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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 has the empiric alert for “Aliphatic Amines”,
c. analogue is structurally similar to the target compound (similarity >40%).
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:
The ER-binding profiler classifies chemicals as non-binders or binders depending on molecular weight and structural characteristics of the chemicals. 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. The target chemical is also classified as a “Aliphatic amines” according to the Organic Functional Groups (US EPA) profiler.
The target substance is an organometallic compound containing zinc (Zn) centres, glycine (Gly) and zinc (II) sulphate (ZnSO4) ligands. The metallic centres of the substance are linked by oxygen coordination bonds of the Gly ligands.
This read-across is based on the hypothesis that source and target substances have similar toxicological properties due to common underlying mechanism after administration. The prediction was performed based on the source compound, which is classified as “Non-binder, non-cyclic” as well as “Aliphatic amines” and its structural similarity to the target compound is higher than 40%. Sodium sulphate was used as the source compound. The screening reproductive toxicity for the source compound was performed according to:
Test guideline: OECD 421
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 421 (Reproduction / Developmental Toxicity Screening 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 screening reproductive toxicity of the zinc (II) glycine sulphate (VI) dihydrate, 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 40%. Therefore, using experimental data of sodium sulphate (Na2SO4) for predicting biological activity for the target compound was justified.
Besides, the category consistencies, the boundaries of the applicability domain are verified by the critical value of log KOW. In case of Zn(Gly)SO4x2H2O, 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. In case of structural similarity and US-EPA categorization the information that “target chemical is out of domain” is caused by different alerts for the main core of the compound (Zn(Gly)SO4) and hydration water. Analogue search was based only on alerts for core of the target compound (Zn(Gly)SO4) which were exact the same as for source compound. Thus, information that “target chemical is out of domain” refers also to the alerts for hydration water and is not critical in this situation. The structural similarity between the source sodium sulphate and the target compound Zn(Gly)SO4x2H2O equals to 40%

Test material

Constituent 1
Chemical structure
Reference substance name:
catena-[(μ-glycine)-diaqua-sulfato-zinc(II)]
EC Number:
805-657-4
Cas Number:
7214-08-6
Molecular formula:
(Zn(SO4)(C2H5NO2) · 2H2O
IUPAC Name:
catena-[(μ-glycine)-diaqua-sulfato-zinc(II)]
Test material form:
solid

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:
NOAEL
Effect level:
ca. 1 000 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 = 1000 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 40% structural similarity between the source and target substances. The toxicity prediction was performed based on the experimental data included in the OECD QSAR Toolbox. Sodium sulphate 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 sodium sulphate.