Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable publication

Data source

Reference
Reference Type:
publication
Title:
Teratogenicity of 2-Ethoxyethanol by Dermal Application
Author:
Hardin, B.D. et al.
Year:
1982
Bibliographic source:
Drug. Chem. Toxicol. 5, 277-294

Materials and methods

Principles of method if other than guideline:
Method: other: Subacute dermal toxicity
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Name of the test substance as stated in the publication: 2-Ethoxyethanol
purchased from: Fisher Scientific (Catalog No. E180, Lot No 701071;

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
Animals were purchased from: Charles River Breeding Laboratories, Wilmington, Massachusetts;
Weight of female virgins 200-225 g

Administration / exposure

Type of coverage:
not specified
Details on exposure:
Route of administration: dermal
Duration of treatment / exposure:
21 days
Frequency of treatment:
4 times per day
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0.25, 0.50 mL
Basis:
other: 4 times daily per animal
No. of animals per sex per dose:
pregnants of control: 22
pregnants at dose 0.25 mL: 21
pregnants at dose 0.50 mL: 24
Control animals:
yes

Examinations

Observations and examinations performed and frequency:
Recording of body weights on days 1, 7, 16, and 21 of gestation
Sacrifice and pathology:
Females were killed by decapitation on day 21;
Recording of organ weight (liver, spleen, kidney, and gravid uterus)

Results and discussion

Effect levels

Dose descriptor:
LOAEL
Effect level:
1 other: mL/day
Based on:
test mat.
Basis for effect level:
other: No signs of maternal toxicity were noted except ataxia in the 0.50 mL (2.0 mL/day) dose group in the last days of treatment; in the 0.25 mL (1 mL/day) dose group malformations in the offspring were observed.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Results of dose-finding study:

No toxic signs were noted except ataxia on treatment days 9 and 10 in the 2.0 mL/day group and on treatment day 10 in the 1.4 mL/day group. Group mean body weights did not differ significantly from at any time, and no dose-related changes were seen. Similarly, liver and kidney weights were not altered by the 2 -ethoxyethanol treatments.

Results of teratology study:

No signs of maternal toxicity were noted except ataxia in the 0.5 mL dose group in the last days of treatment. Mean maternal body weights of the control and treated groups did not differ on days 1, 2, or 16, but on day 21 each group differed significantly from the others. Significant differences in maternal organ weights were seen only in the higher dose group, in which maternal liver weights were reduced while kidney weights were increased. There were no pregnant females with live fetuses in the 0.50 mL dose group, and only 11 of 21 pregnant females at the lower dosage had live fetuses. In the 0.25 mL dose group, both the number of live implants per litter and the mean body weight of fetuses were significantly reduced. Only two externally visible malformations were noted, both in fetuses from the 0.25 mL treatment group: one fetus had an umbilical hernia, another had no tail. Visceral and skeletal examiniations of live fetuses, revealed significantly increased incidences of several defects in the 2 -ethoxyethanol- treated litters: cardiovascular malformations and various types of deviations from normal skeletal development.

Remark of the author of this IUCLID dossier:

Since in the lowest dose group (1 mL per animal and day) malformations in the offspring were observed, this value corresponds to the LOAEL. With a density of 0.919 g/mL at 25 °C the daily applied amount was 919 mg/animal/day. With respect to the average body weight in that dose group on day 21 of gestation (304 +/- 29 g) the applied concentration was 3023 mg/kg/day.

Applicant's summary and conclusion

Conclusions:
2-ethoxyethanol can be classified as a teratogen in Sprague-Dawley rats, as embryo mortality was 100 % at a dose that caused only very mild signs of maternal toxicity (2 mL per animal and day). As in the lowest dose group (1 mL per animal and day) malformations in the offspring were observed, in the opinion of the author of this IUCLID dossier this value corresponds to the LOAEL.