pregnant mice were treated with Ethylene glycol dimethyl ether at various daliy doses (250, 350 and 490 mg/kg bw/d) on days 7 to 10 of gestation.The test item induced marked and dose-related embryotoxic effects. There was an increase in the incidence of dead fetuses in the 490 mg/kg bw/d group. An increase in number of gross abnormalities, such as exencephaly, caudal effect and umbilical hernia, were observed in the 350 mg/kg bw/d and higher dose groups. In all treated groups, increased incidence of skeletal malformations such as fused ribs and vertebrae, skeletal variations such as extra ribs and retardation of skeletal ossification was noted.