1,3,6,8-Pyrenetetrasulfonic acid, sodium salt

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Multiple Quantitative Structure Activity Relationship (QSAR) models were used to predict the mutagenicity potential of the test item Tetrasodium 1,3,6,8-pyrenetetrasulfonate in line with the OECD Guideline for Testing of chemicals No. 471: Bacterial Mutation Test.

The final mutagenicity potential result was predicted by applying a consensus method on the reliable results derived for individual models.

The final mutagenicity result predicted for Tetrasodium 1,3,6,8-pyrenetetrasulfonate assigned by the study investigator: non-mutagenic. The final QSAR result can be associated with a Klimisch score:K2

The same method was used to predict the mutagenicity potential of the analogue test item trisodium 8-hydroxypyrene-1,3,6-trisulfonate.

The final mutagenicity result predicted for trisodium 8-hydroxypyrene-1,3,6-trisulfonate assigned by the study investigator: non-mutagenic. Klimisch score assigned by the study investigtor for the final prediction: K2

Test results published on the ECHA website provided a conclusion of non-mutagenic for mutagenicity potential for the analogue test item trisodium 8-hydroxypyrene-1,3,6-trisulfonate.

Link to relevant study records

Reference

Reference 1

Endpoint:

in vitro gene mutation study in bacteria

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

2 December 2018 and 3 December 2018

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 adequate and reliable documentation / justification

Justification for type of information:

1. SOFTWARE
Nexus DEREK v6.0.1
OECD QSAR Toolbox v4.2 (profiling results)
Danish QSAR Database

2. MODEL (incl. version number)
Nexus DEREK v6.0.1
OECD QSAR Toolbox v4.2 (profiling results)
SciQSAR, LeadScope, Case Ultra

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
Smiles: C1=CC2=C3C(=C(C=C2S(=O)(=O)[O-])S(=O)(=O)[O-])C=CC4=C(C=C(C1=C43)S(=O)(=O)[O-])S(=O)(=O)[O-].[Na+].[Na+].[Na+].[Na+]
Substance name: Tetrasodium 1,3,6,8-pyrenetetrasulfonate
CAS: 59572-10-0

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
KREATiS explanation for Klimisch 2: Final QSAR result is reliable and can reliably replace an experimental result with the OECD Guideline for Testing of chemcials No. 471: Bacterial Reverse Mutation Test.

5. APPLICABILITY DOMAIN
This QSAR model has been designed to be used for regulatory purposes and based on the QSAR results, this report predicts the consensus endpoint value which would be expected when testing the substance under experimental conditions in a laboratory following the OECD Guideline for Testing of chemcials No. 471: Bacterial Reverse Mutation Test.

6. ADEQUACY OF THE RESULT
Based on multiple QSAR models applied, Tetrasodium 1,3,6,8-pyrenetetrasulfonate was predicted as non-mutagenic for the Ames mutagenicity test.
The final QSAR result can be associated with a Klimisch score: K2

Guideline:

other: REACH Guidance on QSARs R.6

Version / remarks:

OECD (2004) Principles for the validation, for regulatory purposes, of (Quantitative) Structure Activity-Relationship Models, http://www.oecd.org/env/ehs/risk-assessment/oecdquantitativestructureactivityrelationshipsprojectqsars.htm

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 471 (Bacterial Reverse Mutation Assay)

Version / remarks:

OECD (2004) Principles for the validation, for regulatory purposes, of (Quantitative) Structure Activity-Relationship Models, http://www.oecd.org/env/ehs/risk-assessment/oecdquantitativestructureactivityrelationshipsprojectqsars.htm

Specific details on test material used for the study:

C1=CC2=C3C(=C(C=C2S(=O)(=O)[O-])S(=O)(=O)[O-])C=CC4=C(C=C(C1=C43)S(=O)(=O)[O-])S(=O)(=O)[O-].[Na+].[Na+].[Na+].[Na+]

Key result

Species / strain:

other: Final consensus result based on results from all models

Metabolic activation:

not applicable

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not determined

Vehicle controls validity:

not applicable

Untreated negative controls validity:

not applicable

Positive controls validity:

not applicable

Species / strain:

other: OECD QSAR Toolbox

Metabolic activation:

not applicable

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not determined

Vehicle controls validity:

not applicable

Untreated negative controls validity:

not applicable

Positive controls validity:

not applicable

Species / strain:

other: Nexus DEREK

Metabolic activation:

not applicable

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not determined

Vehicle controls validity:

not applicable

Untreated negative controls validity:

not applicable

Positive controls validity:

not applicable

Species / strain:

other: Danish QSAR Database

Remarks:

SciQSAR

Metabolic activation:

not applicable

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not determined

Vehicle controls validity:

not applicable

Untreated negative controls validity:

not applicable

Positive controls validity:

not applicable

Species / strain:

other: Danish QSAR Database

Remarks:

Leadscope

Metabolic activation:

not applicable

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not determined

Vehicle controls validity:

not applicable

Untreated negative controls validity:

not applicable

Positive controls validity:

not applicable

Species / strain:

other: Danish QSAR Database

Remarks:

Case Ultra

Metabolic activation:

not applicable

Genotoxicity:

positive

Cytotoxicity / choice of top concentrations:

not determined

Vehicle controls validity:

not applicable

Untreated negative controls validity:

not applicable

Positive controls validity:

not applicable

Species / strain:

other: Danish QSAR Database

Remarks:

Battery

Metabolic activation:

not applicable

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not determined

Vehicle controls validity:

not applicable

Untreated negative controls validity:

not applicable

Positive controls validity:

not applicable

Remarks on result:

no mutagenic potential (based on QSAR/QSPR prediction)

Conclusions:

The final consensus result predicted assigned based on the above results:
Tetrasodium 1,3,6,8-pyrenetetrasulfonate is predicted as non-mutagenic for the Ames Mutagenicity test.
Klimisch score assigned by the study investigator for the final prediction: K2

Executive summary:

Introduction. Multiple Quantitative Structure Activity Relationship (QSAR) models were used to predict the Ames mutagenicity of the test item Tetrasodium 1,3,6,8-pyrenetetrasulfonate. These QSAR models has been designed to be used for regulatory purposes and based on the QSAR results, this report predicts the consensus endpoint value which would be expected when testing the substance under experimental conditions in a laboratory following the OECD Guideline for Testing of chemcials No. 471: Bacterial Reverse Mutation Test.

Methods. The purpose of the in silico study was to predict the Ames Mutagenicity of the test item Tetrasodium 1,3,6,8-pyrenetetrasulfonate. This prediction was performed using the following QSAR models:

·        Nexus DEREK v6.0.1

·        OECD QSAR Toolbox v4.2 (profiling results)

·        Danish QSAR Database

 

The final consensus result for Ames mutagenicity was derived by applying a consensus method on the reliable results derived for individual models.

 

Results.

Based on multiple QSAR models applied,Tetrasodium 1,3,6,8-pyrenetetrasulfonate was predicted as non-mutagenic for the Ames mutagenicity test.

The final QSAR result can be associated with a Klimisch score: K2

Reference 2

Endpoint:

in vitro gene mutation study in bacteria

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Remarks:

Usig QSAR

Adequacy of study:

supporting study

Study period:

2 December 2018 and 3 December 2018

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Justification for type of information:

1. SOFTWARE
Nexus DEREK v6.0.1
OECD QSAR Toolbox v4.2 (profiling results)
Danish QSAR Database

2. MODEL (incl. version number)
Nexus DEREK v6.0.1
OECD QSAR Toolbox v4.2 (profiling results)
SciQSAR, LeadScope, Case Ultra

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
Smiles: [Na+].[Na+].[Na+].OC1=C2C=CC3=C(C=C(C4=CC=C(C(=C1)S([O-])(=O)=O)C2=C34)S([O-])(=O)=O)S([O-])(=O)=O
Substance name: trisodium 8-hydroxypyrene-1,3,6-trisulfonate
CAS: 6358-69-6

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
KREATiS explanation for Klimisch 2: Final QSAR result is reliable and can reliably replace an experimental result with the OECD Guideline for Testing of chemcials No. 471: Bacterial Reverse Mutation Test.

5. APPLICABILITY DOMAIN
This QSAR model has been designed to be used for regulatory purposes and based on the QSAR results, this report predicts the consensus endpoint value which would be expected when testing the substance under experimental conditions in a laboratory following the OECD Guideline for Testing of chemcials No. 471: Bacterial Reverse Mutation Test.

6. ADEQUACY OF THE RESULT
Based on multiple QSAR models applied, trisodium 8-hydroxypyrene-1,3,6-trisulfonate was predicted as non-mutagenic for the Ames mutagenicity test.
The final QSAR result can be associated with a Klimisch score: K2

-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

Read-across information

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
STRUCTURAL SIMILARITY
Both the substances share the same carbon skeleton, which is pyrene. The query substance holds four sulfonates groups while the proposed analogue has one hydroxy group replacing a sulfonate. Both sulfonate and hydroxy groups are hydrophilic in nature. However, the hydroxy group is only ionised at high pHs (pKa of phenol is around 10) while the sulfonate group would remain ionised over the whole range of aqueous pHs. Therefore, Read-Across substance is expected to be slightly less hydrophilic and more volatile than the query substance, which is confirmed by the log KOW and vapour pressure studies.
Both the substances are expected to be stable in pure form or in water, and they are expected to be not volatile (high boiling point, low vapour pressure), highly hydrophilic (low log KOW, high water solubility) due to the presence of four strongly hydrophilic groups.
 
MECHANISMS OF ACTION PREDICTION
The mechanisms of action of both substances are predicted as follows:

Substance MechoA MechoA detail
Query 1.1 non-polar narcosis for all species
Read-Across 1.2 polar narcosis for all species

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See Test material sections of the source and target records for details.

3. ANALOGUE APPROACH JUSTIFICATION
DISCUSSION AND CONCLUSION
Therefore, both the structures are expected to have very similar (eco)toxicological profile. Moreover, Read-Across substance being less hydrophilic than the query substance and having a more toxic MechoA, the prediction of (eco)toxicological endpoints will be a worst-case scenario, because the less hydrophilic a substance is, the more toxic it is.
Consequently, trisodium 8-hydroxypyrene-1,3,6-trisulfonate is judged to be a good Read-Across for tetrasodium 1,3,6,8-pyrenetetrasulfonate.

Guideline:

other: REACH Guidance on QSARs R.6

Version / remarks:

OECD (2004) Principles for the validation, for regulatory purposes, of (Quantitative) Structure Activity-Relationship Models, http://www.oecd.org/env/ehs/risk-assessment/oecdquantitativestructureactivityrelationshipsprojectqsars.htm

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 471 (Bacterial Reverse Mutation Assay)

Version / remarks:

OECD (2004) Principles for the validation, for regulatory purposes, of (Quantitative) Structure Activity-Relationship Models, http://www.oecd.org/env/ehs/risk-assessment/oecdquantitativestructureactivityrelationshipsprojectqsars.htm

Specific details on test material used for the study:

[Na+].[Na+].[Na+].OC1=C2C=CC3=C(C=C(C4=CC=C(C(=C1)S([O-])(=O)=O)C2=C34)S([O-])(=O)=O)S([O-])(=O)=O

Key result

Species / strain:

other: Final consensus result based on results from all models

Metabolic activation:

not applicable

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not determined

Vehicle controls validity:

not applicable

Untreated negative controls validity:

not applicable

Positive controls validity:

not applicable

Species / strain:

other: Experimental data from the ECHA dossier: https://echa.europa.eu/registration-dossier/-/registered-dossier/17360/7/7/1

Genotoxicity:

negative

Species / strain:

other: OECD QSAR Toolbox

Metabolic activation:

not applicable

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not determined

Vehicle controls validity:

not applicable

Untreated negative controls validity:

not applicable

Positive controls validity:

not applicable

Species / strain:

other: Danish QSAR Database

Remarks:

Case Ultra

Metabolic activation:

not applicable

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not determined

Vehicle controls validity:

not applicable

Untreated negative controls validity:

not applicable

Positive controls validity:

not applicable

Species / strain:

other: Danish QSAR Database

Remarks:

Leadscope

Metabolic activation:

not applicable

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not determined

Vehicle controls validity:

not applicable

Untreated negative controls validity:

not applicable

Positive controls validity:

not applicable

Species / strain:

other: Danish QSAR Database

Remarks:

SciQSAR

Metabolic activation:

not applicable

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not determined

Vehicle controls validity:

not applicable

Untreated negative controls validity:

not applicable

Positive controls validity:

not applicable

Species / strain:

other: Danish QSAR Database

Remarks:

Battery

Metabolic activation:

not applicable

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not determined

Vehicle controls validity:

not applicable

Untreated negative controls validity:

not applicable

Positive controls validity:

not applicable

Remarks on result:

no mutagenic potential (based on QSAR/QSPR prediction)

Conclusions:

The final consensus result predicted assigned based on the above results:
trisodium 8-hydroxypyrene-1,3,6-trisulfonate is predicted as non-mutagenic for the Ames Mutagenicity test.
Klimisch score assigned by the study investigator for the final prediction: K2

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Genetic toxicity in vivo

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Both structures for the substances Tetrasodium 1,3,6,8-pyrenetetrasulfonate and 8-hydroxypyrene-1,3,6-trisulfonate are expected to have very similar (eco)toxicological profiles. Moreover, the Read-Across substance being less hydrophilic than the query substance and having a more toxic MechoA, the prediction of (eco)toxicological endpoints will be a worst-case scenario, because the less hydrophilic a substance is, the more toxic it is.

Consequently, trisodium 8-hydroxypyrene-1,3,6-trisulfonate is judged to be a good Read-Across for tetrasodium 1,3,6,8-pyrenetetrasulfonate.

Comparison with the QSAR results for the analogue substance, together with the available data on the analogue substance indicate that testing using 8-hydroxypyrene-1,3,6-trisulfonate would not be expected to show evidence of mutagnicity.

Justification for classification or non-classification

Multiple Quantitative Structure Activity Relationship (QSAR) models were used to predict the Ames mutagenicity of the test item Tetrasodium 1,3,6,8-pyrenetetrasulfonate. These QSAR models has been designed to be used for regulatory purposes and based on the QSAR results, the report predicts the consensus endpoint value which would be expected when testing the substance under experimental conditions in a laboratory following the OECD Guideline for Testing of chemcials No. 471: Bacterial Reverse Mutation Test.

Based on multiple QSAR models applied, Tetrasodium 1,3,6,8-pyrenetetrasulfonate was predicted as non-mutagenic for the Ames mutagenicity test and as such does not meet the criteria for classification.

The final QSAR result can be associated with a Klimisch score:K2