Bis(2-(2-methoxyethoxy)ethyl) ether

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian germ cell study: cytogenicity / chromosome aberration

Remarks:

Type of genotoxicity: chromosome aberration

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

received: 26 Nov 1982

Reliability:

other: the study itself considered to be valid, but the study result of limited relevance due to possible confounding effect on male reproduction system

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Justification of read-across: 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. Justification of limited relevance: the test substance is known to cause toxic effect on testes and reduction/alteration of sperms. The selected test system may not be suitable to assess the genotoxicity.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1983

Report date:

1983

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 478 (Genetic Toxicology: Rodent Dominant Lethal Test)

Deviations:

yes

Remarks:

less pregnacies than recommended

GLP compliance:

not specified

Type of assay:

rodent dominant lethal assay

Test material

Test material information

Constituent 1

Reference substance name:

Bis(2-methoxyethyl) ether

EC Number:

203-924-4

EC Name:

Bis(2-methoxyethyl) ether

Cas Number:

111-96-6

Molecular formula:

C6H14O3

IUPAC Name:

1-methoxy-2-(2-methoxyethoxy)ethane

Constituent 2

Reference substance name:

Diglyme

IUPAC Name:

Diglyme

Constituent 3

Reference substance name:

Bis(2-methoxyethyl)ether

IUPAC Name:

Bis(2-methoxyethyl)ether

Details on test material:

Batch no. 21150
obtained from Aldrich Chemical Company, Wisc., USA
- physical state: clear colourless liquid
- MW 134.18
- LogPow - 0.36
- Vapour pressure (20°C) 60 Pa
- Water solubility miscible

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male

Details on test animals or test system and environmental conditions:

obtained from Charles River (U.K.)

Administration / exposure

Route of administration:

inhalation: vapour

Vehicle:

Nitrogen

Details on exposure:

- Atmosphere generation and analysis in animal tests:
The test atmosphere was produced by bubbling dry, oxygen-free Nitrogen through Bis(2-methoxyethyl)ether contained in a Drechsel bottle immersed in a temperature controlled water bath at 50°C. The Nitrogen/vapor mixture so generated was diluted with filtered, conditioned compressed air and passed into the rat exposure chambers. These were 1.5 m3 capacity stainless steel and glas-chambers in which individually caged rats were confined to a single tier of cage occupying 0.5 m3. The chamber was ventilated at a rate of 12 air changes per hour.
Atmospheres in the chambers were analysed by infrared sprectrocopy with Miran-1A Gas Analysers. Samples of chamber air were pumped continuously through the instruments and the chamber concentrations were automatically recorded. Instrument calibration was performed by a closed-loop calibration system. Known columes of test compound were sequentially injected into the gas analyser with a Hamilton glass microsyringe. After each injection the absorbance reading was allowed to stabilise as indicated on the chart recording.

- Exposure procedure
Rodents were exposed to Diethylene glycol dimethyl ether atmospheres for 7 h/d for 5 days. In the positve control groups EMS (please refer to "positive contols") was administered orally to all animals. Multiple dosed rodents received 100 mg/kg bw/d for 5 days while single-dosed rats received 250 mg/kg bw.

- Dominant lethal testing in male rats
Groups of 10 male adult rats were exposed to Diethylene glycol dimethyl ether for 7h/d on 5 consecutive days, then serially mated at weekly intervals for 10 weeks to untreated, virgin females in ration 1 male:2 females. The female rats were killed and examined 17 days after they were first caged with the males. Dominant lethality was assessed.

Duration of treatment / exposure:

7 h/d

Frequency of treatment:

5 days

Post exposure period:

10 weeks

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
250 ppm
Basis:
analytical conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
1000 ppm
Basis:
analytical conc.

No. of animals per sex per dose:

10

Control animals:

yes, concurrent no treatment

Positive control(s):

Ethyl methanesulfonate (EMS) orally

Examinations

Tissues and cell types examined:

no data

Details of tissue and slide preparation:

no data

Evaluation criteria:

no data

Statistics:

Freeman-turkey Poisson tranformation model

Results and discussion

Test results

Sex:

male

Toxicity:

no effects

Negative controls validity:

valid

Positive controls validity:

valid

Additional information on results:

Pregnancy frequencies were satisfactory in the filtered air control and the 250 ppm exposure group in all weeks, in weeks 1 through 3 and 10 of the 1000 ppm exposure group and in weeks 1 and 4 through 10 of the EMS-treated group. Large reductions in pregnancy frequency occured in the 1000 ppm exposure group in weeks 4 through 9, but particularly in weeks 5 through 7, when frequencies were only at 10%. Recovery fron the influence of Bis(2-methoxyethyl)ether was complete in week 10. EMS treatment also drastically reduced pregnancy frequency in weeks 2 and 3. Total implantations per pregnancy were normal in the air control and 250 ppm exposure group in all weeks, in weeks 1 through 3, 5 and 8 through 10 of the 1000 ppm exposure group and in weeks 5 through 10 of the EMS-treated group. In the 1000 ppm exposure group, there was a small reduction in the number of implantations in week 4, but the reductions in weeks 6 and 7 were particularly large and significant (p < 0.01). EMS effects were seen in weeks 1 through 4 of this experiment. Preimplantation losses, manifest as reductions in corpora lutea graviditatis per pregnancy, were obvious in week 6 and 7 of the 1000 ppm exposure group. A small, statistically significant reduction alsi was seen in week 3 of this group. Analysis of the frequencies of early deaths per pregnancy, following Freeman-turkey Poisson tranformation model, indicated a significant increase in week 5 of the 1000 ppm exposure group (p < 0.05). A similar analysis, but assuming a binomial model, indicated significant increases in early deaths per pregnancy in the 1000 ppm exposure group in weeks 5 (p < 0.01) and 6 (p < 0.001). In the week 7 of the 250 ppm exposure group, there was a significant decrease in early death frequency. EMS treament induced increases in early deaths in weeks 1 to 4.

Any other information on results incl. tables

Analogue approach justification (target chemical: tetraglyme; source chemical: diglyme):

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

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: limited relevance
Based on the read-across approach using glymes as source substances, tetraglyme is considered to be not genotoxic.

Executive summary:

In absence of sufficient data to assess the genotoxicity of tetraglyme, a read across approach is proposed using other glymes as source chemicals. In the reported study, diglyme was positive upon dominant lethality assay but considered to be of limited relevance for the assessment of genotoxicity of glymes. Combining results of all available studies (9 in-vitro studies and 4 in-vivo studies), tetraglyme is considered to be not genotoxic.

Jusitification for assignement of limited relevance for the reported study:

Diglyme was tested in a dominant-lethal assay in rats. Rodents were exposed to diglyme atmospheres for 7 h/d for 5 days. According to the test procedure the animals were serially mated at weekly intervals for 10 weeks to untreated, virgin females in ration 1 male:2 females. The female rats were killed and examined 17 days after they were first caged with the males. Dominant lethality was assessed. A significant increase in preimplatation loss and reduction in implantation was observed in weeks 6 to 7 after exposure of the male to 1000 ppm diglyme. Recovery from this influence was complete in week 10.

With reference to the known spermatotoxic/reproductive toxic properties of diglyme (glymes are known to cause toxic effect on testes and reduction/alteration of sperms) the observed effects are more likely to be due to the toxicity on reproduction organ than the result of a genotoxic mechanism. Although the study itself can be considered to be valid the study result may not truly reflect the genotoxicity of the test substance. Further supporting evidences are provided by three other in-vivo clastogenicity studies.