Registration Dossier

Administrative data

Description of key information

No data regarding the oral exposition is available for tantalum metal (target substance). Thus, available data from tantalum pentachloride were used in a read-across approach. A GLP guideline study according to OECD 422 with tantalum pentachloride was conducted. 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 can be considered to be 1000 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
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:
read-across source
Clinical signs:
no effects observed
Description (incidence and severity):
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.
Mortality:
no mortality observed
Description (incidence):
No mortality occurred in the control, sham control or any of the dose groups during the treatment period of this study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
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.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
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.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
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 biochemistry findings:
no effects observed
Description (incidence and severity):
There were no test item treatment related effects on clinical biochemistry parameters. All parameters were within the historical control data range.

Urinalysis findings:
no effects observed
Description (incidence and severity):
The urinalysis performed in male and female animals revealed no test item treatment related effect.

Behaviour (functional findings):
no effects observed
Description (incidence and severity):
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.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
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 pathological findings:
no effects observed
Description (incidence and severity):
There were no gross lesions that could be attributed to treatment with the test item
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
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 (see Table 7). 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.
Histopathological findings: neoplastic:
no effects observed
Details on results:
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.

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

REPRODUCTIVE INDICES
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.

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 FORMULATION ANALYSIS
The recoveries of analytical samples collected from LD, MD and HD groups at various intervals for the concentration verification,homogeneity and stability analysis were within the acceptance criteria (70% to 110%) except for homogeneity and concentration verification samples of LD group on week 1 (sample code 5a, 6a, 7a and 18a). The recoveries of these samples were below the acceptance criteria. As there were no adverse toxicity observed in the study, the NOAEL considered at 1000 mg/ kg body weight and the recoveries of nominal concentration of HD group during the study being within acceptance criteira i.e all HD group individual values ranging from 93% to 100%, the lower recoveries in the LD group was not considered to impact the validity of the study
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
Critical effects observed:
not specified

The No-Observed-Adverse Effect Level (NOAEL) for systemic toxicity was established at 1000 mg/kg bw/day. Local irritation related to the dose formulation may be elicited in the stomach when the test item was ingested with the condition of the formulation used in this study. Those effects were not dose-effect related (s. Table below).

Table 7: Incidence and mean severity grade of main findings in the stomach

Finding
Incidence/ Mean Severity Grade

Group 1
(control)
Group 2
(sham control)
Group 3
(100 mg/kg bw/day)
Group 4
(300 mg/kg bw/day)
Group 5
(1000 mg/kg bw/day)
Glandular stomach 5 M 5 F 6 M 6 F 5 M 5 F 5 M 5 F 5 M 5 F
Mucous neck cell hypertrophy/proliferation 0 0 6/1.3 4/1.3 0 0 0 0 3/1.7 2/1.0
Increased inflammatory cell infiltrate, mainly submucosa 0 0 2/1.0 1/1.0 0 0 0 0 2/1.0 0
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. 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 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 repeated dose 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).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP guideline study

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No data regarding the oral exposition is available for tantalum metal (target substance). Thus, 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 metal. 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.

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. No adverse effects of tantalum pentachloride were found up to the dose level of 1000 mg/kg body weight/day. Thus, the NOAEL in this study is considered to be 1000 mg/kg bw/day.

Several sources of data from literature report tantalum as being completely inert towards body tissues and fluids in view of its chemical inertness and lack of solubility, stating that it is non-toxic by all routes both acutely and chronically.

A study (Pellmar, 1998) was conducted to investigate the toxicity associated with depleted uranium exposure. Pellets of the metals were surgically implanted into the gastrocnemus muscle of both hindlimbs of male Sprague-Dawley rats. The implantation of tantalum was selected to be a chemically inert control.

After 6 months the levels of tantalum found distributed through tissue were negligible. Examination of the pellets in situ revealed no fibrous tissue adhering to the pellets after implantation with tantalum. Bodyweight gain was as expected and comparable to the non-surgical control. No other effects were noted for the animals implanted with tantalum.

A pilot study (Hahn, 1998) was conducted to provide information critical to the planning of relative carcinogenesis studies relating to depleted uranium in rodents. The purpose of the study was to determine the in vivo solubility of depleted uranium following implantation, changes in surface characteristics of the implant and histological responses of rats and mice. Tantalum was selected to be a chemically inert control.

Depleted uranium foils and tantalum foils were surgically implanted into the subcutis; animals were euthanised and necropsied after 30 or 60 days. Around the tantalum foil implants, there was observed to be a thin connective tissue capsule containing a scant infiltration of chronic inflammatory cells in some animals. There were no physical alterations of the foil reported.

No other effects of tantalum were reported; as a result of this, tantalum was subsequently proposed to be used as the negative control in the prospective 2 year carcinogenesis study.

Toxicokinetic assessments of tantalum have found that little of the administered tantalum is absorbed by the body with the majority being rapidly excreted by the gastrointestinal system or lung clearance mechanisms. Following exposure to tantalum by inhalation, the majority of inhaled tantalum has been found to be deposited in the large airways and rapidly cleared by mucociliary action or by coughing within 4 days while some is swallowed and excreted. Tantalum in the conducting airways has been found to be completely eliminated without significant inflammatory effects or absorption. Tantalum delivered to peripheral airways has been found to be cleared slowly by phagocytosis. During the phagocytotic process, no evidence of fibroblastic or inflammatory response in the pulmonary tissue was noted. Neither airways nor lung parenchyma showed adverse responses to tantalum.

 

Since tantalum is highly insoluble and inert, it is not likely to be absorbed in the body. Short term toxicity data have shown tantalum to be innocuous up to the highest permissible test concentrations while toxicokinetic assessments show that any tantalum, administered to the body, is rapidly excreted. Thus it can be concluded that tantalum does not reside in the body, it is therefore unlikely to be present at levels to elicit adverse effects.

 

This statement can be substantiated with several sources of literature which quote that both acutely and chronically, tantalum and its compounds are non-toxic by all routes and levels experienced under industrial operating conditions, as would be expected from its complete inertness toward body tissues and fluids. Systemic poisoning in workers exposed to tantalum is unknown. It is also reported that no human diseases from tantalum are known.

 

The physiological inertness of tantalum metal has been demonstrated by its long use in surgical implants. A 10 year study of the use of tantalum gauze in the repair of hernias revealed no effects from the gauze itself and powdered tantalum has been found satisfactory as a contrast medium for human laryngology. Tantalum powder has also been used as an insufflating agent in human patients to assess the rates of clearance from different size pulmonary airways without adverse effects.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation 1272/2008, tantalum does not meet the criteria for classification for repeated dose specific organ toxicity.