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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report Date:
2013

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to
Guideline:
other: MAFF Japan Test Guidelines for Agricultural Chemicals 12-Nousan-8147 (2000)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Details on test material:
Purity: 99.4%
Impurities: Not reported

Test animals

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

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.5% methylcellulose with 0.1% Tween 80
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
GD 6-20
Frequency of treatment:
Once daily
Duration of test:
15 days
Doses / concentrationsopen allclose all
Dose / conc.:
25 mg/kg bw/day (nominal)
Dose / conc.:
50 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
No. of animals per sex per dose:
20 females/dose
Control animals:
yes, concurrent vehicle

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, non-treatment-related
Mortality:
mortality observed, non-treatment-related
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean maternal body weights were statistically significantly reduced (4-5%) at 200 mg/kg/day from gestation days 18 through 21, compared to the control group. Overall body weight gains were 15% lower (statistically significant) than control group means and corresponded to reduced weight gains observed during the treatment period. These reductions were most pronounced during the first two days of dosing when the reduction was 77% lower than control group. At this same level, adjusted (minus products of conception) final body weight and overall body weight gains were 3% (not statistically significant) and 27% lower (statistically significant) than control group, respectively.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
At 200 mg/kg/day, mean maternal food consumption was lower than control group during treatment resulting in an 11% overall (days 6-21G) reduction (statistically significant) in food consumption compared to the control group.
Gross pathological findings:
effects observed, non-treatment-related

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Basis for effect level:
body weight and weight gain
food consumption and compound intake

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
External malformations:
effects observed, non-treatment-related
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
There was a statistically significant increased incidence of short (primarily 13th) ribs at 100 and 200 mg/kg/day. The increased incidence of short ribs was not considered adverse since there was no correlative vertebral findings (i.e vertebral ossification delays) observed at this level and delays in ossification of the 13th rib are expected to resolve postnatally.
Visceral malformations:
effects observed, non-treatment-related

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Remarks:
Developmental toxicity
Effect level:
> 200 mg/kg bw/day (nominal)
Sex:
male/female
Remarks on result:
other: Highest concentration tested

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
NOAEL (Maternal toxicity): 100 mg/kg bw/d (Body weight and food consumption)
NOAEL (Developmental toxicity): >200 mg/kg bw/d (Highest concentration tested)
Executive summary:

The study was conducted according to guidelines, U.S. EPA OPPTS 870.3700 and OECD 414 to evaluate the potential maternal and developmental toxicity of the test substance in pregnant rats. Formulations of the test substance in 0.5% methylcellulose with Tween 80 were administered to presumed pregnant rats once daily by gavage on gestation days (GD) 6-20. The day of mating was defined as gestation day 0.

The dose levels used in the current study were 0, 25, 50, 100, and 200 mg/kg/day; control group animals were administered the vehicle. The dose volume was 10 mL/kg for all groups. Samples of the dosing formulations were collected and analyzed near the beginning and end of the dosing period. The results of these analyses confirmed that the formulations were at targeted concentrations, uniformly mixed, and stable under the experimental conditions used during the study.

During the in-life portion of the study, body weights, food consumption, and clinical observations before and after dosing were collected on a daily basis. All dams were euthanized on GD 21 and the gross necropsy included an examination and description of uterine contents including counts of corpora lutea, implantation sites, resorptions, and live and dead fetuses. All live fetuses were examined externally and euthanized; following euthanasia, fresh visceral and head examinations were performed on selected fetuses. The fetal carcasses were then processed and examined for skeletal alterations.

Under the conditions of this study, maternal toxicity was observed at 200 mg/kg/day as evidenced by treatment-related adverse effects on body weight and food consumption parameters when compared with current control group values. There was no early mortality or adverse treatment-related clinical signs of toxicity at any level tested. Additionally, there were no gross pathological findings associated with treatment on this study. Intrauterine growth and survival were unaffected by maternal treatment. There were no treatment-related increases in external, visceral, or skeletal malformations. Non-adverse, treatment-related fetal findings were limited to an increased incidence of short (primarily 13th) ribs at 100 and 200 mg/kg/day. This fetal anomaly was classified as a developmental variation and was considered non-adverse, as ossification was expected to be completed shortly after birth and was, therefore, not a reflection of developmental toxicity.

Based on the results of this study, the no-observed-adverse-effect level (NOAEL) for maternal toxicity was 100 mg/kg/day based on effects on body weight and food consumption parameters at 200 mg/kg/day. The NOAEL for developmental toxicity was considered to be greater than 200 mg/kg/day.