(ethylenedioxy)dimethanol

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1988

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Justification for type of information:

Due to rapid hydrolysis data from hydrolysis products are regarded sufficient to fulfill the data requirements.

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Assessment of the developmental toxicity of ethylene glycol applied cutaneously to CD-1 mice

Author:

Tyl RW, Fisher LC, Kubena MF, Vrbanic MA, Losco PE

Year:

1995

Bibliographic source:

Fundam Appl Toxicol 27: 155-166

Reference 2

Reference Type:

other: unpublished report cited in NTP-CERHR, 2004

Title:

Unnamed

Year:

1988

Reference 3

Reference Type:

publication

Title:

NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Ethylene Glycol

Author:

NTP-CERHR

Year:

2004

Bibliographic source:

http://ntp.niehs.nih.gov/ntp/ohat/egpg/ethylene/eg_monograph.pdf

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

(minor restriction: no data about food consumption)

GLP compliance:

yes

Remarks:

1988

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ethane-1,2-diol

EC Number:

203-473-3

EC Name:

Ethane-1,2-diol

Cas Number:

107-21-1

Molecular formula:

C2H6O2

IUPAC Name:

ethylene glycol

Details on test material:

Purity >99.9%
Purity confirmed analytically by supplier

Test animals

Species:

mouse

Strain:

CD-1

Details on test animals or test system and environmental conditions:

2-weeks of acclimatisation; 53 days at time of mating, time-pregnant mice used; food and water ad libitum, temperature and humidity measured (no further data); 12 h photoperiod

Administration / exposure

Route of administration:

dermal

Vehicle:

water

Details on exposure:

0.1 ml administered on shaved skin of the dorsum (approximately 3x3 cm), occlusive, 6 h per day on gestation day (GD) 6-15

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analytical control of purity; doses prepared gravimetrically

Details on mating procedure:

1 male mated with 1 female; pregnancy verified by vaginal plug

Duration of treatment / exposure:

GD 6-15

Frequency of treatment:

6 h/day

Duration of test:

sacrifice and Caesarean section GD 18

No. of animals per sex per dose:

initial 30 pregnant mice; 22-26 at termination

Control animals:

yes, concurrent vehicle

Details on study design:

The positive control group received 3000 mg/kg bw/day via gavage

Examinations

Maternal examinations:

Clinical signs daily, body weight at GD 0, 6, 9, 12, 15, 18; water consumption every 3 days; necropsy at GD18 including kidney uterus and liver weight; histopathology of the kidney

Ovaries and uterine content:

corpora lutea, implantations, early and late resorption, live and dead fetuses determined

Fetal examinations:

Fetal weight and sex; external, soft tissue and skeletal examinations in all fetuses; head examinations (half per litter)

Statistics:

suitable statistical methods (ANOVA, t-tests with Bonferroni probabilities; Kruskal-Wallis test; Mann-Whitney U-test ); significance at p<0.05

Historical control data:

No

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
No treatment-related maternal toxicity detected at any measured parameter; increased corrected gestational weight change (3.3, 4.4, 4.1 or 5.0*g, respectively) and minimal grade renal lesions (not significant) not regarded as adverse effects by the authors.

Effect levels (maternal animals)

Key result

Dose descriptor:

NOAEL

Effect level:

3 549 mg/kg bw/day

Based on:

test mat.

Remarks on result:

other: no adverse effects observed up to highest dose level tested

Maternal abnormalities

Key result

Abnormalities:

no effects observed

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No developmental toxicity; incidences of external, visceral, skeletal or total variations were not increased; increased incidences of two minor variations (poorly ossified parietal skull bone, majority of the intermediate phalanges of the hindlimb unossified) at the high dose level were considered by the authors to be no adverse effects

Effect levels (fetuses)

Key result

Dose descriptor:

NOAEL

Effect level:

3 549 mg/kg bw/day

Based on:

test mat.

Remarks on result:

other: no adverse effects observed up to highest dose level tested

Fetal abnormalities

Key result

Abnormalities:

no effects observed

Overall developmental toxicity

Key result

Developmental effects observed:

no

Any other information on results incl. tables

The positive control (3000 mg/kg bw/d via gavage) with increased mortality (8/30), significant histopathologic changes in kidneys, significantly reduced fetal body weights/litter, significantly increased soft tissue and skeletal malformations (compare with further gavage studies in Section 7.8.2)

Applicant's summary and conclusion

Conclusions:

No maternal or developmental toxicity in mice after dermal occlusive exposure at dose levels up to 3549 mg/kg bw/day.

Executive summary:

In a study comparable to OECD Guideline 414 with minor restrictions (no data about food consumption) the dermal exposure route was used. Thirty pregnant CD-1 mice per group received at gestation day 6 -15 daily 0.1 ml of 0, 12.5, 50, 100% aqueous solution (corresponding to 0, 404, 1677, 3549 mg/kg bw/d) on the shaved back under occlusive conditions; the patches were removed after 6 h. No maternal or developmental toxicity was induced; the NOAEL in this dermal study is 3549 mg/kg bw/day.