Sulpiride

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Levosulpiride was studied by different test methods and was not found to be genotoxic.

Moreover, the substance was predicted to be non-mutagenic by 3 individual QSAR models. The predictions show good reliability.

Link to relevant study records

Reference

Reference 1

Endpoint:

in vitro gene mutation study in bacteria

Type of information:

(Q)SAR

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Qualifier:

equivalent or similar to guideline

Guideline:

other: ECHA guidance on information requirements and chemical safety assessment Chapter R.6: QSARs and grouping of chemicals.

Type of assay:

bacterial reverse mutation assay

Statistics:

The applicability domain of predictions is assessed using an Applicability Domain Index (ADI) that has values from 0 (worst case) to 1 (best case). The ADI is calculated by grouping several other indices, each one taking into account a particular issue of the applicability domain. Most of the indices are based on the calculation of the most similar compounds found in the training and test set of the model, calculated by a similarity index that consider molecule's fingerprint and structural aspects (count of atoms, rings and relevant fragments).
For each index, including the final ADI, three intervals for its values are defined, such that the first interval corresponds to a positive evaluation, the second one corresponds to a suspicious evaluation and the last one corresponds to a negative evaluation.

List of indices:
- Similar molecules with known experimental value.
- Accuracy of prediction for similar molecules.
- Concordance for similar molecules.
- Atom Centered Fragments similarity check.
- Model descriptors range check.
- Global AD Index.

Key result

Genotoxicity:

negative

The result appears reliable as the predicted compound is into the applicability domain of the model.

Conclusions:

The substance is predicted to be non-mutagenic.

Reference 2

Endpoint:

in vitro gene mutation study in bacteria

Type of information:

(Q)SAR

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Qualifier:

equivalent or similar to guideline

Guideline:

other: ECHA guidance on information requirements and chemical safety assessment Chapter R.6: QSARs and grouping of chemicals.

Type of assay:

bacterial reverse mutation assay

Statistics:

The applicability domain of predictions is assessed using an Applicability Domain Index (ADI) that has values from 0 (worst case) to 1 (best case). The ADI is calculated by grouping several other indices, each one taking into account a particular issue of the applicability domain. Most of the indices are based on the calculation of the most similar compounds found in the training and test set of the model, calculated by a similarity index that consider molecule's fingerprint and structural aspects (count of atoms, rings and relevant fragments).
For each index, including the final ADI, three intervals for its values are defined, such that the first interval corresponds to a positive evaluation, the second one corresponds to a suspicious evaluation and the last one corresponds to a negative evaluation.

List of indices:
- Similar molecules with known experimental value.
- Accuracy of prediction for similar molecules.
- Concordance for similar molecules.
- Atom Centered Fragments similarity check.
- Global AD Index.

Key result

Genotoxicity:

negative

The result appears reliable as the predicted compound is into the applicability domain of the model.

Conclusions:

The substance is predicted to be non-mutagenic.

Reference 3

Endpoint:

in vitro gene mutation study in bacteria

Type of information:

(Q)SAR

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Qualifier:

equivalent or similar to guideline

Guideline:

other: ECHA guidance on information requirements and chemical safety assessment Chapter R.6: QSARs and grouping of chemicals.

Type of assay:

bacterial reverse mutation assay

Statistics:

The applicability domain of predictions is assessed using an Applicability Domain Index (ADI) that has values from 0 (worst case) to 1 (best case). The ADI is calculated by grouping several other indices, each one taking into account a particular issue of the applicability domain. Most of the indices are based on the calculation of the most similar compounds found in the training and test set of the model, calculated by a similarity index that consider molecule's fingerprint and structural aspects (count of atoms, rings and relevant fragments).
For each index, including the final ADI, three intervals for its values are defined, such that the first interval corresponds to a positive evaluation, the second one corresponds to a suspicious evaluation and the last one corresponds to a negative evaluation.

List of indices:
- Similar molecules with known experimental value.
- Accuracy of prediction for similar molecules.
- Concordance for similar molecules.
- Atom Centered Fragments similarity check.
- Global AD Index.

Key result

Genotoxicity:

negative

The result appears reliable as the predicted compound is into the applicability domain of the model.

Conclusions:

The substance is predicted to be non-mutagenic.

Reference 4

Endpoint:

in vitro cytogenicity / chromosome aberration study in mammalian cells

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Guideline:

other: not specified

GLP compliance:

not specified

Type of assay:

other: see executive summary

The mutagenic potential of levosulpiride was studied by using different methods. The point mutation test in Saccharomyces cerevisiae, the bacterial test of B. Ames on Salmonella tiphymurium, the study on the DNA repairing activity, the chromosomal aberration test in human diploid cells, the DNA repair and damage test (evaluated by mitotic crossing-over and by gene conversion in Saccharomyces cerevisiae), and the gene mutation test in Schizosaccharomyces Pombe Pl, did not document any increase in mutation rate induced by levosulpiride. Furthermore, levosulpiride was tested in vitro for possible induction of structural and numerical chromosome aberration in PHA-stimulated human lymphocytes. The compound was added to the medium at various concentrations 48 h after the culture had been set up. The mean structural aberration rates for the levosulpiride cultures were between 0.5 and 3.0% (for aberrant metaphases including gaps) or 0 and 1.5% (for aberrant metaphases excluding gaps) and were thus found within the range of variation of long-term in-house negative controls. No aberration other than gaps, breaks and isolated isochromatid fragments was observed. There was no substance-related increase in comparison to the concurrent negative controls. Numerically aberrant metaphases were also included in the evaluation for structural aberrations. Under these experimental conditions the induction of structural chromosomal aberrations and numerical aberrations in the form of hypoploid and polyploid metaphases induced by levosulpiride is ruled out.

Conclusions:

Levosulpiride was studied by different test methods and was not found to be genotoxic.

Executive summary:

The mutagenic potential of levosulpiride was studied by using different methods. The point mutation test in Saccharomyces cerevisiae, the bacterial test of B. Ames on Salmonella tiphymurium, the study on the DNA repairing activity, the chromosomal aberration test in human diploid cells, the DNA repair and damage test (evaluated by mitotic crossing-over and by gene conversion in Saccharomyces cerevisiae), and the gene mutation test in Schizosaccharomyces Pombe Pl, did not document any increase in mutation rate induced by levosulpiride. Furthermore, levosulpiride was tested in vitro for possible induction of structural and numerical chromosome aberration in PHA-stimulated human lymphocytes. The compound was added to the medium at various concentrations 48 h after the culture had been set up. The mean structural aberration rates for the levosulpiride cultures were between 0.5 and 3.0% (for aberrant metaphases including gaps) or 0 and 1.5% (for aberrant metaphases excluding gaps) and were thus found within the range of variation of long-term in-house negative controls. No aberration other than gaps, breaks and isolated isochromatid fragments was observed. There was no substance-related increase in comparison to the concurrent negative controls. Numerically aberrant metaphases were also included in the evaluation for structural aberrations. Under these experimental conditions the induction of structural chromosomal aberrations and numerical aberrations in the form of hypoploid and polyploid metaphases induced by levosulpiride is ruled out.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Additional information

Available information allows to rule out genotoxicity of sulpiride.

Justification for classification or non-classification

Overall, data available are conclusive but not sufficient for classification.