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EC number: 231-726-8 | CAS number: 7704-98-5
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
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- Oxidation reduction potential
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- Stability: thermal, sunlight, metals
- pH
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- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
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- Nanomaterial pour density
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- Endpoint summary
- Stability
- Biodegradation
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- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
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- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data

Skin sensitisation
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 for cross-reference:
- read-across source
Reference
- Endpoint conclusion:
- no adverse effect observed (not sensitising)
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.
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:
- 2 018
- 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 |
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Chemical | Repetition 1 | Repetition 2 | Repetition 3 | Positive repetitions |
|
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
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EE IL-18SI2 |
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In vivo |
EC50 |
IL-18 |
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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.
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