Registration Dossier

Administrative data

Description of key information

No data is available for tantalum metal (target substance). Thus, tantalum pentoxide (source substance) is used to assess the sensitising potential of tantalum metal in a read-across approach.

An in vitro or in chemico skin sensitisation study does not need to be conducted because adequate data from in vivo skin sensitisation studies are available for the source substance tantalum pentoxide.

Tantalum pentoxide is considered as non sensitising in a dermal skin sensitisation test according to OECD 406. A LLNA according to OECD 429 provided negative, but ambigous results and was therefore varfied by the OECD 429 study.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
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
Positive control results:
Challenge with reference item 2-Mercaptobenzothiazole resulted in a positive response in test animals previously sensitised. The net response values at the 24 and 48 hours observations represented an incidence rate of 80 % and 70 % and net score values of 1.00 and 0.70 respectively. In the control animals no visible changes were found either at the 24 or 48 hours examinations following challenge with the reference item.
On the basis of the results of the reliability check study, the reference item 2-Mercaptobenzothiazole was classified as a skin sensitiser. This demonstrated that the experimental procedure and the test system were appropriate.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
50 % (w/v)
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
None
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 50 % (w/v). No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: None.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
100 % (w/v)
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
None
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 100 % (w/v). No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: None.
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
50 % (w/v)
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
None
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 50 % (w/v). No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: None.
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
100 % (w/v)
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
None
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 100 % (w/v). No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: None.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
50 % (w/v)
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
None
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 50 % (w/v). No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: None.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
100 % (w/v)
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
None
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 100 % (w/v). No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: None.
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
50 % (w/v)
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
None
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 50 % (w/v). No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: None.
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
100 % (w/v)
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
None
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 100 % (w/v). No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: None.

RANGE-FINDING TEST

Intradermal Exposure

It was found that concentrations of 5 and 1% (w/v) in 1% methylcellulose caused very slight erythema at the 1 hour observation. The concentration of 5% (w/v) caused very slight erythema also at the 24, 48 and 72 hours observations, while 0.5 and 2.5% (w/v) in 1% methylcellulose produced no reaction (scores 0-0) in the skin of guinea pigs.

 

Epicutaneous Exposure

It was found that approximately 0.5 mL of the test material formulations at concentrations of 100 and 50 % (w/v) caused very slight erythema at the 1 hour observation and produced no reaction (scores 0-0) on the skin of guinea pigs at the 24, 48 and 72 hour observations.

 

On the basis of results of the Range-Finding Test, the 5 % (w/v) concentration was used for intradermal induction and 100 % (w/v) formulation was used for dermal induction treatment in the main test. Control animals were treated with the vehicle, 1 % methylcellulose. For the challenge exposure, all animals of the treatment and control group were treated with the 100 % (w/v) concentration as a challenge dose and at a concentration of 50 % (w/v) as a safeguard dose.

MAIN TEST

Skin Effects after the Challenge Exposure

 - Test group

After the challenge with the test material at a concentration of 100 % (w/v) in 1 % methylcellulose, no positive response was observed in the treated animals. The mean of the scores was 0.00 according to the 24 and 48-hours results. The right shaved flank area of all animals was treated with a test material concentration of 50 % (w/v) in 1 % methylcellulose as a safeguard dose and no reaction was noted.

 - Control group

After the challenge with the test material at a concentration of 100 % (w/v) in 1 % methylcellulose no visible changes were found at the 24 and 48 hours examinations. The right shaved flank area of control animals was treated with a test material concentration of 50 % (w/v) in 1 % methylcellulose as a safeguard dose and no reaction was noted.

 

Clinical Observations

There were no overt signs of an adverse clinical response to treatment with the test material during the course of the study. During the induction period very slight erythema was observed in 3 test animals 24 hours after the intradermal treatment. No further local skin effects were observed in either the test group or in the control group.

 

Mortality

There were no moribund or dead animals during the study.

 

Body weight

There were no notable differences between the test group and the control group.

Interpretation of results:
GHS criteria not met
Conclusions:
In conclusion, under the conditions of the study, tantalum pentoxide is considered to be not a dermal sensitizer.
Executive summary:

In a dermal sensitization study (OECD 406) with Tantalum pentoxide (>99.8 %) in 1 % methylcellulose, young adult male LAL/HA/BR guinea pigs (10 animals per treatment group and 5 animals per control group) were tested using the method of Magnusson and Kligman. No signs of systemic toxicity were observed in any animal. During the induction period very slight erythema was observed in three test animals 24 hours after the intradermal treatment. No further local skin effects were observed in either the test or control group. In the control and treatment groups the mean score for dermal reactions was 0 at 24 and 48 hours after challenge. In this study, tantalum pentoxide is not a dermal sensitizer.

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 (not sensitising)
Additional information:

No data is available for tantalum metal (target substance). Thus, tantalum pentoxide (source substance) is used to assess the sensitising potential of tantalum metal in a read-across approach.

Due to similar water solubility for tantalum metal and ditantalum pentoxide the resulting toxicity potential would also be expected to be similar. Therefore, the read across to the source substance ditantalum pentoxide is adequately protective. For more details refer to the read-across report attached to IUCLID section 13.

 

The key study was a GMPT study conducted with tantalum pentoxide in accordance with OECD guideline 406 using a Magnusson and Kligman test (Török-Bathó, 2013).No signs of systemic toxicity were observed in any animal. During the induction period very slight erythema was observed in three test animals 24 hours after the intradermal treatment. No further local skin effects were observed in either the test or control group. In the control and treatment groups the mean score for dermal reactions was 0 at 24 and 48 hours after challenge.

Therefore, in this study, tantalum pentoxide is not a dermal sensitiser.

 

Beforehand tantalum pentoxide was tested for sensitising properties in accordance with OECD guideline 429 using the mouse Local Lymph Node Assay (Hargitai, 2013).

No signs of systemic toxicity and/or treatment related effects on body weights were observed in any animal. A stimulation index greater than 3 was noted at the mid concentration of the test item only. Stimulation index value was 3.9 at the treatment concentration of 25% (w/v), whereas the stimulation index values were lower than 3 at both the higher concentration of 50% (w/v) (SI = 2.5) and the lower treatment concentration of 10% (w/v) (SI = 1.8). The stimulation index values were not compatible with a biological dose-related response and a positive response cannot be clearly interpreted from these results.

The study was a pooled assay, so there are no individual animal results that could assist in the interpretation of these findings. It may be the case that the 25% result is skewed by a single outlier. The lack of a clear dose response with a lack of any evidence of systemic toxicity at the high dose means that this study is not easily interpreted. As the stimulation index of the high dose group was 2.5 and no dose response relationship occurred, tantalum pentoxide can be considered as potentially not sensitizing, but the results from this study needed to be verified. This was done using the GMPT according to OECD 406 (Török-Bathó, 2013).

 

One publication (Romaguera, 1995) describes human sensitisation data (see 7.10.4) from a patient with a metal prosthesis made of titanium-tantalum-niobium alloy. Thus the reaction was caused by a mixture of metals and the positive patch test to tantalum chloride of the patient could not be confirmed by 228 controls, the sensitising potential of tantalum metal is questionable.

 

Taking into account the negative outcome of the animal studies, tantalum metal is considered not to be a dermal sensitiser.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

In accordance with criteria for classification for skin sensitisation of Regulation (EC) No. 1272/2008 and Directive 67/548/EEC , the test material tantalum does not meet the criteria for classification as a skin sensitiser, based on the negative response noted in the Maximisation test conducted with the structural analogue tantalum pentoxide. Tantalum pentoxide is considered to be a suitable substances to use for read across as judstified in the read across report attached to chapter 13 of this dossier.