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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No reproductive study conducted with target substance is available. However available data from tantalum pentachloride were used in a read-across approach.


A GLP guideline study according to OECD 422 (combined repeated dose toxicity study with the reproduction/developmental toxicity screening test) conducted with read across substance tantalum pentachloride is available. There were no treatment-related effects observed in the study. The NOAEL for maternal and reproductive/developmental toxicity was considered to be 1000 mg/kg bw/day (the highest dose tested).

Link to relevant study records

Referenceopen allclose all

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the extended one-generation reproductive toxicity study does not need to be conducted because there are no results from available repeated dose toxicity studies that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with reproductive toxicity
Reproductive effects observed:
not specified
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
For justification of read-across please refer to the read-across report attached to IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
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:
other: no adverse effect observed in any investigated endpoint
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effect observed in any investigated endpoint
Reproductive effects observed:
not specified
Conclusions:
In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test no adverse effects were found after oral administration of Tantalum pentachloride in male and female Wistar rats and in the male and female pups. Based on the results, the NOAEL is considered to be 1000 mg/kg bw/day.
Executive summary:

In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) Tantalum pentachloride (99.9%) was administered orally (after hydrolysis and neutralization) to 10 male and female Wistar rats/dose in water by gavage at dose levels of 0, 100, 300, or 1000 mg/kg bw/day. The animals were treated with the test item formulation on 7 days per week for a period of 54 days, i.e. during 14 days of pre-mating and maximum 14 days of mating in both males and females, during the gestation period and up to post-natal day 3 in females. Males were dosed after the mating period until the minimum total dosing period of 28 days was completed.

No adverse effects of Tantalum pentachloride after hydrolysis and neutralisation were found up to the dose level of 1000 mg/kg body weight/day.

There were no clinical signs of toxicological relevance in the dose groups and sham control group when compared to the control group. However, salivation and/or moving the bedding were observed transiently in all males and females of the HD and/ or SC group. These clinical signs were noted immediately after the dose administration, therefore, were considered to be signs of discomfort caused due to treatment.

There were no effects on the survival of the pups from PND 1 through PND 4 in the dose groups and sham control group, when compared to the control group. However, one single pup (pup no. 3 of dam 85) was found dead in the HD group, which was considered incidental.

There were no test item treatment related effects on clinical biochemistry parameters. There were no effects on urine parameters of males and females of dose groups compared to controls. Few specific macroscopic changes were recorded for the male and female animals, which based on microscopic examination were not considered to be of test item treatment relevance.

There were no test item treatment related effects on absolute and relative organ weights for males and females. Statistically significant differences were found in the weights of some organs (thyroid/parathyroid glands, prostate including seminal vesicles and coagulating glands, pituitary gland, liver and thymus of males and/ or females of dose and/ or control groups), which in the absence of a dose response relationship and also in the absence of macroscopic and microscopic findings were not considered to have toxicological relevance.

Under the conditions of this study, treatment-related histomorphologic changes were observed in the stomach of Group 5 (High-dose group). They consisted of mucous neck cell hypertrophy with/without increased submucosal inflammatory cell infiltrate in the glandular stomach. The same changes were also observed in Group 2 (Sham control group), and there were no clear differences in incidence and severity between the sham control group and the high-dose group. It was considered that these histologic changes were due to local stimuli to the glandular stomach mucosa, which could be associated with properties of the dose formulation in the intra-gastric environment, and the gastric lesions were deemed not to be directly related to the test item. The test item produced no histomorphologic evidence of toxicological properties in the male and female reproductive organs including testes, epididymides, prostate glands, coagulating glands, seminal vesicles, ovaries, uterus with cervix and vagina. Furthermore, by the detailed testicular examination, it was judged that there were no treatment-related effects on the testicular histomorphology including spermatogenesis as well. The remainder of findings recorded were within the range of normal background lesions, which may be recorded in animals of this strain and age, or were incidental lesions that were not related to treatment with the test item.

There were no treatment-related effects found regarding to mortality, clinical signs, functional observations, histopathology, organ weights, reproduction, breeding data and pup development up to 1000 mg/kg bw/day. Based on the results, the NOAEL for maternal and reproductive/developmental toxicity is considered to be 1000 mg/kg bw/d. This study is classified as acceptable and satisfies the guideline requirement for an oral repeated dose toxicity study in rat. 

This information is used in a read-across approach in the assessment of the target substance.

For justification of read-across please refer to the attached read-across report (see IUCLID section 13).

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
High.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

 


Available data from tantalum pentachloride were used in a read-across approach. Tantalum pentachloride readily hydrolyses upon contact with water releasing a considerably higher amount of tantalum ions compared to tantalum pentoxide. Thus, any resulting toxicity potential of tantalum pentachloride would also be expected to be higher. Therefore, the read-across to the source substance tantalum pentachloride is adequately protective. Details on the read-across rational are provided in section 13.


Using this read-across approach, in a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) the source substance tantalum pentachloride was administered orally (after hydrolysis and neutralization) to 10 male and female Wistar rats/dose in water by gavage at dose levels of 0, 100, 300, or 1000 mg/kg bw/day. The animals were treated with the test item formulation on 7 days per week for a period of 54 days, i.e. during 14 days of pre-mating and maximum 14 days of mating in both males and females, during the gestation period and up to post-natal day 3 in females. Males were dosed after the mating period until the minimum total dosing period of 28 days was completed. Litter was not exposed. There were no treatment-related effects found regarding to mortality, clinical signs, functional observations, histopathology, organ weights, reproduction, breeding data and pup development up to 1000 mg/kg bw/day. Based on the results, the NOAEL for maternal and reproductive/developmental toxicity is considered to be 1000 mg/kg bw/day.


 


Justification for selection of Effect on fertility via oral route:
GLP guideline study in accordance to OECD 422.

Effects on developmental toxicity

Description of key information

No treatment-related effects in mortality, clinical signs, body weight, food consumption, cesarean parameters or developmental parameters were observed in GLP guideline study conducted according to the OECD 414 with ditantalum pentoxide in rats. The maternal NOAEL was established as at least 1000 mg/kg bw/day and the developmental NOAEL was established as at least 1000 mg/kg bw/day (the highest dose tested).


 


In addition, available data from tantalum pentachloride were used in a read-across approach. A GLP guideline study according to OECD 422 (combined repeated dose toxicity study with the reproduction/developmental toxicity screening test) conducted with read across substance tantalum pentachloride is available. There were no treatment-related effects observed in the study. The NOAEL for maternal and reproductive/developmental toxicity was considered to be 1000 mg/kg bw/day (the highest dose tested).

Link to relevant study records
Reference
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
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)
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
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:
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
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
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
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
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
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
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
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
Abnormalities:
no effects observed
Developmental effects observed:
no
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.  

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

In a developmental toxicity study (OECD 414) ditantalum pentoxide (99.9 % purity) 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 GD 6 to 20. 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. 


In addition, in a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) the read-across partner tantalum pentachloride (99.9% purity) was administered orally to 10 male and female Wistar rats/dose in water by gavage at dose levels of 0, 100, 300, or 1000 mg/kg bw/day. There were no treatment-related effects. The NOAEL for maternal and reproductive/developmental toxicity is considered to be 1000 mg/kg bw/day.

Justification for classification or non-classification

In accordance with information available for this substance, no classification for toxicity to reproduction or developmental toxicity is required under Regulation (EC) No. 1272/2008  (CLP Regulation).

Additional information