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Diss Factsheets

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
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 general mechanistic alert for “Estrogen Receptor Binding”,
b. analogue is structurally similar to the target compound (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 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 the source chemicals are classified as non-binders according to the Estrogen Receptor Binding profiler. In case of the target none of the structural and parametric requirements are met, therefore the target chemical is classified as “Non-binder, non-cyclic”.
no effect is expected. Also, analogue is structurally similar to the target compound in 22.9%.
Three compounds met the assumed requirements (Table 5). One analogue was initially excluded due to no specified OECD guideline. Considering the worst-case scenario, as well as OECD 422 guideline recommendations, cobalt (II) oxalate (CAS 814-89-1) was chosen as the source compound and taken into account for the prediction.
Table . Identified analogues that met the assumed requirements for screening reproductive toxicity predictions
Chemicals Screening Reproductive Toxicity [mg/kg bdwt] OECD guideline
Sodium glucoheptonate
CAS 31138-65-5 1000 OECD 422
Cobalt (II) oxalate
CAS 814-89-1 100 OECD 422
Glycerol 1,3-Dimethacrylate
CAS 28497-59-8 50 No information
The screening reproductive toxicity for the source compound was performed according to:
Test guideline: OECD 422
Endpoint: NOEL
Test organism: rat
The read-across prediction of the screening reproductive 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

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
IIn 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 screening reproductive toxicity of titanyl (IV) diascorbate dehydrate, the read-across hypothesis considers that source and target compounds have the same structural features related to Estrogen Receptor Binding. Based on the Dice measure, the structural similarity between analogues and the target compound was equal to 22,9%. Therefore, using experimental data of cobalt (II) oxalate 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 (cobalt (II) oxalate) and the target compound (TiO(Asc)2 x2H2O) equals to 22,9%

Test material

Constituent 1
Chemical structure
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

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Immunological findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

no effectn observed

Effect levels (P0)

Dose descriptor:
NOEL
Effect level:
ca. 100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: see remarks

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Immunological findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Details on results:
no effects observed

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P1)

no effects observed

Effect levels (P1)

Remarks on result:
not determinable due to absence of adverse toxic effects

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Sexual maturation:
no effects observed
Anogenital distance (AGD):
no effects observed
Nipple retention in male pups:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Other effects:
no effects observed

Developmental neurotoxicity (F1)

Behaviour (functional findings):
no effects observed

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
no effects observed

Details on results (F1)

no effect observed

Effect levels (F1)

Remarks on result:
not determinable due to absence of adverse toxic effects

Results: F2 generation

General toxicity (F2)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Sexual maturation:
no effects observed
Anogenital distance (AGD):
no effects observed
Nipple retention in male pups:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Other effects:
no effects observed

Developmental neurotoxicity (F2)

Behaviour (functional findings):
no effects observed

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
no effects observed

Effect levels (F2)

Remarks on result:
not determinable due to absence of adverse toxic effects

Overall reproductive toxicity

Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
no classified (The screening reproductive toxicity for the target substance is predicted at level NOEL = 100 mg/kg bdtwt/d)
Executive summary:

The target compound has the same structural features as source compound according to Estrogen Receptor Binding. The analogues search was performed assuming at least 20% structural similarity between the source and target substances. The toxicity prediction was performed based on the experimental data included in the OECD QSAR Toolbox. Cobalt (II) oxalate would have the same structural features as well as the experimental data related to its

screening reproductive toxicity was available. Therefore, the prediction is based only on the cobalt (II) oxalate.