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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:
key study
Study period:
2022-03-11 to 2022-10-03
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2022
Report date:
2022

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
Adopted: 25 June 2018
Deviations:
no
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
Ditantalum pentaoxide
EC Number:
215-238-2
EC Name:
Ditantalum pentaoxide
Cas Number:
1314-61-0
Molecular formula:
O5Ta2
IUPAC Name:
ditantalum pentaoxide
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source :Sponsor
- Batch: 210515
- Purity: 99.9%
- Expiry Date:12 November 2026 (shelf life)

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Crl: WI(Han).
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany or Charles River Laboratories France, L'Arbresle Cedex, France.
- Age at study initiation: 10-14 weeks
- Weight at study initiation: 180-230 g
- Fasting period before study: not stated
- Housing: Polycarbonate cages (Makrolon type MIII, height 18 cm) containing sterilized wooden fibers as bedding item (Lignocel S 8-15, JRS-J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) equipped with water bottles.
Animals will be individually housed.
- Diet: SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany, ad libitum
- Water: tap water ad libitum
- Acclimatisation period: At least 5 days prior to dosing

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24
- Humidity (%): 40-70
- Air changes (per hr): At least 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

During the current study, the test item dosing formulations were prepared with corn oil. As
the substance is a metal compound and did not dissolve in concentrated nitric acid, nitric
acid/hydrogen peroxide or concentrated hydrochloric acid, the substance was also not
expected to react with any oil-like substance like corn oil and thus was expected to be stable
in corn oil for the period from formulation until administration.
In addition, to limit the impact, the test item preparation were performed with approved
procedures and documented in detail. Formulations were visually inspected for homogeneity
prior to use and all formulations were used within 2 hours after adding vehicle to the test
item. Additionally, test item formulations were prepared protected from light.

VEHICLE
- Justification for use and choice of vehicle (if other than water): ditantalum pentaoxide did not dissolve in aqueous solutions
- Amount of vehicle (if gavage): 4 mL/kg
Analytical verification of doses or concentrations:
no
Remarks:
Analysis of test item in vehicle for concentration, homogeneity, and stability was not performed, as no feasible analytical method was available.
Duration of treatment / exposure:
Days 6 to 20 post-coitum inclusive
Frequency of treatment:
daily gavage
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
300 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
20 females per dose
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least once daily 0 to 1 hours post-dose, starting on Day 6 post coitum up to and including the day prior to necropsy.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: On Days 2, 6, 15 and 21 post-coitum

BODY WEIGHT: Yes
- Time schedule for examinations: On Days 2, 6, 9, 12, 15, 18 and 21 post-coitum

FOOD CONSUMPTION : Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

WATER CONSUMPTION :Yes
- Time schedule for examinations: Regular basis throughout the study.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 16 post-coitum
- Organs examined: thyroid gland, kidney, liver, iliac and mandibular lymph node, diaphragm muscle, placenta, skin

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
- Other: number and distribution of live and dead fetuses
Blood sampling:

- Serum: 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]
- Anogenital distance of all live rodent pups: Yes
Statistics:
Means, standard deviations (or % coefficient of variation or standard error, when deemed appropriate), percentages, numbers, and/or incidences will be reported as appropriate by dataset.

Parametric
Levene’s test will be used to assess the homogeneity of group variances.
The groups will be compared using an overall one-way ANOVA F-test if Levene’s test is not
significant or the Kruskal-Wallis test if it is significant. If the overall F-test or Kruskal-Wallis
test is found to be significant, then pairwise comparisons will be conducted using Dunnett’s
or Dunn’s test, respectively.

Non-parametric
The groups will be compared using an overall Kruskal-Wallis test. If the overall
Kruskal-Wallis test is found to be significant, then the above pairwise comparisons will be
conducted using Dunn’s test.
Historical control data:
Charles River Den Bosch has historical data on the background incidence of fetal malformations and developmental variations in this species from the same strain and source

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No test material-related clinical signs were noted during the treatment period.
Any clinical signs noted during the treatment period occurred within the range of background
findings to be expected for rats of this age and strain which are housed and treated under the
conditions in this study and did not show any apparent dose-related trend. At the incidence
observed, these were considered to be unrelated to treatment with the test material.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Endocrine findings:
effects observed, non-treatment-related
Description (incidence and severity):
Serum levels of T3 and T4 were considered to be unaffected by treatment with the test material.
At 100 and 1000 mg/kg/day, TSH levels were higher (1.23x and 1.24x of control, not statistically significant). Considering the small magnitude of the effect and as the mean values were within historical control data1, the increase in TSH was considered to be unrelated to treatment with test material.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed

Maternal developmental toxicity

Number of abortions:
not specified
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
The numbers corpora lutea and implantation sites, and pre- and postimplantation loss in the control and test groups were similar and in the range of normal biological variation.
Early or late resorptions:
no effects observed
Description (incidence and severity):
The numbers corpora lutea and implantation sites, and pre- and postimplantation loss in the control and test groups were similar and in the range of normal biological variation.
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
no effects observed

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: No adverse effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
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
Anogenital distance of all rodent fetuses:
no effects observed
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were two external malformations observed in this study. Fetus No. 16-L1 in the control group presented with an absent anus and fetus No. 85-R9 at the high dose (1000 mg/kg/day) presented with omphalocele. The single occurrences and/or presence in the control group only ruled out a relationship to the treatment with the test material
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Skeletal variations were observed in the forelimb, pelvic girdle, (supernumerary) ribs, scapula, skull, sternebra and vertebra and occurred across all groups. However, a relationship to treatment with the test material was ruled out due to infrequent observations, absence of a dose-related incidence trend, and/or only scored in control fetuses.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Visceral variations were limited to supernumerary liver lobes and convoluted/minimally dilatated ureters. Infrequent occurrences, insignificant differences to the control group and/or occurrence in a control fetus ruled out any relationship to the treatment with the test material

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
No maternal and developmental toxicity was observed for Ta2O5 CERAMIC Grade in a prenatal developmental toxicity study conducted in rats. Following NOAELs for Ta2O5 CERAMIC Grade were established:
Maternal NOAEL: at least 1000 mg/kg/day.
Developmental NOAEL: at least 1000 mg/kg/day.
Executive summary:

In a developmental toxicity study ditantalum pentoxide (99.9 % a.i.) was administered to 22 time-mated female Wistar Han rats by gavage at dose levels of 0, 100, 300, or 1000 mg/kg bw/day from days 6 through 20 of gestation.

There were no treatment-related effects in mortality, clinical signs, body weight, food consumption, or cesarean parameters.  The maternal NOAEL is 1000 mg/kg bw/day.  

There were no treatment-related effects in developmental parameters. The developmental NOAEL is 1000 mg/kg bw/day. 

The developmental toxicity study in the rat is classified acceptable and satisfies the guideline requirement for a developmental toxicity study (OECD 414) in rats.