Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: See read-across justification attached.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2007

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: ICH Harmonised Tripartite Guideline: Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility S5(R2)
Deviations:
no
Principles of method if other than guideline:
Combined rat fertility and embryo-fetal development study (combined segments I and II).
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Test material form:
solid: crystalline
Details on test material:
- Name of test material: L-Thymidine

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)IGS BR

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5 % (wt/vol)
Details on exposure:
- Dosing of males, 28 days prior to cohabitation through the day before completion of cohabitation
- Dosing of females, 15 days prior to cohabitation through gestation day 17
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Males and females were cohabitated (1:1) for a maximal period of 21 days. Females not mated within the first 14 days of cohabitation were assigned an alternate male rat from the same dose group that had mated and remained in cohabitation for a maximum of seven additional days. Likewise, males not mated within the first 14 days of cohabitation were assigned an alternate female rat and remained in cohabitation for a maximum of three additional days.
Duration of treatment / exposure:
Male rats (25 animals/group) were orally administered the test item at doses of 0, 100, 500, or 1,000 mg/kg/day, starting 28 days prior to cohabitation and continuing through the day before the completion of cohabitation. Female rats (25 animals/group) were dosed starting 15 days prior to cohabitation and continuing through gestation day 17. Male rats were sacrificed at the completion of cohabitation, whereas females were sacrificed on gestation day 21.
Frequency of treatment:
Daily treatment.
Duration of test:
Male treatment was started 28 days prior to cohabitation. Treatment of females was started 15 days prior to cohabitation. Treatment was completed on gestation day 21.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 500 and 1000 mg/kg bw/day
Basis:

No. of animals per sex per dose:
25/sex/group
Control animals:
yes, concurrent vehicle
Details on study design:
Male fertility toxicity was evaluated based on mating and impregnating rate; sperm count, mobility, and morphology; and microscopic examinations of testes and epididymides.

Examinations

Ovaries and uterine content:
Female fertility was evaluated based on estrous cycling, mating and pregnancy rate, number of corpora lutea, number and distribution of implantation sites, early resorption, and microscopic examination of ovaries.
Fetal examinations:
Fetotoxicity and teratologic potential were evaluated based on mid and late resorptions; the numbers of live and dead fetuses; external sex; body weight; and gross external alterations and microscopic internal alterations, such as major malformations, minor external visceral and skeletal anomalies, and common skeletal variants.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: other:
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

In the combined segment I and II study in rats, there were no test article-related changes in male or female fertility following the administration of the test item. However, the pregnancy rate was 76 % in rats dosed at 500 mg/kg/day and 72 % in rats dosed at 1000 mg/kg/day; these rates were slightly lower than that of the control group (92 %) but still remained within the historical control range of the testing facility.

Applicant's summary and conclusion

Conclusions:
In the combined segment I and II study in rats, there were no test article-related changes in male or female fertility following the administration of the test item. No fetal abnormalities were observed.
Executive summary:

A combined rat fertility and embryo-fetal development study (combined segments I and II) was carried out according to ICH Harmonised Tripartite Guideline: Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility S5(R2). Male fertility toxicity was evaluated based on mating and impregnating rate; sperm count, mobility, and morphology; and microscopic examinations of testes and epididymides. Female fertility was evaluated based on estrous cycling, mating and pregnancy rate, number of corpora lutea, number and distribution of implantation sites, early resorption, and microscopic examination of ovaries. Fetotoxicity and teratologic potential were evaluated based on mid and late resorptions; the numbers of live and dead fetuses; external sex; body weight; and gross external alterations and microscopic internal alterations, such as major malformations, minor external visceral and skeletal anomalies, and common skeletal variants.

There were no test article-related changes in male or female fertility following the administration of the test item. However, the pregnancy rate was 76% in rats dosed at 500 mg/kg/day and 72% in rats dosed at 1,000 mg/kg/day; these rates were slightly lower than that of the control group (92%) but still remained within the historical control range of the testing facility.

In conclusion in this combined segment I and II study in rats, there were no test article-related changes in male or female fertility following the administration of the test item. No fetal abnormalities were observed.