Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
Jun 2001 - Feb 2002
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report Date:
2002

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
2001
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: HanIbm:WIST (SPF)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Duration of treatment / exposure:
day 6 to day 20 of presumed gestation
Frequency of treatment:
once daily
Doses / concentrationsopen allclose all
Dose / conc.:
20 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
Dose / conc.:
400 mg/kg bw/day (nominal)
Dose / conc.:
600 mg/kg bw/day (nominal)
No. of animals per sex per dose:
24
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
- clinical observations
- mortality
- body weight
- food consumption
- macroscopic pathological examination
Ovaries and uterine content:
- number of corpora lutea in each ovary
- weight of the uterus including contents
Fetal examinations:
- external examination
- weighing
- visceral and skeletal examination
Statistics:
All data were recorded on-line and processed with the software package REPROTOX running on the NOVATOX System for evaluation.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (nominal)
Basis for effect level:
mortality
body weight and weight gain
food consumption and compound intake

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
External malformations:
effects observed, non-treatment-related
Skeletal malformations:
effects observed, non-treatment-related
Visceral malformations:
effects observed, non-treatment-related

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (nominal)
Sex:
not specified
Basis for effect level:
fetal/pup body weight changes
skeletal malformations

Applicant's summary and conclusion

Conclusions:
Maternal toxicity (two deaths at 600 mg/kg bw/day, reduced food consumption and body weight gain at 400 and 600 mg/kg) was seen. At both dose levels, minor developmental delay (ossification) and reductions in fetal weights were recorded.
On the basis of these results, the no observable adverse effect level (NOAEL) for both maternal and developmental toxicity was 200 mg/kg bw/day. There was no indicationof teratogenic potential.