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Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1996
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
not specified
Details on mating procedure:
Male: For 2 weeks prior to mating and 2 weeks of mating.
Female: For 2 weeks prior to mating, 2 weeks of mating and throughout pregnancy until day 3 postpartum.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Male: For 2 weeks prior to mating and 2 weeks of mating.
Female: For 2 weeks prior to mating, 2 weeks of mating and throughout pregnancy until day 3 postpartum.
Frequency of treatment:
Daily
Details on study schedule:
Premating exposure period: Male: 14 days, female: 14 days
Remarks:
Doses / Concentrations:
30, 100, 300, 1,000 mg/kg/day (in 0.5% Na-CMC)
Basis:
no data
No. of animals per sex per dose:
Male; 1,000 mg/kg, Female; 1,000 mg/kg
Control animals:
yes, concurrent vehicle
Clinical signs:
no effects observed
Mortality:
no mortality observed
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
not specified
Basis for effect level:
mortality
Reproductive effects observed:
not specified
Conclusions:
In an OECD 422 study, conducted according to GLP, the NOAEL (male/female rate) of NDC for reproductive performance and offspring viability >1,000 mg/kg.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
2
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In an OECD Guideline 422 study, conducted according to GLP, the NOAEL (male/female rats) of NDC for reproductive performance and offspring viability, is >1,000 mg/kg b.w./day (highest dose tested) (Ministry of Health and Welfare, Japan (MHW) 1996).


Short description of key information:
In an OECD 422 study, conducted according to GLP, the NOAEL (rats) of NDC for reproductive performance and offspring viability, is greater than 1,000 mg/kg b.w./day (Ministry of Health and Welfare, Japan (MHW) 1996).

Justification for selection of Effect on fertility via oral route:
Conducted according to OECD 422 and to GLP.

Treatment with the test material, resulted in no maternal or fetal toxicity at doses up to 1000 mg/kg/day. Therefore, the maternal no-observed-adverse-effect level (NOAEL) was 1000 mg/kg/day and the fetal NOAEL was 1000 mg/kg/day.

Effects on developmental toxicity

Description of key information
 Treatment with the test material, resulted in no maternal or fetal toxicity at doses up to 1000 mg/kg/day. Therefore, the maternal no-observed-adverse-effect level (NOAEL) was 1000 mg/kg/day and the fetal NOAEL was 1000 mg/kg/day.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
6 June 2018 to 2 July 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
Purity: > 99%
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Labs: Raleigh, NC
- Age at study initiation: 9 to 12 weeks
- Weight range at Mating: 200 to 225 g
- Weight Range at First Dose: 215.0 to 266.5 g
- Fasting period before study: The animals were no fasted during the study.
- Housing: Animals were individually housed in one room in polycarbonate cages suspended on stainless steel racks. Each cage was affixed with a cage card containing pertinent animal and study information.
- Diet (e.g. ad libitum): Certified Global Teklad Laboratory Diet 2018 (pellets) provided ad libitum.
- Water (e.g. ad libitum): Filtered water
- Acclimation period: At least two days prior to the first dose.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 26°C
- Humidity (%): 30 to 70%
- Air changes (per hr): Minimum of 10 air changes per hour.
- Photoperiod (hrs dark / hrs light): 12-hour light/ 12-hour dark
Route of administration:
oral: gavage
Vehicle:
other: 0.5% (w/v) methylcellulose (4000 cps) in DI water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

Suspensions of test material were prepared fresh daily on each day of dosing and stirred continuously from the time of preparation (at least 30 minutes prior to dosing) to the end of dosing on each day. All dosing was completed within a period of 5 hours or less on each day of dosing. The animals were dosed daily from GD 5 to 20 (day of confirmation of mating = GD 0) vial oral gavage at a volumne of 10 mL/kg. Dose volumnes were based on the most recent body weights.


VEHICLE
- Vehicle: 0.5% (w/v) methylcellulose (4000 cps) in DI water
Duration of treatment / exposure:
16 days
Frequency of treatment:
Once daily
Duration of test:
21 days
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
25 female per group
Control animals:
yes
Details on study design:
This study was designed to use the fewest number of animals possible, consistent with the objective of the study, the scientific needs of the Sponsor, contemporary scientific standards, and in consideration of applicable regulatory requirements.

The oral route was selected because it is the relevant route of exposure to humans and is also being used per the current OECD 414 Testing Guideline.

The dose levels were selected based on the results of a previous range finding study performed.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Greater than or equal to two times daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Upon arrival and on GD 5,8,11,14,17 and 21

BODY WEIGHT: Yes
- Time schedule for examinations: On GD 5,8,11,14,17 and 21


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21
- Examination of: the external surface of the body, all orficies, thoracic, and abdominal cavities, and their contents was performed with special empahsis on the structural abnormalities or pathologic changes which might have influenced the pregnancy.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: [all per litter ]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter]
- Head examinations: Yes: [half per litter]
Statistics:
Quantitative data from the treated groups were compared statistically to the data of the control group using one-way Analysis of Variance (ANOVA) techniques; sexes were analyzed separately.

Some quantitative data were analyzed using the Kolmogorov-Smirnov test for normality, the Levene Median test for equal variance, and by one-way Analysis of Variance (ANOVA). If either the normality or equal variance test failed, then the analysis was continued using the non-parametric Kruskal-Wallis ANOVA on rank-transformed data. For parametric data, if the ANOVA indicated statistical significance among experimental groups then the Dunnett’s t-test was used to delineate which groups (if any) differed from the control. For non-parametric data, if the ANOVA indicated statistical significance among experimental groups then the Dunn’s test was used to delineate which groups (if any) differed from the control. The probability value of less than 0.05 (two-tailed) was used as the critical level of significance for all tests.

An analysis of covariance was performed on mean male fetal weight per litter, mean female fetal weight per litter, and mean combined fetal weight per litter (sexes pooled), with the total number of fetuses pre litter used as the covariate in all analyses. All tests were conducted at the 0.05 level of significance.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Treatment with the test material had no effect on physical examinations. One female rat (3f; 300 mg/kg/day) exhibited alopecia of the abdomen during physical examinations on GD 5, 8, and 11, and then was observed as normal through GD 21. This observation was considered incidental and not test substance-related as it only occurred in one animal.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
All animals survided until the scheduled termination.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
No significant differences were noted for mean body weights or body weight changes adjusted for gravid uterine weight. Group 2 (100 mg/kg/day) had significantly higher mean body weight gain from GD 11 to 14 compared to the control, but this was the only dose group and interval to exhibit a significant body weight change during the study. Mean absolute body weight change was not significantly different across groups over the entire study period (GD5 to 21), therefore the difference from GD 11 to 14 was not considered test substance-related.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Treatment with the test material had no effect on food consumption; mean total food consumption (GD 5 to 21) did not differ significantly across groups. Mean food consumption was significantly higher in some treated groups compared to the control at various intervals: GD 5 to 8 (Groups 2 [100 mg/kg/day] and 4 [1000 mg/kg/day]); GD 11 to 14 (Group 2); and GD 14 to 17 (Groups 3 [300 mg/kg/day] and 4). With the exception of interval GD 11 to 14, the differences in food consumption did not correlate with changes in body weight. The increase in food consumption at varying intervals was not considered test substance related, as there was no effect on mean total food consumption, no corresponding dose response and no effect on body weight noted.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
Treatment with the test material had no effect on gross pathology observations; no visible lesions were noted.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Number of abortions:
no effects observed
Description (incidence and severity):
Mean number of corpora lutea, implantations, early resorptions and total deaths were comparable across groups and no significant differences were noted.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Mean number of corpora lutea, implantations, early resorptions and total deaths were comparable across groups and no significant differences were noted.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
Mean number of corpora lutea, implantations, early resorptions and total deaths were comparable across groups and no significant differences were noted.
Early or late resorptions:
no effects observed
Description (incidence and severity):
Mean number of corpora lutea, implantations, early resorptions, total deaths, and live fetuses were comparable across groups and no significant differences were noted. Thus, there was no embryotoxicity after administration of the test material.
Dead fetuses:
no effects observed
Description (incidence and severity):
Mean number of total deaths and live fetuses were comparable across groups and no significant differences were noted. Thus, there was no embryotoxicity after administration of the test substance
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
One dam in Group 4 (1000 mg/kg/day) was not pregnant which is not considered test substance related, as dosing begins on GD 5, after confirmation of mating and implantation.
Other effects:
no effects observed
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs
food consumption and compound intake
mortality
Fetal body weight changes:
no effects observed
Description (incidence and severity):
No statistically significant differences were observed among Group 1 and the other treatment groups for male, female or combined male and female fetal body weights. Thus, administration of the test substance during embryo and fetal development did not affect fetal body weight and growth.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Two malformations were observed in Group 4. One fetus had a short tail and one fetus had no tail (acaudia). The malformations were not considered test substance-related, due to the low incidence of external malformations, no corresponding dose response, or reduction in fetal body weight, which is an indication of normal fetal growth even in the presence of external malformations. Additionally, this is a common malformation observed in Sprague Dawley rats. No other abnormalities were observed.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were two fetuses from two litters with skeletal malformations. One Group 4 fetus had absent caudal, lumbar, and sacral vertebra, which corresponded to the external observation of acaudia. The second Group 4 fetus had fused ribs (left- 8th fused to 9th and 10 to 13th fused; right- 9th to 11th fused and 12th fused to 13th), which occurred in the fetus observed with the external malformation of a short tail. The malformations were not considered test material-related, due to the low incidence of these malformations, absence of a dose response and no reduction in fetal body weight which is an indication of normal fetal growth even when malformations are present. Additionally, these findings are common malformations observed in Sprague Dawley rats.

The variations observed were as follows: 12 fetuses (7 litters) in Group 1, 13 fetuses (9 litters) in Group 2, 15 fetuses (8 litters) in Group 3, and 22 fetuses (10 litters) in Group 4. The defects were observed in the ribs (rudimentary), sternebrae (unossified or incomplete ossification), and centrum of the lumbar or thoracic regions of the vertebral column (incomplete ossification or hemicentric).

All variations were considered within normal range and were not considered test substance-related. No other variations or malformations were observed.
Visceral malformations:
no effects observed
Description (incidence and severity):
No variations or malformations were observed during visceral examinations.
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
A cleft palate was observed in one Group 2 fetus during head examinations. Due to the singular nature of this finding and known incidence of this finding in historical control data, this was not considered test substance-related. No other abnormalities were observed.
Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
external malformations
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Lowest effective dose / conc.:
1 000 mg/kg bw/day (nominal)
Treatment related:
no
Conclusions:
Treatment with the test material, resulted in no maternal or fetal toxicity at doses up to 1000 mg/kg/day. Therefore, the maternal no-observed-adverse-effect level (NOAEL) was 1000 mg/kg/day and the fetal NOAEL was 1000 mg/kg/day.
Executive summary:

This study determined the potential maternal and/or developmental toxicity of the test matieral in pregnant Sprague Dawley rats when administered via oral gavage during the embryo-fetal development period. Dams were administered vehicle control or the test material once daily via oral gavage from gestational day (GD) 5 to 20, and were subjected to a full gross necropsy with uterine and fetal examinations on presumed GD 21.

When administered during the embryo and fetal developmental period, the test material did not induce maternal or embryo toxicity. There were no effects on pregnancy and uterine parameters, including the number of live fetuses as a percentage of post-implantation sites. There were no effects on fetal body weight or malformations noted that were test material-related.

In conclusion, treatment with the test material resulted in no maternal or fetal toxicity at doses up to 1000 mg/kg/day. Therefore, the maternal no-observed-adverse-effect level (NOAEL) was 1000 mg/kg/day and the fetal NOAEL was 1000 mg/kg/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
chronic
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
10 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
2
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Reproductive toxicity

Based on a NOAEL of > 1,000 mg/kg b.w./day, in accordance with Regulation No 1272/2008, NDC is not classified for reproductive toxicity.

Developmental toxicity

Treatment with the test material, resulted in no maternal or fetal toxicity at doses up to 1000 mg/kg/day. Therefore, the maternal no-observed-adverse-effect level (NOAEL) was 1000 mg/kg/day and the fetal NOAEL was 1000 mg/kg/day.

Additional information