Registration Dossier

Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study and GLP
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1996

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
purity: 98.0 %

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Males should be dosed during 2 weeks before matingto detect the majority of effects on male fertilty.
Females should be dosed for 2 weeks in order to elicit any adverse effects on oestrus.
the animals are then mated.
the test substance is administered to both sexes throughout the mating period and pregnancy and up to day 4 of lactationwhen all animals including offspring were killed
Details on mating procedure:
no data
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Males: 45 days
Females: from 14 days before mating to day 3 of lactation
Frequency of treatment:
no data
Details on study schedule:
-
Doses / concentrations
Remarks:
Doses / Concentrations:
0 (vehicle), 8, 40, 200 mg/kg day
Basis:
other: Vehicle: corn oil
No. of animals per sex per dose:
Males: 12
Females: 12/group
Control animals:
yes
Details on study design:
Males should be dosed during 2 weeks before matingto detect the majority of effects on male fertilty.
Females should be dosed for 2 weeks in order to elicit any adverse effects on oestrus.
the animals are then mated.
the test substance is administered to both sexes throughout the mating period and pregnancy and up to day 4 of lactationwhen all animals including offspring were killed
Positive control:
no

Examinations

Parental animals: Observations and examinations:
Males should be dosed during 2 weeks before mating to detect the majority of effects on male fertilty. Females should be dosed for 2 weeks in order to elicit any adverse effects on oestrus.
determination on number of pregnant females
Oestrous cyclicity (parental animals):
Females should be dosed for 2 weeks in order to elicit any adverse effects on oestrus.
Sperm parameters (parental animals):
Males should be dosed during 2 weeks before matingto detect the majority of effects on male fertilty.
Statistics:
mon-parametric analysis
Reproductive indices:
copulation index, fertility index, gestation index, inplantation index, delivery indec
Offspring viability indices:
live birth index, viability index on day 4

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

Dose descriptor:
NOEL
Effect level:
ca. 200 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: no effects on mating,fertility or estrous cycle; see "remarks on results"

Results: F1 generation

Effect levels (F1)

Dose descriptor:
NOEL
Generation:
F1
Effect level:
ca. 40 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
other: "see remarks on results"

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

The compound showed no effects on mating, fertility or the estrous cycle. One female given 150 mg/kg died during delivery.

All pups were stillborn with two females and all pups died during the lactation period with three females given 200 mg/kg. In addition the number of live pups born decreased, and the number of stillbirth pups tended to increase. The live birth index, viability index of pups at Day 4 after birth and delivery index were decreased or showed a tendency for decrease in the same group, suggesting functional disturbances in delivery or lactation caused by the test substance.

Applicant's summary and conclusion

Executive summary:

In a combined repeat dose and reproductive/developmental toxicity screening test according to OECD guideline 422 and GLP, male and female rats received following doses of test substance: 0 (vehicle), 8, 40, 200 mg/kg/day. 12 male rats were treated for 45 days and 12 females /group were treated from 14 days before mating to day 3 of lactation. In terms of reproductive/developmental toxicity, one female given 200 mg/kg died during delivery. All pups were stillborn in two females and all pups died during the lactation period in three females of the treated group given 200 mg/kg. In the same group the number of live pups born was decreased and the live birth index, viability index of the pups at Day 4 after birth and delivery demonstrated tendencies for index decrease. NOELs for reproductive performance of males and females, and pup development are considered to be 200 mg/kg/day for males and females and 40 mg/kg/day for pups development.