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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
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: see 'Remark'
Remarks:
Methodology is valid for screening purposes. A single dose is selected from a screening study that is designed to produce maternal toxicity with mortality in the range 5-20% being deemed acceptable. Three key end points are percent viable litters, pup peri/postnatal survival (dead births) and pup body weight gain. The exposure period was 2 days shorter than recommended by current OECD guideline 414. Rationale for weight of evidence approach using read across substances is described in the overall section summary. Rationale for weight of evidence approach using read across substances is described in the overall section summary.

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1984
Reference Type:
publication
Title:
Evaluation of 60 chemicals in a preliminary developmental toxicity test.
Author:
Hardin DB, Schuler RL, Burg JR et al
Year:
1987
Bibliographic source:
Teratogen, carcinogen Mutagen 7:29-48

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: Chernoff Kavlock assay.
Deviations:
not applicable
Principles of method if other than guideline:
Pregnant mice are treated during organogenesis and the number of live pups, birth and growth and survival to 2-3 days of age are monitored. Test is a screen to identify candidates for further testing. Interpretation of results from this assay are as follows using 6 key end points from the following:
Mild developmental toxicity indicated by effects on litter size, pup weight, survival, or weight gain,
Potential teratogen indicated by litter size <8 pups (mean or reduced post natal survival (<80%
Fetotoxicity indicated by reduced postnatal weight gain (<30% in 5 days) and no reduction in survival.
Fetuses were not examined for defects.
GLP compliance:
no
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Physical state: liquid
- No further data.
- Purity: >99%

Test animals

Species:
mouse
Strain:
CD-1
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Labs, Wilmington MA, specified pathogen free.
- Age at study initiation: 6-8 weeks
- Housing: Individual (5 per cage during acclimation). Solid bottomed cages. Bedding used of a type known not to induce microsomal enzymes (Bed-O-Cobs, Sani-chip, San-i-cel or sterilized white wood shavings). Changed once per week but not after GD17.
- Diet: Commercial chow (either BP nutrition rat mouse breeder diet no 3, Purina chow no 5002 or Zeigler Brothers NOH-07 diet) available ad libitum.
- Water: untreated tap water, available ad libitum
- Acclimation period: 5 days. Underweight mice discarded.

ENVIRONMENTAL CONDITIONS
- No data.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Distilled water
Details on exposure:
VEHICLE
- Justification for use and choice of vehicle: distilled water
- Amount of vehicle (if gavage): 10ml/kg.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Time mated
Day 1 defined as when copulatory plug observed. Mice received pre-mated on or before GD1-3.
Duration of treatment / exposure:
GD 7-14
Frequency of treatment:
Daily.
No. of animals per sex per dose:
50
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: previous rangefinder study (5 doses) on non pregnant animals to select an LD10 over an 8 day dosing period.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily from GD18.

DETAILED CLINICAL OBSERVATIONS: not examined

BODY WEIGHT: Yes
- Time schedule for examinations: GD 7, 18 and day 3 post partum. Weight on GD 7 used to calculate dose for whole of study period.
Ovaries and uterine content:
not examined
Fetal examinations:
- Litters removed within 12 hrs of delivery and number of live and still born pups recorded. Litter weight recorded. Pups returned to dam and then parameters remeasured after 48hrs.
- External examinations: No
- Skeletal examinations: No
- Head examinations: No
Statistics:
Body weight data by analysis of variance. Proportion of surviving dams giving birth to viable litters by Fisher Irwin exact test. Number of live and stillborn pups, percent survival by analysis of variance and Student’s t test.
Indices:
no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
14% mortality. (Target dose level set to produce 10%). This level of mortality confirms study as valid. Mortality in control group was 0.

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
See table below:

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
ca. 5 500 mg/kg bw/day
Basis for effect level:
other: embryotoxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Details of embryotoxic/teratogenic effects

   Test group  Control
 Viable litters  32/33 (97%)*  31/32 (97%)
 Number of live pups/litter at birth (average)  10  10
 Number of dead pups/litter  0  0.1
 Pup post natal survival  98%  100%
 Pup weight gain (days 1 -3 post partum)  0.9g  0.4g
 Pup birth weight  1.6g  1.5g*

* statistically significantly different. However, the small percentage difference (~6%) may be of questionable biological significance.

Applicant's summary and conclusion

Conclusions:
A screening test shows no potential developmental toxicity (embryotoxicity) but at very high dose levels.
Executive summary:

2 -(2 -ethoxyethoxy)ethanol when administered by gavage to pregnant female mice during GD7-14 at a dose level of 5500mg/kg causes no significant embryotoxicity. Parameters unaffected compared to controls include litter viability, pups per litter, number of dead pups, pup survival and pup weight gain. Pup weight at birth was statistically significantly reduced, but since this change was only 6%, it is of limited biological significance.  On the basis of this screening study, it was concluded that this substance was a low priority for further developmental toxicity studies and that developmental toxicity is not an important characteristic of this substance.