Registration Dossier

Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23 June 1988 to 1 November 1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report Date:
1990

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EPA OPP 83-4 (Reproduction and Fertility Effects)
GLP compliance:
yes
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): XRD-498

- Molecular weight:253.3 Daltons

- Physical state:White, very fine crystals
- Analytical purity:99.7%


- Purity test date: 10 January 1989
- Lot/batch No.: AGR 240043

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: rodent chow
Details on mating procedure:
- M/F ratio per cage:1:1
- Length of cohabitation: 7 days
- Proof of pregnancy: vaginal plug and sperm in vaginal smear considered day 1 of pregnancy
- After 7 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: a third 7-day cohabitation period was used for females as necessary
- After successful mating each pregnant female was caged (how): singly in stainless steel cages with wire mesh floors
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
F0 generation was dosed for for 10 weeks.
F1 adults were dosed for 12 weeks.
Frequency of treatment:
Daily
Details on study schedule:
- F1 parental animals not mated until 12 weeks after selected from the F1 litters.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 - control
Basis:
actual ingested
Remarks:
Doses / Concentrations:
100 mg/kg body weight/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
500 mg/kg body weight/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000 mg/kg body weight/day
Basis:
actual ingested
No. of animals per sex per dose:
30 animals per sex per dose group
Control animals:
yes

Results and discussion

Results: P0 (first parental animals)

Effect levels (P0)

Dose descriptor:
NOEL
Effect level:
1 000 other: mg/kg bw/day (actual ingested)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Remarks on result:
other: Generation: F0, F1a, F1b, F2 (migrated information)

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

The F1a pups, which served as parental generation for the F2 animals, matured and successfully produced litters with no evidence of treatment-related effects.

Applicant's summary and conclusion

Conclusions:
Based on the results of this study, the no-observable-effect-level for reproductive effects was 1000 mg/kg bw/day. No paternal or maternal toxicity was demonstrated at any dose level tested including the high dose level of 1000 mg/kg bw/day.
Executive summary:

Fischer-344 rats were fed XRD-498 at dose levels of 0, 100, 500, or 1000 mg/kg bw/day in the diet. Following 10 weeks of exposure, the F0 rats were mated to produce F1a and F1b litters. At weaning, 30 F1a pups/sex/dose level were randomly selected to become the F1 adults. After 12 weeks of exposure to XRD-498, the F1 adults were mated to produce the F2 litters. Reproductive performance and neonatal survival and development were evaluated to assess the reproductive effects of treatment. Body weights, body weight gains, feed consumption, clinical observations, kidney weights, and gross pathologic and results of histopathologic examinations were evaluated for evidence of toxicity. Reproductive performance of the F0 and F1 adult rats was not affected by XRD-498 treatment. No effects attributable to XRD-498 treatment were found in the growth and development of the F1a, F1b, and F2 pups. The F1a pups, which served as parental generation for the F2 animals, matured and successfully produced litters with no evidence of treatment-related effects. No parental toxicity was demonstrated in the F0 or F1 adult rats, even at the high dose level of 1000 mg/kg bw/day. Based on the results of this study, the no-observable-effect-level for reproductive effects was 1000 mg/kg bw/day (limit test). No paternal or maternal toxicity was observed at any dose level tested.