Registration Dossier

Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysis of dosing formulations was undertaken with regard to concentration and homogeniety on Weeks 1,3 and 6 of the study.
Duration of treatment / exposure:
The males were treated for 2 weeks prior to mating, through mating and until necropsy after 4 weeks of treatment.
The females were treated for 2 weeks prior to mating, throughout mating, gestation and until termination on ca. Day 4 of lactation.
Frequency of treatment:
Once daily, 7 days per week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
100 mg/kg
Basis:
actual ingested
Remarks:
Doses / Concentrations:
300 mg/kg
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000 mg/kg
Basis:
actual ingested
No. of animals per sex per dose:
10 males and 10 females
Control animals:
yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Daily, commencing one week prior to treatment until termination

FOOD CONSUMPTION: Yes
- Time schedule: Weekly

WATER CONSUMPTION: Yes
- Time schedule: Weekly

Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in offspring: the number of live pups and number found dead were recorded as soon as possible after completion of parturition. The live pups were sexed, counted, examined for the precense of milk in the stomach and for any externally visible abnormalities daily until Day 4 of lactation.

Postmortem examinations (parental animals):
GROSS NECROPSY: the cranial, thoracic and abdominal contents were examined macroscopically

ORGAN WEIGHTS: For males the testes and epididymides.

HISTOPATHOLOGY: For males each of the testes and epididymides. For females each of the ovaries.
Both for top dose and control animals only.
Statistics:
Body weight and food comsumption data were subjected to analysis of variance or the Kruskal-Wallis non-parametric analysis as appropriate.
Organ weight data were analysed by analysis of variance and analysis of covariance.
Histology data were analysed by Fischers Exact Probability test
Reproductive indices:
The following fertility indices were evaluated for each group: Fertility index (male), Fertility index (female), Gestation Index.
Offspring viability indices:
The following fertility indices were evaluated for each group: Birth Index, Live Birth Index, Viability Index

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed

Reproductive function / performance (P0)

Reproductive performance:
no effects observed

Effect levels (P0)

Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Absence of treatment-related effects

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed

Effect levels (F1)

Dose descriptor:
NOEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Absence of treatment-related effects

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
There were no obvious effects on parental toxicity, nor were there any obvious effects of treatment on fertility, pregnancy performance or pup development. The NOEL was 1000 mg/kg for both adults and pups.