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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: OECD Guideline 422 Combined Study
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007
Report Date:
2007

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

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
Housing and Husbandry: F0 generation rats assigned to the main
satellite/recovery mated portions of the study were individually
housed in stainless steel, wire-bottomed cages, except during
the cohabitation and postpartum periods. During cohabitation, each
pair of male and female rats was housed in the male rat's cage.
Beginning no later than DG20, F0 generation female rats assigned
to natural delivery were individually housed in nesting boxes.
The study room was maintained under conditions of positive airflow,
Temperature and humidity were monitored and maintained. Animals
were given standard diet and water ad libitum under a 12 hour
light and 12 hour dark photoperiod.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Method Overview: Sixty male and 80 female rats were randomly assigned to four dosage groups, 15 male rates and 20 female rats per dosage group. The test material was administered orally (via gavage) on a daily basis beginning 14 days before a 14 day cohabitation period. Dosage continued through the day prior to sacrifice, after completion of the cohabitation period (minimum of 39 days of administration). In female rats, dosage continued up to and including day 4 of lactation. Male and female rats assigned to the satellite recovery portion of the study were not administered the test substance and/or the vehicle for 14 days prior to sacrifice starting when the first main study female rat assigned to the main study reached day 4 of lactation.

Dosage Selection: Doses were selected on the basis of results from a range-finding study. In that study there were no mortalities at doses as high as 2000 mg/kg/day. Body weight gains of the males only were reduced in the 1000 and 2000 mg/kg/day groups during the first week, and although they subsequently rebounded, the early reductions resulted in overall reduction at the end of the test period. Therefore, doses of 0, 250, 500 and 100 mg/kg/day were selected for the definitive test.

Details on mating procedure:
During cohabitation, each pair of male and female rats was housed in the male rat's cage.
Duration of treatment / exposure:
at least 39 days (males); through lactation day 4 (females)
Doses / concentrations
Remarks:
Doses / Concentrations:
0 (corn oil vehicle), 250, 500 and 1000 mg/kg/day
Basis:

No. of animals per sex per dose:
15 male rates and 20 female rats per dosage group
Control animals:
yes, concurrent vehicle
Details on study design:
Stock Preparation: A blended stock suspension was prepared once at
the testing facility and stored at room temperature, protected
from light. Suspensions of the blended test substance and/or
vehicle for dosage administration were prepared daily and also
stored at room temperature, protected from light. Prepared
formulations were stirred continuously during dosage administration.

Examinations

Parental animals: Observations and examinations:
Parameters Evaluated: All of the main and recovery rats were examined for viability, clinical observations, detailed clinical observations (main study rats only), body weight and body weight changes and feed consumption values. Maternal behavior was observed at various times for specific purposes. In addition, each litter was evaluated for viability at least twice daily and clinical observations once daily. Each litter was counted once daily. Pup weights were recorded on lactation days (DL) 1 and 4 for litters of dams assigned to the main study hematology and clinical chemistry portion of the study. Pup body weights were also recorded periodically for various purposes. Urine and blood samples were collected for evaluation periodically and a functional observational battery (FOB) and motor activity assessment was conducted on study day (DS) 40 (male rats) or DL5 (female rats). All surviving main study rats were sacrificed on the day following the last administration of the test substance and/or the vehicle, after a minimum of 39 days of dosage. Satellite/recovery mated female rats were sacrificed on DL18. Satellite/recovery non-mated male and female rats were sacrificed 4 days after the first main study rat reached DL4.
Postmortem examinations (parental animals):
Necropsy: The following tissues were weighed and/or retained from all rats: liver, kidneys, testes, epididymides, seminal vesicles with coagulation gland and prostate (male only), and ovaries, vagina, a mammary gland and uterus with cervix (female only). The following tissues were retained from the five male and female rats (main study) assigned to hematology, clinical biochemistry and histological evaluations: small and large intestines (Peyer's patches), lungs, trachea, esophagus, mandibular and mesenteric lymph nodes, peripheral nerve (sciatic), stomach, seminal vesicles with coagulating gland, spinal cord, thyroid, urinary bladder, prostate, vagina and a mammary gland, bone marrow and gross lesions. Additionally, the brain, adrenals, spleen, thymus and heart were weighed and retained for possible histological evaluation from the five male and female rats (main study) assigned to hematology, clinical biochemistry and histological evaluations. All gross lesions were examined histologically. Histological examination was performed on all (main study rats assigned to clinical chemistry evaluation only) control and high test substance dose group rats, and on the thymus and thyroids from all in the 250, 500 and 1000 mg/kg/day dosage groups. Pups that died were examined and/or preserved for future analysis. On DL4, pups from litters of dams assigned to the clinical chemistry and hematology portion of the study were sacrificed, as were pups from litters of dams assigned to the FOB portion of the study on DL5. Necropsied were performed.

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
no effects observed
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:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

Non-Reproduction Effects: No treatment-related mortalities were
observed. Body weight gains of male rats only were significantly
reduced in the 1000 mg/kg/day dosage group only. See the
accompanying summary in the repeated dose toxicity section.

Reproduction: No effects were observed on estrous, mating,
fertility, natural delivery or litter observations at any dose.
Pregnancy occurred in 10, 8, 10 and 10 female rats in the four
respective dosage groups. All male rats with the exception of
one in the 250 mg/kg/day dosage group mated successfully.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: Reproductive parameters

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Details on results (F1)

No effects were observed on estrous, mating, fertility, natural delivery or litter observations at any dose.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on the lack of significant effects on any of the reproduction parameters, the reproduction NOAEL is 1000 mg/kg/day.
Executive summary:

This study determined the effects of the test substance on reproductive parameters. Groups of rats were exposed by oral gavage to concentrations of 0, 250, 500 or 1000 mg/kg/day of test substance. Males were exposed daily for 39 days, and females were exposed daily through lactation day 4. Animals were observed regularly for body weight, mortality, clinical signs, food consumption, and behaviour. At the end of the study, the animals were sacrificed and examined for gross pathology, organ weights, histopathology, clinical chemistry, hematology, and urinalysis. In addition, each litter was evaluated for viability at least twice daily and clinical observations once daily. Each litter was counted once daily. Pup weights were recorded on lactation days 1 and 4 for litters of dams assigned to the main study hematology and clinical chemistry portion of the study. Pup body weights were also recorded periodically for various purposes. There were no significant effects to reproductive parameters. The NOAEL for reproduction in rats is 1000 mg/kg/day.