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Toxicity to reproduction: other studies

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Administrative data

Endpoint:
toxicity to reproduction: other studies
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
Received: 26 August 1984
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Scientifically sound non-guideline study with restrictions.

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1985
Report Date:
1984
Reference Type:
publication
Title:
Unnamed

Materials and methods

Test guideline
Qualifier:
no guideline followed
Deviations:
not applicable
Principles of method if other than guideline:
Triethylene glycol dimethyl ether was administered to femal mice for eight consecutive days and to pregnant mice from gestation days 7 to 14. MTD (maximum tolerated dose) was determined in non-pregnant mice and developmental toxicity was examined.
GLP compliance:
not specified
Type of method:
in vivo

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
Test chemical was provided by NIOSH (National Institute for Occupational Safety and Health)

Test animals

Species:
mouse
Strain:
CD-1
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories (Wilmington, Mass., USA)
- Age at study initiation:61-71 days
- Housing: 5 animals (MTD Study) or individually (Reproductive Study) per solid bottom cage with corn-cob bedding
- Diet (e.g. ad libitum): Wayne Lab Blox, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-24°C

- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
MTD Study:
5 Dose levels were tested with 10 mice in each dose group. Triethylene glycol dimethyl ether was administered by gavage at the same time each day for 8 consecutive days in 0.25 mL quantities. Treatment concentrations were based on the average animal weight on the day prior starting the dosing regime. Individual body weights were recorded on day 1 and day 8 of treatment, and on days 4 and 8 after the final dose (during recovery phase). Deaths were recorded cumulatively over the experimental period and necropsies were performed to determine if death was due to puncture of the esophagus during treatment.

Reproductive Study:
50 pregnant mice were randomly assigned to the treatment and control group. The mice were individually housed in separate cages. They were dosed for 8 consecutive days starting on day 7 of gestation. Treatment concentrations were based on the average day 6 dam weight. Maternal body weights were recorded on days 7 and 18 of gestation, and on day 3 postpartum.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
Day 7 to day 14 of gestation
Frequency of treatment:
daily
Duration of test:
Day 0 of gestation - day 3 postpartum
Doses / concentrations
Remarks:
Doses / Concentrations:
3500 mg/kg bw/d
Basis:
actual ingested
No. of animals per sex per dose:
MTD Study:
10 female mice
Dose levels: 445, 890, 1780, 3560 or 7120 mg/kg bw/d

Reproductive Study:
50 pregnant females
Dose level: 3500 mg/kg bw/d
Control animals:
yes, concurrent vehicle
Details on study design:
Please refer to "Details on exposure"
Statistics:
The weights of the treated groups recorded in the MTD portion of the investigation were compared with the respective control weight using the general linear model with coded linear regressions. Toxicity values (LD50) and confidence intervals were determined using SAS probit analysis program. The reproductive index, maternal survival, and the total number of live pups per litter were analysed using chi-square analysis. Maternal weight gains over the gestational period were compared with the control using one-way analysis of variance.

Results and discussion

Effect levels

open allclose all
Dose descriptor:
other: LD50
Effect level:
4 136.7 mg/kg bw/day (actual dose received)
Sex:
female
Dose descriptor:
other: MTD
Effect level:
3 500 mg/kg bw/day (actual dose received)
Sex:
female
Dose descriptor:
NOAEL
Effect level:
< 3 500 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: based on 97% survival of pregnant mice
Dose descriptor:
other: NOAEL (developmental)
Effect level:
< 3 500 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: based on 100 % fetotoxicity

Observed effects

Please refer to "Remarks on results"

Any other information on results incl. tables

MTD Study

Diethylene glycol dimethal ether did not induce significant weight loss compared to the control body weight. Since the criterion of weight loss was not diagnostic for adult toxicity, MTD values were based on gross mortality. Using the cumulative mortality data, a dose was chosen for the MTD level that empirically exhibited a low level (LD10) of lethality. Moderate toxicity was noted for Ethylene glycol dimethyl ether. The MTD was derived at 2000 mg/kg bw/d.

Reproductive Study

Maternal lethality, as indicated by a reduction in percent maternal survival, was significant in the Diethylene glycol dimethyl ether group. The test item affected the reproductive index, a parameter reflecting severe prenatal lethality, significantly. In fact, none of the pregnant mice delivered any viable pups.

Table1: Effects of Treatment on Mortality and Weight in Non-Pregnant Mice

Compound

Dose
[mg/kg bw/d]

Cumulative
Mortality1

Average weight
[g]2

 

 

 

 

Distilled Water

-

0/3

23.56±1.06

 

 

 

 

Ethylene glycol
dimethyl ether

335

0/0

25.51±0.64

 

670

0/0

25.31±0.50

 

1340

0/0

25.68±0.67

 

2680

1/0

23.66±0.53

 

5360

10/0

-

 

 

 

 

1          Represented as number dead due to treatment/number dead by esophageal puncture

2          Average weight of animals on day 8 of treatment (±SE)

 

 Table2:   Effect of Compound Exposure during Pregnancy on Maternal Survival and Weight Gain

Compound

Dose
[mg/kg bw/d]

Total
pregnant

%Maternal
survival1

Weight gain
[g]2

 

 

 

 

 

Distilled
water

-

43

100

19.89±3.26

 

 

 

 

 

Ethylene glycol
dimethyl ether

3000

45

603

-

 

 

 

 

 

1          Comparison of the number of pregnant surivors with the total number pregnant (determined by treatment of uteri with 1% Sodium sulfide

2          Average increase in dams which produced litters (day 7 to day 18 ± SE)

3          Statistically significant at p<0.005

Applicant's summary and conclusion

Conclusions:
Based on the observed mortality and fetolethality the NOAEL (maternal, developmental) in mice is considered to be smaller than 3500 mg/kg bw/d. The MTD (8 daily applications) in female non-pregnant mice was set at 3500 mg/kg bw/d.
Executive summary:

Triethylene glycol dimethyl ether was administered to female mice for eight consecutive days and to pregnant mice from gestation days 7 to 14. MTD (maximum tolerated dose) was determined in non-pregnant mice and developmental toxicity was examined.

MTD Study

Diethylene glycol dimethyl ether did not induce significant weight loss compared to the control body weight. Since the criterion of weight loss was not diagnostic for adult toxicity, MTD values were based on gross mortality. Using the cumulative mortality data, a dose was chosen for the MTD level that empirically exhibited a low level (LD10) of lethality. Moderate toxicity was noted for Triethylene glycol dimethyl ether. The MTD was derived at 3500 mg/kg bw/d.

Reproductive Study

Maternal lethality, as indicated by a reduction in percent maternal survival, was significant in the Triiethylene glycol dimethyl ether group (3500 mg/kg bw/d). The test item affected the reproductive index, a parameter reflecting severe prenatal lethality, significantly. In fact, none of the pregnant mice delivered any viable pups.