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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
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:
other: OECD Guideline 422. Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test.
Principles of method if other than guideline:
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.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)
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 gestation day (DG) 20, 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:
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 1000 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)
Frequency of treatment:
daily
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

Maternal 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. 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 lactation day (DL) 5 (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.

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.
Fetal examinations:
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 DLs 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.

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. Necropsies were performed.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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

Details on maternal toxic effects:
Non-Developmental 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. No reproductive
effects were observed. See the accompanying summaries in the
repeated dose and reproduction toxicity sections.

Effect levels (maternal animals)

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

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
Developmental Effects: As described in the reproduction section
above, no effects were observed on any of the reproductive or
developmental parameters at any of the doses tested. The
number of pups found dead or presumed cannibalized on
postpartum days 2-4 was significantly increased, with a
concomitant significant decrease in the viability index in
the 250 mg/kg/day dosage group. These were not considered
treatment-related because they were not dosage dependent and
did not occur in the rats assigned to the recovery group. The
number of mated rats that were pregnant, delivered live litters,
or had stillborn pups, pups dying postpartum days 1 or 4-5, were
not significantly different in any of the treatment groups
compared to the vehicle control group. The duration of gestation,
number of implantation sites per litter, and gestation index
were also not significantly different. No effects on any of the
developmental parameters were observed.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on the lack of developmental effects, the developmental NOAEL is 1000 mg/kg/day. The NOAEL for maternal toxicity was also 1000 mg/kg/day.
Executive summary:

This study determined the effects of the test substance on developmental 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 developmental parameters. There were also no maternal toxic effects. The NOAEL for developmental toxicity in rats is > 1000 mg/kg/day. The NOAEL for maternal toxicity was also 1000 mg/kg/day.