titanyl (IV) diascrobate

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

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 >20%).
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. Only one analogue, sodium pyruvate (CAS 113-24-6), met all assumed requirements. The short-term repeated dose toxicity study for analogue was measured according to the OECD 412 and this value was taken into account for the prediction.
The short-term repeated dose toxicity for the source compound was performed according to:
Test guideline: OECD 412
Endpoint: NOAEL
Test organism: rat
Duration: 28 day
The read-across prediction of the short-term repeated dose toxicity for the target substance was performed based on the “one to one” approach.

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 short-term repeated dose 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 20%.
Therefore, using experimental data of sodium pyruvate 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 pyruvate) and the target compound (TiO(Asc)2 x2H2O) equals to 17.1%.

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:

NOAEL

Effect level:

0.034 mg/L air

Basis for effect level:

other: not specific (QSAR)

Target system / organ toxicity

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

The short-term repeated dose toxicity for the target substance is predicted at level NOAEL = 0,0339 mg/l air

Executive summary:

The target compound undergoes a hydrolysis reaction. The analogues search was performed assuming at least 20% 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 pyruvate would have similar hydrolysis products as well as the experimental data related to its short-term repeated dose toxicity was available.

Therefore, the prediction is based only on the sodium pyruvate.