Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1992
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1992
Report Date:
1992

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Specific details on test material used for the study:
Purity 99.5% (Merck)

Test animals

Species:
rat
Strain:
Wistar

Administration / exposure

Route of administration:
oral: drinking water
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Day 6-19 of gestation
Frequency of treatment:
Daily via drinking water
Duration of test:
20 days to necropsy
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
600 mg/kg bw/day (nominal)
No. of animals per sex per dose:
20-21 pregnant Females
Control animals:
yes, concurrent no treatment

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: Maternal toxicity - decreased body weight (10%) and water consumption (20%)

Results (fetuses)

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
skeletal malformations

Fetal abnormalities

Key result
Abnormalities:
effects observed, treatment-related
Localisation:
skeletal: forelimb
skeletal: hindlimb

Overall developmental toxicity

Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
100 mg/kg bw/day (nominal)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects occurring together with maternal toxicity effects, but not as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
Results of this study indicate that 2-EHA is teratogenic, showing a dose-dependent increase in the frequency of skeletal malformations starting at a dose level of 100 mg/kg
Executive summary:

The results indicate that 2-EHA is teratogenic, i.e., increases malformations in Wistar rats at doses which are apparently not maternally toxic, embryotoxic, or fetotoxic. There was a dose-dependent increase in the frequency of skeletal malformations starting at a dose level of 100 mg/kg. 300 mg/kg was slightly fetotoxic in females as indicated by the reduced body weight in female fetuses.

2-EHA affected particularly skeletal development of the fetuses. The spectrum of changes ranged from skeletal variants to clubfoot, including a few cases of retarded lumbar and ulna ossification.

At doses of 100 mg/kg and above, 2-EHA caused dose-dependent skeletal malformations (clubfoot, absence of fibula, polydactyly), while the development of visceral tissues was less affected.

These results indicate that 2-EHA is teratogenic in rats already at doses which are not yet maternally toxic. The skeleton appears to be the main target of 2-EHA in developing rats