Registration Dossier

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics
Type of information:
other: Review article
Adequacy of study:
weight of evidence
Study period:
Not reported
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Objective of study:
absorption
distribution
excretion
metabolism
Qualifier:
no guideline followed
Principles of method if other than guideline:
The article is a review of all available literature information pertaining to the behaviour of tantalum both in vitro and in vivo. The purpose of the evaluation of the biological performance of tantalum is to assess its suitability as a biomaterial.
GLP compliance:
not specified
Radiolabelling:
yes
Remarks:
One study used 182Ta
Details on absorption:
In vivo
Tantalum is considered to have a very low solubility and, as such, limited absorption in the body is anticipated. Intake of both Ta and Ta2O5 has been reported to produce very low levels of Ta absorption from either the respiratory or gastrointestinal system.
Details on distribution in tissues:
In a study by Venugopal and Luckey, soluble 182Ta was injected in animal models and only 15 % was retained, the balance was rapidly excreted. The order of storage proportion was given as bone > GI tract > pelt > muscle > liver > kidneys > testes > spleen with ~ 40 % retained in bone. In vitro studies of soluble 182Ta fail to show any specific Ta-protein binding. Intracellular uptake of soluble 182Ta in human lung tissue obtained by biopsy showed 71 % of Ta remaining within cytosol with an organelle Ta content: nucleus > mitochondria > microsomes > lysomes. Clearance from blood into tissues is fairly prompt with as much as 1.57 % of injected dose (in rats) being found in bone after 48 hours.
Details on excretion:
In vivo
In a case reported by Rizzato et al., levels of tantalum in the lung were recorded to be 325 ppm but only 1 ppm in whole blood and 3 ppb in urine in an individual who had been exposed to a mixture of airborne hard metals for a period of 13 years, ceasing 4 years prior to the study. In the absence of disease which impairs microcilliary action, particulate Ta clears promptly from the lungs, airways and oesophagus in both animals and humans.
Details on metabolites:
Tantalum arouses very little adverse biological response in either reduced or oxidised forms. There are no reports of it having any adverse effect on metabolic function.

According to the van Mulder and Pourbaix review of tantalum's electrochemical stability, it is covered by a very low solubility tantalum oxide film over all combinations of pH and potential of biological interest. It was also reported that the Ta/Ta2O5 equilibrium reaction is impossible to characterise directly due to the protective power of the oxide. Tantalum metal is considered to be a very noble material.

Local host response

When powdered Ta is implanted, particles up to 50 µm are transported within the lymphatic system, probably by macrophage action, while larger particles are immobilised. Individual particles are easily phagocytised without evidence of phagocyte death; however, particle aggregates do elicit foreign body giant cell responses and fibrous encapsulation.

When Ta is implanted as a foil, wire or mesh, the predominant local tissue response is the formation of a thin, glistening membrane without significant evidence of inflammation.

When Ta is implanted as foil, wire, rod or ball in bone, there is significant evidence that is can become osteointegrated without an intervening soft layer tissue or capsule.

Conclusions:
Accoridng to this reviwe publication, tantalum is highly insoluble and resistant to chemical attack. Intake of tantalum produces very low levels of absorption with the majority being rapidly excreted by the gastrointestinal system or lung clearance mechanisms. Of the tantalum that is retained in the body, the majority is found to reside in bones. Following implantation with tantalum, particles have been found to be transported in the lymphatic system, probably by macrophage action. Individual particles have been reported to be phagocytised with larger particles being encapsulated by formation of a thin membrane. In consideration of the low level absorption and effective elimination of tantalum from the body, tantalum has been found to be innocuous with no adverse effects noted and no reports on metabolic function. It is reported that no human diseases from tantalum are known.
Executive summary:

In order to consider the biological performance of tantalum, a review article was published to evaluate existing in vitro and in vivo data to assess its suitability as a biomaterial.

The review summarises the corrosion resistance of tantalum in physiological media and the low level of absorption following intake to the body. The majority of tantalum is reported to be rapidly excreted by the gastrointestinal system or lung clearance mechanisms. Of the tantalum that is retained in the body, the majority is found to reside in bones.

Following implantation with tantalum, particles have been found to be transported in the lymphatic system, probably by macrophage action. Individual particles have been reported to be phagocytised with larger particles being encapsulated by formation of a thin membrane. In consideration of the low level absorption and effective elimination of tantalum from the body, tantalum has been found to be innocuous with no adverse effects noted and no reports on metabolic function. It is reported that no human diseases from tantalum are known.

Description of key information

Tantalum is a ductile, silver grey metal which forms an adherent and stable oxide layer when exposed to air at room temperature. It is chemically inert, insoluble in water and considered as not being bioavailable following oral ingestion or dermal exposure.

As mechanical irritation of mucous membranes and the respiratory system can occur following exposure to tantalum dust due to particle effects, occupational exposure limits are set in various countries and these can be used for risk assessment purpose.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

1.0       Introduction

Physical-chemical properties and available data of in vitro and in vivo studies have been used to determine the toxicokinetic profile of Tantalum. 

2.0       Physicochemical properties

Tantalum is a ductile, silver grey metal with a molecular weight of 180.9 g/mol. Tantalum metal forms an adherent and stable oxide layer when exposed to air at room temperature, and for this reason it is insoluble in water (water solubility less than or equal to 21.3 µg/L). Because of the protective and chemically inert oxide, tantalum is not attacked by concentrated nitric, hydrochloric or sulphuric acids at temperatures below 200 °C.

3.0       Absorption

3.1       Oral absorption

The resistance imparted to tantalum by the passivating surface thermal oxide layer to even concentrated hydrochloric acid at temperatures below 200 °C makes any dissociation within a living organism impossible, and likewise any subsequent absorption from the gastro-intestinal tract.

An experimental study, which is only available as brief summary (Shiraishi, 1972), suggests that orally administered 182Ta was absorbed to greater extent in suckling rats than in adults, with an ‘initial rapid loss’ evident also in suckling animals. This study was disregarded as there is no information on whether 128Ta was administered as metal or in more soluble form (e.g. tantalate)

The lack of a significant oral absorption is supported by results of a guideline OECD 423 acute oral toxicity study (Blanchard E.L., 2000a), which determined the LD50 to be greater than 2000 mg/kg bw and where no signs of toxicity and no effects on body weight were observed, and by data in the public domain (e.g. Black, 1994) indicating the LD50 as being greater than 8000 mg/kg bw.

Based on this data, no oral absorption for tantalum is assumed for risk assessment purposes.

3.2       Dermal absorption

No data on dermal absorption of tantalum are available. Even though the molecular weight of tantalum (180.9) would suggest possible dermal uptake, the substance is insoluble in water and therefore it cannot partition from the stratum corneum to the epidermis.

The physiological inertness of tantalum metal has been demonstrated by its long use in surgical implants like permanent implantation in bone, in fracture repair and dental applications, as vascular clips, in the repair of cranial defects (either as a direct cerebral covering or to fill defects in cranial bony tissue), as a flexible stent to prevent arterial collapse, and as a stent to treat biliary and arteriovenous (haemodialysis) fistular stenosis. In his review Black (1994) reports that “When Ta is implanted as a foil, wire or mesh, in soft tissues in either animals or humans, the predominant local tissue response is formation of a thin, glistening membrane without significant evidence of inflammation. Steineman describes this response generically as a ‘vital’ response, characterized by loose and vascularized fibrous tissue with, in some cases, the presence of an epithelium in contact with the implant; he notes that it occurs also for pure Ti and titanium alloys as well as for zirconium, niobium and platinum. A similar reaction is observed when tantalum is used as foil, rod or ball in bone, where the implant became osteointegrated i.e. direct apposition of new bone occurs, without an intervening soft tissue layer or capsule". No dermal absorption for tantalum is assumed for risk assessment purposes.

3.3       Inhalation

Tantalum is considered to be a good contrast medium for X-ray of the lungs and airways. Following exposure to tantalum by inhalation in dogs, 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 (Nadel, 1968).

In his review Black (1994) reports a study by Rizzato et al. which studied a patient with ‘hard metal lung disease’. After 13 years of exposure to a variety of hard metals, ceasing 4 years prior to the study, this individual had Ta levels of 325 ppm in the lung but only 1 ppm in whole blood and 3 ppb in urine.

These data indicate that the half-life of inhaled tantalum can last a considerable time however, the retained tantalum does not appear to be bioavailable for absorption. Consistent with this assumption are results of the fully compliant acute inhalation toxicity study (Wilcox, 2001) in which only exaggerated breathing was observed during and few days after 4-h exposure to a dust concentration of 5.18 mg/L, with no mortality, no effects on body weight and no finding at necropsy.

Although in an in vivo study for eye irritation (Blanchard, 2000) only very slight and transient redness of the conjunctiva was observed, not triggering for classification, it is considered that tantalum may cause mechanical irritation to the mucous membranes and the respiratory tract in work places. Occupational exposure limits are set in various countries and can be used for risk assessment purposes.

4.0       Distribution

In his review Black (1994) reports that “In-vitro studies of soluble 182Ta fail to show any specific Ta-protein binding. Intracellular uptake of soluble 182Ta, in human lung tissue obtained by biopsy, shows 71 % of Ta remaining within the cytosol with an organelle Ta content (in decreasing order): nucleus > mitochondria >microsomes > lysomes. Clearance from blood into tissues is fairly prompt with as much as 1-57 % of injected dose (in rats) being found in bone after 48 h”.

5.0       Metabolism

Given the inert nature of tantalum, it is not expected to be subjected to any metabolic process but instead to be eliminated as such.

6.0       Elimination

As mentioned in studies using soluble 128Ta, the faeces represent the main route of elimination of tantalum.

In a study by Bianco (1974) in which dogs were administered with radiolabel tantalum dust, either by nose-only exposure or by intubation for a period of less than one hour, findings indicate that tantalum had a prolonged retention time in the lungs with a mean biological removal half-time of greater than 2 years. Mucociliary transport, the dominant clearance mechanism was longer following tantalum exposure than exposure to other insoluble dusts. The study indicated a rapid early tracheobronchial phase and a later prolonged alveolar clearance phase.

In the 5thedition of Patty’s Toxicology (2001) is reported that “Pulmonary clearance of tantalum dust following insufflations in dogs was dependent on particle size; a 1-µm powder was removed from the alveolar regions with a clearance half-life of 2.1 years and 5 or 10- µm powders were removed with a half-time of 333 days. Rapid postinsufflation uptake of the pulmonary lymph nodes was observed with up to 12 % on the initial alveolar burden present in the lymph nodes at 240 days and 6 % present at 816 days”.

 

Notwithstanding the long half-lives observed for tantalum, in his “Metal toxicity in mammals-2” Venugopal (1973) states that “There are no reports of the accumulation of Ta in tissues or the existence of any homeostatic excretory mechanism for Ta”.

 

7.0       Conclusion

Tantalum is a ductile, silver grey metal which forms an adherent and stable oxide layer when exposed to air at room temperature. It is chemically inert, insoluble in water and considered as not being bioavailable following oral ingestion or dermal exposure.

As mechanical irritation of mucous membranes and the respiratory system can occur following exposure to tantalum dust due to particle effects, occupational exposure limits are set in various countries and these can be used for risk assessment purposes