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Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

No data is available for Zirconium disilicide (target substance) as in the framework of an OECD 471 study the substance was not soluble in a range of solvents for preparing the dilution series of the test material. Thus, it was not possible to conduct the study with the target substance. To assess the mutagenicity potential of Zirconium disilicide available data from Zirconium oxychloride (source substance) is used in a read-across approach. In a bacterial reverse gene mutation assay the source substance was tested negative in S. typhimurium strains TA1535, TA1537, TA98 and TA100.

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Endpoint:
in vitro gene mutation study in bacteria
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
It was technically not possible to conduct an in vitro reverse mutation assay with the target substance zirconium disilicide. The target substance was not soluble in any of the solvents used (Aqua dest, DMSO, ethanol and tetrahydrofuran).
As no further data is available for the target substance to assess mutagenicity, available data from a suitable read-partner was used. The hexahydrate of zirconium dichloride oxide (ZrOCl2: CAS No. 7699-43-6; ZrOCl2 6xH2O: CAS No. 25399-81-9) was tested in an in vitro bacterial reverse mutation assay (Mortelmans, 1986).
As indicated in ECHA‘s guidance on QSAR and grouping of chemicals (ECHA Chapter R.6, 2008a), comparison of the water solubility is an important aspect in determining the similarity between compounds for purposes of the read-across strategy. This approach assumes that the extent of water solubility approximates the bioavailability of a substance. Therefore, inorganic substances of similar water solubility would have similar toxicity, based on the fact that both substances would release the same toxicological metal species. The use of source substances which have a higher water solubility compared to the target substance can be considered as an appropriate worst-case read-across approach for potential systemic and environmental effects and is adequately protective.
The source substance ZrOCl2 show a higher water solubility than ZrSi2 and hence results in a higher release of zirconium ions compared to zirconium disilicide. Thus, the used read-across partner is considered as suitable.
Despite the low water solubility of the target substance, data is available from a bio-elution test. The release of zirconium ions from ZrSi2 is very low in artificial body fluids. For human health endpoints, it is the relative bioavailability of zirconium at target site(s) that determines the potential occurrence and severity of the systemic effects to be assessed for the read-across of zirconium substances. The source substance ZrOCl2 is considered to be highly soluble in water. At physiological pH zirconium will precipitate. Therefore, the zirconium release of this substance is expected to be similar low as for the target substance under physiological conditions and thus, read-across is considered to be adequately safe and will not underestimate the toxicity.
Reason / purpose:
read-across source
Key result
Species / strain:
other: TA1535, TA1537, TA100 and TA98
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity, but tested up to precipitating concentrations
Vehicle controls validity:
not examined
Untreated negative controls validity:
valid
Positive controls validity:
valid
Additional information on results:
For detailed results please refer to table 1 in box "Any other information on results incl. tables"
Remarks on result:
other: non-mutagenic

Table 1: Summary of Results            
Concentration
 µg/plate
TA100 Concentration
 µg/plate
TA1535
without S9 with 10% hamster S9 with 10% rat S9 without S9 with 10% hamster S9 with 10% rat S9
Mean SEM Mean SEM Mean SEM Mean SEM Mean SEM Mean SEM Mean SEM Mean SEM Mean SEM
Negative Control 142 4.6 127 1 150 5.5 Negative Control 31 2.6 9 1.3 34 2.4 24 3.5 34 3.3 29 1.5
Positive Control 268 19.3 1572 41.5 742 48.2 Positive Control 344 6.9 175 23.2 505 12.5 326 15.2 223 19.9 114 6.1
10 - - - - - - 10 28 5.2 - - 36 2.3 - - 45 5.8 - -
33 - - - - - - 33 29 3.5   36 3.2 - - 39 2.2 - -
100 125 8.2 158 9.5 136 4.5 100 30 2.4 22 3.0 41 3.5 33 2.3 42 6.6 30 1.0
333 108 10.9 169 10.5 126 7.1 333 30 1.0 29 6.4 38 6.1 37 3.1 35 3.7 33 3.6
1000 116 13.1 156 7.0 134 3.7 1000 30p 1.0 20 4.2 30p 0.3 35 4.9 38p 6.8 31 3.2
3333 149p 13.5 144p 14.0 77p 38.8 3333 - - 26p 3.8 - - 0p 0.0 - - 29p 6.8
6666 48p 24.0 126p 5.2 35p 35.3 6666 - - 0p 0.0 - - 0p 0.0 - - 0p 0.0

p= precipitation present in plates

Table 1 continued: Summary of Results
Concentration
 µg/plate
TA1537 TA98
without S9 with 10% hamster S9 with 10% rat S9 without S9 with 10% hamster S9 with 10% rat S9
Mean SEM Mean SEM Mean SEM Mean SEM Mean SEM Mean SEM
Negative Control 7 2.9 7 0.7 12 3.2 25 0.0 32 0.9 30 3.5
Positive Control 109 8.7 536 34.9 197 7.6 793 25.9 1385 100.5 556 36.2
10 - - - - - - - - - - - -
33 - - - - - - - - - - - -
100 8 0.9 13 4.2 7 1.2 21 4.3 34 2.7 30 0.6
333 8 1.9 8 1.9 9 2.6 28 1.5 34 2.6 32 4.2
1000 8 1.8 12 2.0 9 2.2 21 4.6 32 5.8 27 4.1
3333 9p 1.8 7p 2.5 13p 0.9 19p 1.5 30p 3.0 28p 2.2
6666 0p 0.0 0p 0.0 0p 0.0 0p 0.0 0p 0.0 0p 0.0

p= precipitation present in plates

Conclusions:
In conclusion, it can be stated that during the described mutagenicity test and under the experimental conditions reported, the test item can be considered as non-mutagenic.
Executive summary:

In a reverse gene mutation assay in bacteria conducted similar to OECD test guideline 471, strains TA98, TA100, TA1535 and TA1537 of Salmonella typhimurium were exposed to Zirconium oxychloride hexahydrate in 95% ethanol at concentrations of 10, 33, 100, 333, 1000, 3333 and 6666 µg/plate in the presence and absence of mammalian metabolic activation. The positive controls induced the appropriate responses in the corresponding strains. There was no evidence of induced mutant colonies over background in all tester strains. Therefore, Zirconium oxychloride hexahydrate is considered to be non-mutagenic in this Salmonella typhimurium reverse gene mutation assay.

Endpoint:
in vitro gene mutation study in bacteria
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2017-06-13 to 2017-08-17
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 471 (Bacterial Reverse Mutation Assay)
Version / remarks:
adopted 21st July 1997
Deviations:
no
GLP compliance:
yes (incl. certificate)
Type of assay:
bacterial reverse mutation assay
Target gene:
Histidine locus
Species / strain / cell type:
S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102
Details on mammalian cell type (if applicable):
not specified
Test concentrations with justification for top dose:
not specified
Vehicle / solvent:
not specified
Untreated negative controls:
not specified
Negative solvent / vehicle controls:
not specified
True negative controls:
not specified
Positive controls:
not specified
Details on test system and experimental conditions:
not specified
Rationale for test conditions:
not specified
Evaluation criteria:
not specified
Statistics:
not specified
Species / strain:
other: TA 98, TA 100, TA 1535, TA 1537
Metabolic activation:
not applicable
Genotoxicity:
not determined
Cytotoxicity / choice of top concentrations:
not determined
Vehicle controls validity:
not examined
Untreated negative controls validity:
not examined
Positive controls validity:
not examined
Additional information on results:
The test item could not be prepared in an appropriate solvent and diluted prior to treatment. Due to the properties of the material, Zirconium disilicide was not soluble in any of the solvents used (A. dest, DMSO, ethanol and tetrahydrofuran). No stable suspension which is suitable for the preparation of the dilution series could be obtained. Therefore it was not possible to perform any further steps in this study.
Remarks on result:
not measured/tested
Conclusions:
Zirconium disilicide was not soluble in any of the solvents used. Therefore, it was not possible to perform an Ames test.
Executive summary:

In this study, the test item Zirconium disilicide could not be prepared in an appropriate solvent and diluted prior to treatment. Due to the properties of the material, Zirconium disilicide was not soluble in any of the solvents used (A. dest, DMSO, ethanol and tetrahydrofuran). No stable suspension which is suitable for the preparation of the dilution series could be obtained. Therefore it was not possible to perform any further steps in this study. Since the test item could not be prepared in an appropriate solvent and diluted prior to treatment, it was not possible to perform an Ames test with Zirconium disilicide.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

No data is available for Zirconium disilicide (target substance) as in the framework of an OECD 471 study the substance was not soluble in a range of solvents for preparing the dilution series of the test material. Thus, it was not possible to conduct the study with the target substance. That the target substance is highly insoluble was also seen in a T/D test conducted in accordance with OECD 29 (see IUCLID section 4.8).

To assess the mutagenicity potential of Zirconium disilicide available data from Zirconium oxychloride (source substance) is used in a read-across approach. For justification of read-across please refer to the read-across report attached to IUCLID section 13.

In a bacterial reverse gene mutation assay, which was conducted similar to OECD test guideline 471, the source substance was tested negative in S. typhimurium strains TA1535, TA1537, TA98 and TA100.

Justification for classification or non-classification

Based on available data from a suitable read-across partner, the target substance Zirconium disilicide does not warrant classification for mutagenicity.