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Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
Adopted: 22 March 1996
GLP compliance:
yes
Remarks:
Japan Existing Chemical Data Base: All the tests reported were performed in accordance with the chemicals GLP under the Law concerning Examination and Regulation of Manufacture, etc. of Chemical Substances and also meet the requirements of the OECD GLP.
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
water for injection
Frequency of treatment:
1x / day
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
12.5 mg/kg bw/day (nominal)
Dose / conc.:
50 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
Control animals:
yes, concurrent vehicle
Mortality:
no mortality observed
Ophthalmological findings:
not examined
Immunological findings:
not examined
Reproductive function: oestrous cycle:
no effects observed
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
200 mg/kg: no pregnant females
50 mg/kg:
- fertility index ((number of pregnant females/number of pairs with succesful copulation) x 100) = 58.3%
- corpora lutea decrease
- implantation index (number of implantation scars / number of corpora lutea) = 28.5%
Key result
Dose descriptor:
NOAEL
Effect level:
12.5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
50 mg/kg: viability index (number of live pups on day 4 of lactation / number of live pups born) = 68.8% => only 12 pups, relevance 3 mortalities is unclear
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
50 mg/kg: body weight pups increased but normal since only limited number of pups per dam at this dose
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
Other effects:
no effects observed
Description (incidence and severity):
- No external abnormalities
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
12.5 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
mortality
Key result
Reproductive effects observed:
yes
Lowest effective dose / conc.:
50 mg/kg bw/day (actual dose received)
Treatment related:
yes
Relation to other toxic effects:
reproductive effects occurring together with other toxic effects, but not as a secondary non-specific consequence of other toxic effects
Dose response relationship:
yes
Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
12.5 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

No pregnant females were observed at 200 mg/kg in the combined repeated dose toxicity study with the reproduction/developmental toxicity screening study. The fertility index (number of pregnant females/number of pairs with successful copulation), number of corpora lutea, implantation scars and implantation index were all significantly lower at 50 mg/kg. The observed pre-implantation loss could result from an adverse effect on gamete transport or function, resulting in failed fertilisation, or it can be a consequence of direct effects on the preimplantation embryo or indirect effects on the uterus or endocrine status of the dam.

At the dose level of 50 mg/kg only slight systemic toxicity is observed in the male and female parent animals. Therefore the substance is classified Repr. 1B.

Additional information