Bis(2-methoxyethyl) ether

Toxicity to reproduction: other studies

Administrative data

Endpoint:

toxicity to reproduction: other studies

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

received: 22 July 1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-guideline study following scientifically sound study design (mechanistic study) with restricted reporting.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1987

Report date:

1986

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Pregnant CD-1 mice were treated with a single dose of Diethylene glycol dimethyl ether on gestation day 11. Fetuses were collected on gestation day 18 and examined for gross external malformations.

GLP compliance:

not specified

Type of method:

in vivo

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:

Diethylene glycol dimethyl ether

IUPAC Name:

Diethylene glycol dimethyl ether

Details on test material:

Purchased from Aldrich Chemical Company (Milwaukee, WI, USA)
Lot: 0115LE
Purity: >=99%

Test animals

Species:

mouse

Strain:

CD-1

Sex:

female

Details on test animals or test system and environmental conditions:

Time-mated female CD-1 mice were obtained from Charles River Laboratories (Kingston, NY, USA). Mice were shipped on gestation day 4 (day of plug = 0) and received on gestation day 5. Throughout the experiment, mice were housed in groups of five in solid-bottom cages with absorbent bedding and with free access to food and water. Light was provided on a 12 h light-dark cycle.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

Treatments were administered by gavage in a standard volume of 10 mL/kg bw. On gestation day 11 control mice were dosed with distilled water as the vehicle, and experimental mice received Diethylene glycol dimethyl ether in distilled water of 4 mmol/kg bw (537 mg/kg bw). on gestation day 18 mice were killed by carbon dioxide aphyxiation. Gross maternal body weights and gravid uterus weights were recorded. Live and dead implants were counted, and live fetuses were removed, weighed and preserved in 70% Ethanol for subsequent staining with Alizarin red. Stained specimens were examined for paw malformations.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

no data

Duration of treatment / exposure:

single exposure

Frequency of treatment:

single application

Duration of test:

18 days

Doses / concentrations

Remarks:

Doses / Concentrations:
537 mg/kg bw/d
Basis:
actual ingested

No. of animals per sex per dose:

control: 13
treatment: 17

Control animals:

yes, concurrent vehicle

Details on study design:

Please refer to "Details on exposure"

Statistics:

Adjusted maternal body weight (body weight at termination minus gravid uterus weight), fetal body weight (average weights per litter), and numbers of live and dead implants per litter and concurrent control group were analysed by analysis of variance. The incidence of fetal malformations (the number of litters with one or more fetuses affected) was evaluated by one-sided Fisher's exact test. All analyses werecarried out by means of the Statistical Analysis System (SAS Institute Inc., NC, USA).

Results and discussion

Effect levels

1

Dose descriptor:

NOAEL

Remarks:

(maternal)

Effect level:

537 mg/kg bw/day (actual dose received)

Sex:

female

Basis for effect level:

other: no effects observed

2

Dose descriptor:

NOAEL

Remarks:

(developmental)

Effect level:

< 537 mg/kg bw/day (actual dose received)

Sex:

female

Basis for effect level:

other: increased incidence of paw defects

Observed effects

Please refer to "Remarks on results"

Any other information on results incl. tables

Litters were collected from control and treated group in the early afternoon of gestation day 18. Two dams in the control group and one in the treatment group delivered all or part of their litters before sacrifice. Pups from those litters were examined for external malformations and paw defects. There was no evidence of cannibalization in any of these litters.

At a dose of 4 mmol/kg bw (537 mg/kg bw) Diethylene glycol dimethyl ether did not affect adjusted maternal body weight. Similarly, it was not associated with a reduced number of live fetuses or an increased number of dead implantation site.

Gross fetal malformations seen at necropsy included open eye and exencephaly, but these did not appear to be treatment related. Paw defects were rarely seen in control fetuses but occured with significantly increased frequency in litters of mice treated with the test item. Diethylene glycol dimethyl ether affected 39.7% per litter.

Polydactyly was a rare observation. Syndactyly was the most common digital defect observed, appearing with significantly increased frequency in hindpaws of the Diethylene glycol dimethyl ether treated litters. Short digit were not seen in any of the 61 control litters (637 fetuses) but occured in both fore- and hindpaws of the treated litters. The frequency was significantly increased in hindpawsof Diethylene glycol dimthyl ether treated litters. Oligodactyly was not observed in any control litter, but appeared at a significant frequency in hindpaws of dosed litters.

Table 1:  Litter data at 537 mg Diethylene glycol dimethyl ether/kg bw

	Control (Water)	Diethylene glycol dimethyl ether
Maternal body weight^1 N=	33.9±3.1 12	33.6±2.0 17
Implants per litter
Live fetuses	10.9±4.1	11.5±2.0
Dead + resorbed N=	0.3±0.5 13	0.1±0.2 17
Fetal body weight^2 N=	1.43±0.15 13	1.40±0.2017

¹             Gravid uterus not weighed

²                 Mean of litter means

Table 2:  Paw malformations by type and location at
537 mg Diethylene glycol dimethyl ether /kg bw

 

	Control (Water)	Diethylene glycol dimethyl ether
No. examined-litters (fetuses)	15(164)	18 (201)
Paw defects- litters (fetuses)
Polydactyly Forepaws                          No.                                          %^1 Hindpaws                          No.                                          %^1	0   0	0   0
Syndactyly Forepaws                          No.                                          %^1 Hindpaws                          No.                                          %^1	0   0	2 (3) 11.1 (1.4) 13^***(62) 72.2 (30.9)
Short Digits Forepaws                          No.                                          %^1 Hindpaws                          No.                                          %^1	0   0	2 (2) 11.1 (0.8) 10^***(21) 55.6 (10.4)
Oligodaytyly Forepaws                          No.                                          %^1 Hindpaws                          No.                                          %^1	0   0	3 (4) 16.7 (1.8) 7^**(7) 38.9 (3.2)
Total Forepaws                          No.                                          %^1 Hindpaws                          No.                                          %^1	0   0	5^*(10) 27.8 (4.4) 13^***(77) 72.2 (38.0)

¹             % of fetuses = average % per litter

^*             p<0.05

^**                p<0.01

^***          p<0.001

Applicant's summary and conclusion

Conclusions:

The application of 537 mg/kg bw Diethylene glycol dimethyl ether did not result in maternal effects but led to an increased incidence in paw defects in the fetuses.

Executive summary:

Pregnant CD-1 mice were treated with a single dose of Diethylene glycol dimethyl ether on gestation day 11. Fetuses were collected on gestation day 18 and examined for gross external malformations. This application did not result in maternal effects but led to an increased incidence in paw defects in the fetuses.