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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study design according to OECD Guideline 421. Study in Japanese without complete English translation.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
Lot/batch No.: PAK5633
Purity: 98.3 %

Test animals

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

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
males: 50-52 days
females: from 14 days before mating to day 3 of lactation

terminal kill:
males: days 51-53
females: day 4 of lactation
Frequency of treatment:
once daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 6, 30, 150 or 750 mg/kg bw/day
Basis:

No. of animals per sex per dose:
12 m / 12 f
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: 1 day
Positive control:
No

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION: Yes
Sperm parameters (parental animals):
Yes
Litter observations:
Yes
Postmortem examinations (parental animals):
Yes
Postmortem examinations (offspring):
Yes
Statistics:
Yes
Reproductive indices:
Yes
Offspring viability indices:
Yes

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
effects observed, treatment-related

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
effects observed, treatment-related
Reproductive function: sperm measures:
effects observed, treatment-related
Reproductive performance:
effects observed, treatment-related

Details on results (P0)

In males, exophtalmos was noted in 2 animals at 750 mg/kg bw. Transiently lowered food consumption was also noted at 750 mg/kg bw. No changes caused by the substance were noted in terms of body weight, necropsy findings, organ weights, or sperm examination. On histopathological examination, vacuolization of lens fibers and hyperplasia of epithelium lentis were noted in 2 and 1 animal, respectively, at 750 mg/kg bw.
In females, mydriasis was noted at 750 mg/kg bw. Transiently lowered body weight were evident at 750 mg/kg bw during the pregnancy period and transiently reduced food consumption was noted before mating. No changes caused by the substance were noted with regard to necropsy, organ weights, or histopathological examination.

The individual results are summarised in the attached file Tables and Figures.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
750 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance

Results: F1 generation

General toxicity (F1)

Clinical signs:
effects observed, treatment-related
Mortality / viability:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Sexual maturation:
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings:
effects observed, treatment-related

Details on results (F1)

Regarding reproductive/developmental toxicity, no changes caused by the substance were noted in terms of the copulation index, gestation length, delivery conditions, nursing conditions, fertility index, number of corpora lutea, implantation rate, or gestation index.
Regarding the pups, no changes caused by the substance were noted in the number of pups, number of stillbirths, number of live pups born, sex ratio, delivery index, birth index, live birth index, viability index, or body weight.

The individual results are summarised in the attached file Tables and Figures.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
750 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: Pup development

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
From this study a NOAEL of 750 mg/kg bw for reproductive performance and pup development was derived.
Executive summary:

In this study performed according to OECD Guideline 421, male and female Crj :CD (SD) rats were dosed orally via gavage with 0, 6, 30, 150 or 750 mg/kg bw over 50-52 days (m) and from 14 days before mating to day 3 of lactation. Terminal kill in males was on days 51-53 and in females on day 4 of lactation.

In males, exophtalmos was noted in 2 animals at 750 mg/kg bw. Transiently lowered food consumption was also noted at 750 mg/kg bw. No changes caused by the substance were noted in terms of body weight, necropsy findings, organ weights, or sperm examination. On histopathological examination, vacuolization of lens fibers and hyperplasia of epithelium lentis were noted in 2 and 1 animal, respectively, at 750 mg/kg bw.

In females, mydriasis was noted at 750 mg/kg bw. Transiently lowered body weight were evident at 750 mg/kg bw during the pregnancy period and transiently reduced food consumption was noted before mating. No changes caused by the substance were noted with regard to necropsy, organ weights, or histopathological examination.

Regarding reproductive/developmental toxicity, no changes caused by the substance were noted in terms of the copulation index, gestation length, delivery conditions, nursing conditions, fertility index, number of corpora lutea, implantation rate, or gestation index.

Regarding the pups, no changes caused by the substance were noted in the number of pups, number of stillbirths, number of live pups born, sex ratio, delivery index, birth index, live birth index, viability index, or body weight.

From this study a NOAEL of 750 mg/kg bw for reproductive performance and pup development was derived.