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Toxicological information

Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation: in vitro
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
Titanium salts
Adequacy of study:
supporting study
Study period:
Acadamic study - 2018
Reliability:
1 (reliable without restriction)
Justification for type of information:
See read-across rationale in 7.4 Sensitization summary section.
Cross-reference
Reason / purpose:
read-across source
Reference

Metal hydride – Titanium hydride (CAS 7704-98-5; EC 231-726-8)

Sensitization

Background:To induce sensitization, metal ions need to penetrate through the outer stratum corneum barrier layer of the skin and reach the underlying viable epidermis. Then, to become immunologically reactive, metal ions must bind to macromolecules such as proteins to form a hapten complex. Antigen presenting cells display this hapten complex on their cell surfaces and when the hapten is recognized as foreign by naïve T-lymphocyte cells, these cells undergo differentiation to form hapten-specific effector and memory helper T-cells (e.g., a person becomes sensitized). Upon repeated contact with the offending metal, at exposure levels that result in sufficient metal ion release and stratum corneum penetration, memory T-cells are recruited to the site of skin contact and elicit an inflammatory reaction (Stefaniak et al., 2014; Gibbs et al., 2018).

Regarding skin sensitization of titanium hydride as requested under REACH regulation1907/2006, no data are currently available. To meet the skin sensitization endpoint requirement, read-across strategy with titanium salts and titanium dioxide has been used. It has to be noted that titanium dioxide at nanoform scale is extensively used in cosmetic (e.g. sunscreen, make-up), toothpastes and medical devices. Even if some papers in the literature raise sensitization concern regarding the use of TiO2 as nanoform, the related papers for these specific applications have been voluntary excluded from this dossier as titanium hydride is not intended to be used as nanoform for direct consumer use.

Titanium salts & Titanium oxide:

Testing of potential sensitizers of metals is traditionally carried out by applying the metal test chemical in the form of salt to the skin of animals or reconstructed skin under standard conditions. Preferably the salt should dissolve to form metal ions. In that respect, a couple of papers publicly available have been found and shortly described allowing to fulfill the sensitization requirement in the REACH dossier.

Ikarashi et al. 1996

Sensitization potency of a titanium salt (TiCl4) was studied using the guinea-pig maximization test (GPMT) and adjuvant and patch test (APT). In addition, a sensitive mouse lymph node assay was also ran (SLNA). As result, one of the five animals treated with TiCl4 showed a weak skin response with 5% challenge. When these animals were rechallenged, 3 of 5 (60%) responded to TiCl4, and the response intensity became stronger. TiCl4 was retested by using more animals. As a result, 5 of 10 (50%) animals showed skin reactions by challenge. After SLNA, it appears that TiCl4 caused mild increases in lymph node weight, LNC number and LNC proliferation. However, the SLNA defined TiCl4 as negative according to the criteria. According to the research team, titanium is not considered as skin sensitization while a "sensitization capacity" cannot be excluded.

 

Gibbs et al., 2018 (Review)

In the frame of testing the applicability domain of the in vitro reconstructed human epidermis (RhE) IL-18 assay developed to identify contact allergens. Twenty eight chemicals including 15 metal salts were topically exposed to RhE. Nickel, chrome, gold, palladium were each tested in two different salt forms, and titanium in 4 different salt forms. Metal salts were labelled (YES/NO) as sensitizer if a threshold of more than 5 fold IL-18 release was reached. Titanium salts (Titanium (IV) isopropoxide, Titanium (IV) bis(ammonium lactato) dihydroxide solution and Titanium (IV) oxide) were scored as extreme weak sensitizers/irritants. From analysis of the applicability domain of the assay, it appears that titanium ion do not penetrate the stratum corneum which may explain why titanium is a weak sensitizer.

 

Warheit et al., 2007

In this paper, ten different toxicity studies were conducted with newly developed ultrafine TiO2 particle-types. Part of this set of studies, askin sensitization study (LLNA, OECD guideline N°429) in mice was ran. Result of this test was not a dermal sensitizer to mice under the test conditions.

 

Conclusion:According to the papers found in the literature and publicly available, titanium salts and titanium oxide would not be classified as dermal sensitizer. On this basis, the non-sensitization of titanium dihydride has been extrapolated. In addition, water solubility of titanium hydride at various pH was assessed and showed that the test item is insoluble (<0.1 mg/L) in water at pH which maximises the solubilisation (pH 5.8). This argument strengthens the non-allergic property of titanium dihydride.  

 

Literature

Gibbs S, Kosten I, Veldhuizen R, Spiekstra S, Corsini E, Roggen E, Rustemeyer T, Feilzer AJ, Cees J. Kleverlaan CJ. 2018. Assessment of metal sensitizer potency with the reconstructed human epidermis IL-18 assay. Toxicology 393: 62–72.

 

Ikarashi Y, Momma J, Tsuchiya T, Nakamura A. 1996. Evaluation of skin sensitization potential of nickel, chromium, titanium and zirconium salts using guinea-pigs and mice. Biomaterials 17: 2103–2108.

 

Stefaniak AB, Duling MG,Geer L, and Virji MA. 2014. Dissolution of the metal sensitizers Ni, Be, Cr in artificial sweat to improve estimates of dermal bioaccessibility. Environ Sci Process Impacts 16: 341–351.

Warheit DB, Hoke RA, Finlay C, Donner EM, Reed KL, Sayes CM. 2007. Development of a base set of toxicity tests using ultrafine TiO2 particles as a component of nanoparticle risk management. Toxicology Letters 171: 99–110.

Endpoint conclusion:
no adverse effect observed (not sensitising)

Data source

Reference
Reference Type:
publication
Title:
Assessment of metal sensitizer potency with the reconstructed human epidermis IL-18 assay.
Author:
Susan Gibbs, Ilona Kosten, Rosalien Veldhuizen, Sander Spiekstra, Emanuela Corsini, Erwin Roggen, Thomas Rustemeyer, Albert J. Feilzer, Cees J. Kleverlaan
Year:
2018
Bibliographic source:
Toxicology 393 (2018) 62–72

Materials and methods

Results and discussion

Any other information on results incl. tables

1) Prediction model

   IL-18 SI>=5 at =<EC40      

 

 
  Chemical Repetition 1  Repetition 2 Repetition 3 

Positive

repetitions

 
Classification

Ti (IV) isopropoxide

 -

 -

 -

 0/3

Non sensitizer

Ti (IV) bis(ammonium lactato) dihydroxide solution

 -

 -

 -

 0/3

Non sensitizer

Ti (IV) oxide

 -

 -

 -

 0/3

Non sensitizer

Note: The prediction model states that if 2/3 independent runs results in ≥ 5 fold increase in IL-18 secretion at RhE viability ≤40% compared to vehicle then the chemical scores as a sensitizer. The maximum IL-18 SI observed in the dose response at a cell viability ≤ 40% relative to the vehicle is shown. Note the chemical concentration at which the maximum IL-18 SI

occurs may differ between independent runs due to batch and donor variation in RhE (see detailed prediction model in Materials and Methods of the original paper). Chemical concentrations in the dose response were 2 fold serial dilutions with highest concentration being 200 mg/ml. (−) No values obtained at cell viability≤ 40% relative to the vehicle and/or IL-18 was below the detection limit of the ELISA.

2) Comparision of in vivo data with RhE EC50 and IL-18 SI2

 Chemical classification

according to LLNA

 Human

category

scale

 LLNA-EC3 (%) prediction      

 Human NOEL (µg/cm2)       

prediction

EE EC50

 

 

EE IL-18SI2 

 

 

 In vivo

 EC50

 IL-18

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The paper studied the sensitization of metal salts using RhE assay to estimate the expected sensitization induction level by interpolating in vitro EC50 and IL-18 SI2 values to predict LLNA EC3 and/or human NOEL from standard curves generated using reference contact sensitizers. In order to test the sensitizing potential of metal salts as replacement for metal ions leaching from routinely used medical devices further, and to gain more insight into the mechanism by which different metal salts for the same metal may influence the read out of the current skin patch test. Titanium was tested in 4 different salt forms to investigate the influence of molarity, valency and cytotoxicity on the outcome of the assay.
In this paper, none of the 4 tested titanium salts resulted in a decrease in metabolic activity of RhE indicating that these salts do not penetrate the stratum corneum and therefore, is a poor candidate as sensitizer when using patch testing assay to determine titanium allergy.