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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No data regarding the toxicity to reproduction is available for tantalum metal (target substance). Thus, available data from tantalum pentachloride were used in a read-across approach.


In a GLP guideline study according to OECD 422 with tantalum pentachloride, no adverse effects were observed after oral administration of the source substance tantalum pentachloride in male and female Wistar rats at the highest tested dose of 1000 mg/kg bw/day. Based on the results, the NOAEL  was considered to be 1000 mg/kg bw/day.

Link to relevant study records

Referenceopen allclose all

Endpoint:
fertility, other
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
Not reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study data from literature relating to non-standard test methods. The experiment was conducted in accordance with accepted scientific principles.
Principles of method if other than guideline:
A study was conducted to investigate the transfer of depleted uranium from mother to foetus to gain an understanding of the degree of foetal exposure from maternal implanted uranium. The impact of the depleted uranium on the dam’s ability to become pregnant and carry her litter to term was also investigated. Tantalum was used in the study as a chemically inert control.
GLP compliance:
not specified
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: (P) Females: 250 - 300 g
- Housing: Two females were housed with one untreated male during the breeding phase. From Gestation day 0 until gestation day 20 females were housed individually.
Route of administration:
implantation
Vehicle:
unchanged (no vehicle)
Details on exposure:
16 female rats were surgically implanted with 12 tantalum pellets, a non-surgical control was included.
Details on mating procedure:
- M/F ratio per cage: 1:2.
- Proof of pregnancy: Gestational Day (GD) 0 was determined by the presence of sperm in the vaginal washing.
- After successful mating each pregnant female was caged (how): individually.
Duration of treatment / exposure:
Animals were bred 7 - 14 days post-implantation; dams were euthanised on GD 20.
Frequency of treatment:
The test material was implanted during one surgical procedure. The implant remained in place until the animals were euthanised.
No. of animals per sex per dose:
16
Control animals:
yes, concurrent no treatment
Parental animals: Observations and examinations:
Pregnant rats were monitored daily for weight gain, food intake and water intake.
Postmortem examinations (parental animals):
Following euthanisation, dams were immediately subjected to caesarean-section and the uterine horns removed.
The uterine horns were examined for any resorption sites.
Postmortem examinations (offspring):
Following euthanisation of the dams, foetuses were dissected out and all the placentae for that litter were collected. Litters were examined and a record made of:
-the total number of foetuses
-the number of viable foetuses
-the sex ratio
-any overt signs of teratological effects
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Reproductive performance:
no effects observed
The maternal results are summarised in Table 1.
There was no effect on maternal food and water intake, weight gain during pregnancy and time-to-pregnancy.
Implanted pellets did not affect the ability of the rats breed or maintain the pregnancy until the day of euthanasia.
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Gross pathological findings:
no effects observed
The litter data are summarised in Table 2
No effects were seen on the following litter parameters:
-the number of pups
-the number of males vs. females
-foetal weights

All litters were examined for overt signs of teratology and none were noted.
Reproductive effects observed:
not specified

Table 1 Effects of Implanted Tantalum on Maternal Parameters

Variable

No Surgery

12 Implanted Ta Pellets

# Dams bred

16

16

Days to pregnancy (SEM)

3.9 (± 1.76)

2.08 (± 0.23)

Mean weight gain (g)

133.79 (± 8.13)

138.32 (± 6.49)

Mean food intake (g)

23.44 (± 0.67)

24.51 (± 0.68)

Mean water intake (mL)

43.85 (± 2.59)

44.45 (± 2.60)

 

Table 2 Effects of Tantalum on Litter Data

Variable

No Surgery

12 Implanted Ta Pellets

Total # foetuses

13.8 (± 0.79)

13..5 (± 0.78)

# Males

6.6

6.3

# Females

7.2

7.2

# Non-viable

0

1

Average pup weight

3.56 (± 0.20)

3.164 (± 0.09)

Conclusions:
The implanted tantalum pellets had no effect on the reproductive performance of the animals in this study.
Executive summary:

A study was conducted to investigate the transfer of depleted uranium from mother to foetus to gain an understanding of the degree of foetal exposure from maternally implanted uranium. The impact of the depleted uranium on the dam’s ability to become pregnant and carry her litter to term was also investigated. Tantalum was used in the study as a chemically inert control.

Pregnant rats were monitored daily for weight gain, food intake and water intake. Following euthanisation, dams were immediately subjected to caesarean-section. The uterine horns were removed and foetuses were dissected out.

Litters were examined and a record made of the total number of foetuses, the number of viable foetuses, the sex ratio and any overt signs of teratological effects.

There was no effect on maternal food and water intake, weight gain during pregnancy and time-to-pregnancy; implanted pellets did not affect the ability of the rats breed or maintain the pregnancy until the day of euthanasia.

No effects were seen on the litters relating to the number of pups, the number of males vs. females and foetal weights. All litters were examined for overt signs of teratology and none were noted.

There were no effects reported in this study relating to implantation of the test material.

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
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
Clinical signs:
not specified
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
not specified
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Description (incidence and severity):
Furthermore, by the detailed testicular examination, it was judged that there were no treatment-related effects on the testicular histomorphology including spermatogenesis as well.
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No mortality occurred in the control, sham control or any of the dose groups during the treatment period of this study.
Slight to severe salivation was noted in some males and females of the HD group and one male of the SC group on single occasion of treatment. Furthermore, moving the bedding was observed transiently in all males and all females of the HD and the SC group and in one male of the MD group. The clinical signs salivation and moving the bedding were immediately after the dose administration and therefore were considered to be a sign of discomfort caused due to test item treatment with no toxicological relevance.
Isolated incidence of abnormal breathing irrespective of the dose group on single occasion of treatment were considered to be incidental.
Alopecia or crust on various body parts, vocalisation or partial regurgitation of formulation were noted in isolated males and/or females of the dose groups and/or control groups. These clinical signs were transient in appearance and showed up irrespective of the groups. Therefore, they were considered to be incidental. None of the females showed signs of abortion or premature delivery.
During the weekly detailed clinical observation, no relevant differences between the groups were found.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
In both males and females, there was no test item treatment related effect on body weight in the dose groups during the study period. There were no statistically significant differences between the dose groups, sham control group and the control group. There was no test item treatment related effect on food consumption in male. In females there was statistically significantly lower food consumption (up to 11% lower compared to controls) observed in the female LD, the MD and the HD group during the first week of treatment showing dose response relationship. However, with the progress of the study no such changes in food consumption was observed. Hence, the finding was not considered to be an adverse effect.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
There were no test item treatment related effects on the reproductive indices (copulation, fertility, delivery and viability indices) in the dose groups when compared to the control group. However, a slightly reduced copulation index (number of copulated females / number of pairs) of 90 % in the MD group compared to 100 % in all other groups. In the absence of dose response relationship the finding was not considered to be of toxicological relevance. The viability index was marginally lower in the HD group (99.29%) as compared to the control group (100%). This was due to the death of one single pup (no. 3) of female no. 85. As this finding was limited to a single pup it was considered incidental.

PRECOITAL INTERVAL AND DURATION OF GESTATION
There were no effects on the duration of precoital interval and the duration of gestation in the dose groups and sham control group, when compared to the control group

PRE-and POST-NATAL DATA
There were no test item treatment related effects on the number of corpora lutea, number of implantation sites, number of live pups (PND 0 and PND 4) and percentage of pre- and post-implantation loss in the dose groups and sham control group, when compared to the control group

ORGAN WEIGHTS (PARENTAL ANIMALS)
In males, there were no statistically significant differences in the absolute and relative organ weights of the dose groups and sham control group when compared to the corresponding control group. In females, there was a statistically significantly higher absolute and relative liver weight in the MD group (higher by 13 to 16 % vs control) and a higher absolute liver weight in the sham control (higher by 15% vs control) compared to the control group animals. In the absence of a dose response relationship and an absence of macroscopic and microscopic findings, this was not considered to have toxicological relevance.

GROSS PATHOLOGY (PARENTAL ANIMALS)
There were no gross lesions that could be attributed to treatment with the test item

HISTOPATHOLOGY (PARENTAL ANIMALS)
Histomorphologic changes considered to be due to systemic toxic effects of the test item were not observed in any organs and tissues examined in this study. However, local irritative effects which were considered to be related to the properties of the test item formulation were observed in the stomach. They consisted of mucous neck cell hypertrophy with/without increased submucosal inflammatory cell infiltrate in the glandular stomach of animals from Group 5 (High-dose group). 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. Even only NaOH or NaCl, depending upon the concentration used, can act as an irritant to cause mucosal necrosis in the stomach, especially in the glandular stomach. Moreover, it is known that mucous neck cell hypertrophy/proliferation occurs as a response to mild irritation to mucosa. It is likely that increased inflammatory cell infiltrate recorded in some animals is also a response to irritation to mucosa. Thus, the gastric lesions were deemed not to be directly related to the test item.

HAEMATOLOGY and COAGULATION
In males and females, no test item treatment related effects were observed for haematological parameters. However, there was a statistically significantly increase of large unstained cells (LUC) in male sham control group compared to control animals. But considering that no statistically significant changes in LUC of dose groups compared to control animals and also no dose response relationship was observed, no effect in LUC was considered. There was also statistically significantly lower RBC and monocyte counts in female MD groups. In the absence of dose response relationship, the findings were not considered to be of toxicological relevance. All mean and most of the individual values were within the historical control data range. There was also higher LUC in female MD and HD group, but in the absence of statistical significance, the finding was not considered adverse.
Blood coagulation was not affected in males due to test item treatment. In females there was statistically significantly longer prothrombin time (PT) in the HD group compared to the corresponding controls. This finding was within the historical control range and therefore was not considered to be adverse.

CLINICAL CHEMISTRY
There were no test item treatment related effects on clinical biochemistry parameters. All parameters were within the historical control data range.

URINALYSIS
The urinalysis performed in male and female animals revealed no test item treatment related effect.

(NEURO)BEHAVIOUR
No relevant effects were observed in any of the parameters of the functional observation battery before and at the end of the treatment period. There were no biologically relevant differences in body temperature between the groups.

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 toxicity observed in the study
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
LITTER DATA:
There were no test item treatment related effects on litter data including total number of pups born, number of live pups, still births and runts on PND 0 as well as number of male pups, number of female pups and sex ratio on PND 0 and PND 4. There were no statistically significant changes noted for these litter data

LITTER WEIGHT DATA
There were no effects on pup mean weight, total litter weight, male and female litter weight on PND 0 and PND 4. There were no statistically significant change in dose groups compared to corresponding controls.

PUP SURVIVAL DATA
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. A marginally higher mean mortality of pups between PND 1 and PND 4 was observed in the HD group (0.71%) compared to the control group (0.00%). This outcome did not achieve statistical significance and was attributed to the death of one single pup of one single dam on PND 1. Thus, it was considered incidental and not related to the treatment with the test item.

PUP EXTERNAL FINDINGS
No test item related gross external abnormalities of toxicological relevance were observed in the pups of any of the groups.
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 toxicity observed in the study
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. 

The test item is considered suitable read across partner due to the complete dissolution and higher solubility of TaCl5 compared to tantalum metal.

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
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No data is available for tantalum metal (target substance). Thus, data from tantalum pentachloride (source substance) was 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. Thus, the resulting toxicity potential of tantalum pentachloride would also be expected to be higher. Therefore, the read across to the source substance tantalum pentachloride is considered adequately protective. Details on the read-across rational are provided in section 13.

In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) 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. 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.

Tantalum is a heavy metal that forms an oxide layer when exposed to air at room temperature. Due to the protection by this oxide layer, tantalum is insoluble in water. It is resistant to acids at ambient temperature and to many organic and inorganic compounds. Tantalum is attacked by concentrated mineral acids such as HF, fused alkalis, and fuming sulphuric acid only; i.e., tantalum is dissolved only under extremely oxidising conditions that are not compatible with administration to animals.

Due to its insolubility it can be assumed that tantalum metal even if applied as pure powder will not be absorbed in the gastrointestinal tract. The negligible bioavailability after oral application allows the prediction that tantalum will not illicit any adverse reproductive effects. Moreover, the use of tantalum in medical implants, with no observed effect, helps illustrate its inherent lack of toxicity. This predictability makes testing into reproductive effects unnecessary.

 

Supporting information is included in the form of literature data.

A study was conducted (Benson, 1998) to investigate the transfer of depleted uranium from mother to foetus to gain an understanding of the degree of foetal exposure from maternally implanted uranium. The impact of the depleted uranium on the dam’s ability to become pregnant and carry her litter to term was also investigated. Tantalum was used in the study as a chemically inert control.

Pregnant rats were monitored daily for weight gain, food intake and water intake. Following euthanisation, dams were immediately subjected to caesarean-section. The uterine horns were removed and foetuses were dissected out.

Litters were examined and a record made of the total number of foetuses, the number of viable foetuses, the sex ratio and any overt signs of teratological effects.

There was no effect on maternal food and water intake, weight gain during pregnancy and time-to-pregnancy; implanted pellets did not affect the ability of the rats breed or maintain the pregnancy until the day of euthanasia.

No effects were seen on the litters relating to the number of pups, the number of males vs. females and foetal weights. All litters were examined for overt signs of teratology and none were noted.

There were no effects reported in this study relating to implantation of the test material.


Effects on developmental toxicity

Description of key information

No data regarding the toxicity to developmental toxicity is available for tantalum metal (target substance). Thus, available data from ditantalum pentoxide were used in a read-across approach.


In a GLP guidance study with the source substance ditantalum pentoxide according to OECD 414, no adverse effects were observed. Therefore, the NOAEL was considered to be 1000 mg/kg bw/d, i.e. 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
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

The water solubility of Ta metal has been determined to be <0.021 mg/L at 20 °C. The substance is considered inert and highly insoluble which also restricts bioavailability. Tantalum metal forms an oxide layer when exposed to air at room temperature. Due to the protection by this oxide layer, tantalum is insoluble in water. It is resistant to acids and to many organic and inorganic compounds. Tantalum is only attacked by concentrated mineral acids such as HF, fused alkalis and fuming sulphuric acid; i.e., tantalum is dissolved only under extremely oxidising conditions that are not compatible with administration to animals. Due to its insolubility it can be assumed that tantalum metal even if applied as pure powder will not be absorbed in the gastrointestinal tract. Furthermore, results from extraction tests showed that tantalum will not be dissolved in physiological media; hence tantalum will not be available to the body, at a significant level, to cause an adverse effect. As the registered substance is pure tantalum, the 0 valence state indicates a low potential for biochemical interaction.


With respect to systemic toxicity, in a prenatal developmental toxicity GLP study according to OECD 414 with ditantalum pentoxide no adverse effects were observed up to the highest dose tested. Therefore, the maternal and developmental NOAEL is considered to be 1000 mg/kg bw/d


Additionaly, in a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422), tantalum pentachloride (a more soluble tantalum compound, with a similar toxicological profile) showed no developmental toxicity at the highest dosage group of 1000 mg/kg bw/day in rats.


Supporting evidence is available from a non guideline study investigating the reproductive and prenatal effects of subcutaneously implanted uranium foil. Tantalum was used as a chemically inert control showing no adverse effects on dams and fetuses. In addition, no adverse effects have been reported in any other human health related endpoint, and no or no significant human exposure is expected based on the identified uses even though tantalum is used as contrast agent for laryngotracheograms or bronchographies. Based on this data, conducting reproductive or developmental toxicity studies with tantalum metal is not considered justified. This is also in line with animal welfare considerations.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation 1272/2008, the target substance does not require classification for reproductive or developmental toxicity.

Additional information