titanyl (IV) diascrobate

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Link to relevant study records

Reference

Reference 1

Endpoint:

in vitro gene mutation study in bacteria

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2019

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

OECD Guideline 471 (Bacterial Reverse Mutation Assay)

GLP compliance:

yes (incl. QA statement)

Type of assay:

bacterial reverse mutation assay

Species / strain / cell type:

S. typhimurium TA 1535, TA 1537, TA 98 and TA 100

Genotoxicity:

negative

Remarks on result:

other: negative result

Conclusions:

Based on the results obtained under the experimental conditions applied, the test item did not induce gene mutations by base pair changes or frameshifts in the genome of the strains used.
In conclusion, the test item TITANIUM DIASCORBATE has no mutagenic activity on the bacterial tester strains under the test conditions used in this study.

Reference 2

Endpoint:

in vitro cytogenicity / micronucleus study

Remarks:

Type of genotoxicity: chromosome aberration

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

2019

Reliability:

1 (reliable without restriction)

Justification for type of information:

The computational simulation was performed based on the read-across approach. The readacross is one of the so-called alternative test methods recommended by REACH, where the
predictions are based on the experimental data available for the most similar compounds. The predictions were performed according to the Read-Across Assessment Framework (RAAF),
which assumes six different risk assessment scenarios of chemical compounds.
Applied tool:
The OECD QSAR Toolbox, version 4.3
Procedure of analysis:
II. Profiling of the target substance in order to retrieve relevant information related to mechanism of action and observed or simulated metabolites
III. Analogue (source compound) search based on selected criteria:
a. analogue hydrolysis similarly like the target compound (hydrolysis simulator (neutral))
b. analogue has similar transformation products as the target compound (metabolism simulators, similarity >40%).
IV. Data collection for the analogues (OECD Toolbox database/ECHA CHEM).
V. Toxicity prediction for the target substance
VI. Category consistency check in order to assess the quality of the prediction
Applied scenario:
Scenario 1
Toxicity prediction for the target substance:
This read-across is based on the hypothesis that source and target substances have similar toxicological properties like substrates because they hydrolysed to common products.
The target substance is an organometallic compound containing titanium (IV) centre, and ascorbate (Asc) ligands. The metallic centres of the substance are linked by oxygen coordination bonds of the Asc ligands.
Four analogues have been found according to the assumed requirements. Three of four compounds had no specific information regarding used OECD guideline. Thus, only one compound was taken into consideration (Sodium erythorbate). The in vitro cytogenicity test in mammalian cells for analogue was measured according to the OECD 473 and this value was taken into account for the prediction.
Identified analogues that met the requirements for in vitro cytogenicity study in mammalian cells predictions
Chemicals in vitro cytogenicity study in mammalian cells OECD guideline
Gluconolactone
CAS 90-80-2 negative No information
Chlorhexidine Gluconate
CAS 18472-51-0 negative No information
Sodium erythorbate
CAS 6381-77-7 negative OECD 473
Sodium glucoheptonate
CAS 31138-65-5 negative No information
The chromosome aberration for the source compound was performed according to:
Test guideline: OECD 473
Endpoint: chromosome aberration
Test organism: Mammalian cells
“One to one” read-across approach was used to predict the cytogenicity of target substance expressed by in vitro mammalian chromosome aberration test.

Principles of method if other than guideline:

In order to meet regulatory needs, reliability of the predicted results should be assessed. In case of classic quantitative structure-activity relationships (QSAR) modelling, this idea can be
realised by analysing, whether the predicted value is located within so-called applicability domain. The applicability domain is a theoretical region, defined by the range of toxicity values
and structural descriptors for the training compounds, where the predictions may be considered as realistic ones. In a specific case of read-across, the assessment is performed based on the
assessment of degree of similarity between the source and target compounds (in %). Moreover, the internal consistency of the group of source compounds (called „category” in OECD Toolbox
nomenclature, independently which approach: analogue approach or category approach is used). The category consistency check could be based on the parameters describing the structural similarity and/or properties as well as mechanistic similarity of the tested compounds.
For example, all members of the category (analogues as well as target substance) need to have the same functional groups and endpoint specific alerts.
In the case of read-across-based prediction of the in vitro cytogenicity of the titanyl (IV) diascorbate dihydrate, the read-across hypothesis considers that source and target compounds have similar transformation products. Based on the Dice measure, the structural similarity between hydrolysis products of source and target substances was at least 40%. Therefore, using experimental data of sodium erythorbate for predicting biological activity for the target compound was justified.
Besides, the category consistency, the boundaries of the applicability domain are verified by the critical value of log KOW. In case of TiO(Asc)2 x2H2O, the log KOW value is not available.
What is more, in case of “one to one” approach, this criterion would be met only if source and target compounds are the same substance. Thus, information that “domain is not defined” is not critical in this situation.
The structural similarity between the source (sodium erythorbate) and the target compound (TiO(Asc)2 x2H2O) equals to 43.9%.

Species / strain:

mammalian cell line, other:

Metabolic activation:

not specified

Genotoxicity:

other:

Remarks:

QSAR

Cytotoxicity / choice of top concentrations:

no cytotoxicity

Additional information on results:

The in vitro mammalian chromosome aberration for the target substance is predicted as negative.

Remarks on result:

no mutagenic potential (based on QSAR/QSPR prediction)

Conclusions:

The in vitro mammalian chromosome aberration for the target substance is predicted as negative.

Executive summary:

The target compound undergoes a hydrolysis reaction. The analogues search was performed assuming at least 40% structural similarity between hydrolysis products of source and target substances. The toxicity prediction was performed based on the experimental data included in the OECD QSAR Toolbox. Sodium erythorbate would have similar hydrolysis products as well as the experimental data related to its in vitro cytogenicity was available. Therefore, the

prediction is based only on the Sodium erythorbate.

Reference 3

Endpoint:

in vitro gene mutation study in mammalian cells

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

2019

Reliability:

1 (reliable without restriction)

Justification for type of information:

The computational simulation was performed based on the read-across approach. The readacross is one of the so-called alternative test methods recommended by REACH, where the predictions are based on the experimental data available for the most similar compounds. The predictions were performed according to the Read-Across Assessment Framework (RAAF),
which assumes six different risk assessment scenarios of chemical compounds.
Applied tool:
The OECD QSAR Toolbox, version 4.3
Procedure of analysis:
I. Profiling of the target substance in order to retrieve relevant information related to mechanism of action and observed or simulated metabolites
II. Analogue (source compound) search based on selected criteria:
a. analogue has the same structural features as the target compound according to:
i. in vivo mutagenicity (Micronucleus) alerts by ISS profiler
ii. Protein binding by OECD profiler
b. analogue is structurally similar to the target compound (similarity >50%)
III. Data collection for the analogues (OECD Toolbox database/Genotoxicity pesticides EFSA).
IV. Toxicity prediction for the target substance
V. Category consistency check in order to assess the quality of the prediction
Applied scenario:
Scenario 2
Toxicity prediction for the target substance:
This read-across is based on the fact that the organism is not exposed to common compounds but rather, as a result of similarity, to chemicals which have similar (eco)toxicological and fate
properties.
The target substance is an organometallic compound containing titanium (IV) centres, ascorbate (Asc) ligands. The metallic centres of the substance are linked by oxygen
coordination bonds of the Asc ligands. The target and source chemicals have H-acceptor-path3-H-acceptor, a structural alert highlighted by in vivo mutagenicity (Micronucleus) alerts by ISS profiler. Also, the target and source chemicals are classified as “Acetates” according to Protein binding by OECD profiler.
Moreover, analogue is structurally similar to the target compound in more than 50%. One compound that met these requirements was found (L-ascorbic acid, CAS 50-81-7). The gene mutation for analogue was measured according to the OECD 476 and this value was taken into account for the prediction.
The gene mutation for the source compound was performed according to:
Test guideline: OECD 476
Endpoint: Gene mutation
Test organism: Mammalian cells
The read-across prediction of the gene mutation for the target substance was performed based on the “one to one” approach.

Principles of method if other than guideline:

In order to meet regulatory needs, reliability of the predicted results should be assessed. In case of classic quantitative structure-activity relationships (QSAR) modelling, this idea can be
realised by analysing, whether the predicted value is located within so-called applicability domain. The applicability domain is a theoretical region, defined by the range of toxicity values
and structural descriptors for the training compounds, where the predictions may be considered as realistic ones. In a specific case of read-across, the assessment is performed based on the
assessment of degree of similarity between the source and target compounds (in %). Moreover, the internal consistency of the group of source compounds (called „category” in OECD Toolbox
nomenclature, independently which approach: analogue approach or category approach is used). The category consistency check could be based on the parameters describing the structural similarity and/or properties as well as mechanistic similarity of the tested compounds.
For example, all members of the category (analogues as well as target substance) need to have the same functional groups and endpoint specific alerts.
In the case of read-across-based prediction of the gene mutation of the titanyl (IV) diascorbate dihydrate, the read-across hypothesis considers that source and target compounds are classified as “Acetates” according to Protein binding by OECD and have the same alert (H-acceptor-path3-H-acceptor) according to the in vivo mutagenicity (Micronucleus) alerts by ISS profiler. Moreover, based on the Dice measure analogue is structurally similar to the target compound in more than 50%.
Besides, the category consistency, the boundaries of the applicability domain are verified by the critical value of log KOW. In case of titanyl (IV) diascorbate dihydrate, log KOW value is not
available. What is more, in case of “one to one” approach, this criterion would be met only if source and target compounds are the same substance. Thus information that “domain is not
defined” is not critical in this situation. The structural similarity between the source (L-ascorbic acid) and the target compound (titanyl (IV) diascorbate dihydrate) equals to 55 %.

Species / strain:

mammalian cell line, other:

Genotoxicity:

negative

Remarks on result:

no mutagenic potential (based on QSAR/QSPR prediction)

Conclusions:

The gene mutation for the target substance is predicted as negative.

Executive summary:

The source and target compounds are classified as “Acetates” according to Protein binding by OECD and have the similar protein binding alert responsible for the toxic effect based on the in vivo mutagenicity (Micronucleus) alerts by ISS profiler. Moreover, analogues are structurally similar to the target compound in more than 50%. The toxicity prediction was performed based on the experimental data included in the OECD QSAR Toolbox. One chemical would meet the requirements related to their profile and structure as well as the experimental data related to its in vitro gene mutation were available. Therefore, the prediction is based on L-ascorbic acid.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Justification for classification or non-classification

no classified