titanyl (IV) diascrobate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

Mai 2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

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 hydrolysis similarly like the target compound (hydrolysis simulator (neutral))
b. analogue has similar transformation products as the target compound (metabolism simulators, similarity >50%).
III. Data collection for the analogues (OECD Toolbox database/ECHA CHEM).
IV. Toxicity prediction for the target substance
V. 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.
The only one sodium L-ascorbate (NaAsc) analogue has been found according to the assumed requirements; therefore, it was used as the source compound. The acute oral toxicity for analogue was measured according to the OECD 401 and this value was taken into account for the prediction.
The acute oral toxicity for the source compound was performed according to:
Test guideline: OECD 401
Endpoint: LD50
Test organism: rat
The read-across prediction of the acute oral toxicity for the target substance was performed based on the approach “one to one”.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2019

Report date:

2019

Materials and methods

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 acute oral toxicity 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 50%. Therefore, using experimental data of sodium ascorbate 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 (NaAsc) and the target compound (TiO(Asc)2 x2H2O) equals to 53.7%

Test material

Test material information

Constituent 1

Reference substance name:

(5R)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-2,5-dihydrofuran-2-one titanium

EC Number:

814-615-4

Cas Number:

122958-50-3

Molecular formula:

TiO(Asc)2 x2 H2O

IUPAC Name:

(5R)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-2,5-dihydrofuran-2-one titanium

Results and discussion

Effect levels

Key result

Dose descriptor:

LD50

Effect level:

1 410 mg/kg bw

Clinical signs:

other:

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute oral toxicity for the target substance is predicted at level LD50 = 1 410 mg/kg bdwt

Executive summary:

The target compound undergoes a hydrolysis reaction. The analogues search was performed assuming at least 50% 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 L-ascorbate would have similar hydrolysis products as well as the experimental data related to its acute oral toxicity was available. Therefore, the prediction is based only on the NaAsc.