Registration Dossier
Registration Dossier
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EC number: 626-424-1 | CAS number: 59572-10-0
Endpoint summary
Administrative data
Description of key information
Multiple Quantitative Structure Activity Relationship (QSAR) models were used to predict the Skin Sensitization potential of the test item Tetrasodium 1,3,6,8-pyrenetetrasulfonate.
The final skin sensitization result was predicted by applying a consensus method on the reliable results derived for individual models.
The final Skin Sensitization result predicted for Tetrasodium 1,3,6,8-pyrenetetrasulfonate assigned by the study investigator: non sensitizing to the skin. The final QSAR result can be associated with a Klimisch score:K2
The same method was used to predict the Skin Sensitization potential of the analogue test item trisodium 8-hydroxypyrene-1,3,6-trisulfonate.
The final skin sensitization result predicted for trisodium 8-hydroxypyrene-1,3,6-trisulfonate assigned by the study investigator: non sensitizing to skin. Klimisch score assigned by the study investigtor for the final prediction: K2
Test results published on the ECHA website provided a conclusion of non sensitizing to skin for Skin Sensitization potential for the analogue test item trisodium 8-hydroxypyrene-1,3,6-trisulfonate.
Key value for chemical safety assessment
Skin sensitisation
Link to relevant study records
- Endpoint:
- skin sensitisation: in chemico
- 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 limited documentation / justification
- Justification for type of information:
- 1. SOFTWARE
Nexus DEREK v6.0.1
OECD QSAR Toolbox v4.2
2. MODEL (incl. version number)
Nexus DEREK v6.0.1
OECD QSAR Toolbox v4.2
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 Chemicals No. 429: Skin Sensitisation.
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 Chemicals No. 429: Skin Sensitisation.
6. ADEQUACY OF THE RESULT
Based on multiple QSAR models applied, Tetrasodium 1,3,6,8-pyrenetetrasulfonate was predicted as non-sensitising to the skin.
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 429 (Skin Sensitisation: Local Lymph Node 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+]
- Details on the study design:
- Following QSAR models were applied to predict the Skin Sensitisation potential for Tetrasodium 1,3,6,8-pyrenetetrasulfonate:
Nexus DEREK
DEREK predicts the skin sensitisation potential of a substance based on the triggered structural alerts for this endpoint. If the substance is a sensitiser, DEREK also provides the EC3 value. The report also provides detailed information about each triggered alert.
OECD QSAR Toolbox v4.2
The latest version of the OECD QSAR Toolbox facilitates the profiling of a query substane based on the following skin sensitisation relevant profilers incorporated into its interface:
Profilers
General Mechanistic
Protein binding potency GSH
Protein binding potency Cys (DPRA 13%)
Protein binding by OASIS
Protein binding by OECD
Protein binding potency Lys (DPRA 13%)
Endpoint Specific
Protein Binding Potency h-CLAT
Protein binding alerts for skin sensitization by OASIS
Protein binding alerts for skin sensitization according to GHS - Key result
- Parameter:
- other: The final consensus result
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- The final consensus result based on result from all models.
- Run / experiment:
- other: Protein binding potency GSH
- Parameter:
- other: OECD QSAR Toolbox v4.2 Profilers for Skin Sensitisation
- Remarks:
- General Mechanistic
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- not determinable
- Remarks:
- Not possible to classify according to these rules (GSH)
- Run / experiment:
- other: Protein binding potency Cys (DPRA 13%)
- Parameter:
- other: OECD QSAR Toolbox v4.2 Profilers for Skin Sensitisation
- Remarks:
- General Mechanistic
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- DPRA less than 9% (DPRA 13%) >> No protein binding alert
- Run / experiment:
- other: Protein binding by OASIS
- Parameter:
- other: OECD QSAR Toolbox v4.2 Profilers for Skin Sensitisation
- Remarks:
- General Mechanistic
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- No alert found
- Run / experiment:
- other: Protein binding by OECD
- Parameter:
- other: OECD QSAR Toolbox v4.2 Profilers for Skin Sensitisation
- Remarks:
- General Mechanistic
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- No alert found
- Run / experiment:
- other: Protein binding potency Lys (DPRA 13%)
- Parameter:
- other: OECD QSAR Toolbox v4.2 Profilers for Skin Sensitisation
- Remarks:
- General Mechanistic
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- DPRA less than 9% (DPRA 13%) >> No protein binding alert
- Run / experiment:
- other: Keratinocyte gene expression
- Parameter:
- other: OECD QSAR Toolbox v4.2 Profilers for Skin Sensitisation
- Remarks:
- Endpoint Specific
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- not determinable
- Remarks:
- Not possible to classify according to these rules
- Run / experiment:
- other: Protein binding alerts for skin sensitization by OASIS
- Parameter:
- other: OECD QSAR Toolbox v4.2 Profilers for Skin Sensitisation
- Remarks:
- Endpoint Specific
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- No alert found
- Run / experiment:
- other: Protein binding alerts for skin sensitization according to GHS
- Parameter:
- other: OECD QSAR Toolbox v4.2 Profilers for Skin Sensitisation
- Remarks:
- Endpoint Specific
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- No alert found
- Run / experiment:
- other: Respiratory sensitisation
- Parameter:
- other: OECD QSAR Toolbox v4.2 Profilers for Skin Sensitisation
- Remarks:
- Endpoint Specific
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- No alert found
- Run / experiment:
- other: Protein Binding Potency h-CLAT
- Parameter:
- other: OECD QSAR Toolbox v4.2 Profilers for Skin Sensitisation
- Remarks:
- Endpoint Specific
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- No alert found
- Parameter:
- other: Nexus DEREK
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- No structural alerts were triggered for skin sensitisation
- Other effects / acceptance of results:
- Results with OECD QSAR Toolbox v4.2
As per the profiling results, the query substance will be predicted as non-sensitising to the skin.
Results with Nexus DEREK
No structural alerts were triggered for skin sensitisation. - Interpretation of results:
- GHS criteria not met
- Conclusions:
- The final consensus result predicted assigned based on the above results:
Tetrasodium 1,3,6,8-pyrenetetrasulfonate is predicted as a non-sensitising to the skin.
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 Skin Sensitisation potential 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 Chemicals No. 429: Skin Sensitisation.
Methods. The purpose of the in silico study was to predict the Skin Sensitisation potential 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
The final Skin Sensitisation potential 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-sensitising to the skin.
The final QSAR result can be associated with a Klimisch score: K2
- Endpoint:
- skin sensitisation: in chemico
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Remarks:
- Using 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
2. MODEL (incl. version number)
Nexus DEREK v6.0.1
OECD QSAR Toolbox v4.2
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 Chemicals No. 429: Skin Sensitisation.
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 Chemicals No. 429: Skin Sensitisation.
6. ADEQUACY OF THE RESULT
Based on multiple QSAR models applied, trisodium 8-hydroxypyrene-1,3,6-trisulfonate was predicted as non-sensitising to the skin.
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 429 (Skin Sensitisation: Local Lymph Node 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
- Details on the study design:
- Following QSAR models were applied to predict the Skin Sensitisation potential for trisodium 8-hydroxypyrene-1,3,6-trisulfonate:
Nexus DEREK
DEREK predicts the skin sensitisation potential of a substance based on the triggered structural alerts for this endpoint. If the substance is a sensitiser, DEREK also provides the EC3 value. The report also provides detailed information about each triggered alert.
OECD QSAR Toolbox v4.2
The latest version of the OECD QSAR Toolbox facilitates the profiling of a query substane based on the following skin sensitisation relevant profilers incorporated into its interface:
Profilers
General Mechanistic
Protein binding potency GSH
Protein binding potency Cys (DPRA 13%)
Protein binding by OASIS
Protein binding by OECD
Protein binding potency Lys (DPRA 13%)
Endpoint Specific
Protein Binding Potency h-CLAT
Protein binding alerts for skin sensitization by OASIS
Protein binding alerts for skin sensitization according to GHS - Key result
- Parameter:
- other: The final consensus result
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- The final consensus result based on result from all models.
- Parameter:
- other: Experimental data from the ECHA dossier: https://echa.europa.eu/registration-dossier/-/registered-dossier/17360/7/5/1
- Remarks on result:
- no indication of skin sensitisation
- Run / experiment:
- other: Protein binding potency GSH
- Parameter:
- other: OECD QSAR Toolbox v4.2 Profilers for Skin Sensitisation
- Remarks:
- General Mechanistic
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- not determinable
- Remarks:
- Not possible to classify according to these rules (GSH)
- Run / experiment:
- other: Protein binding potency Cys (DPRA 13%)
- Parameter:
- other: OECD QSAR Toolbox v4.2 Profilers for Skin Sensitisation
- Remarks:
- General Mechanistic
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- DPRA less than 9% (DPRA 13%) >> No protein binding alert
- Run / experiment:
- other: Protein binding by OASIS
- Parameter:
- other: OECD QSAR Toolbox v4.2 Profilers for Skin Sensitisation
- Remarks:
- General Mechanistic
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- No alert found
- Run / experiment:
- other: Protein binding by OECD
- Parameter:
- other: OECD QSAR Toolbox v4.2 Profilers for Skin Sensitisation
- Remarks:
- General Mechanistic
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- No alert found
- Run / experiment:
- other: Protein binding potency Lys (DPRA 13%)
- Parameter:
- other: OECD QSAR Toolbox v4.2 Profilers for Skin Sensitisation
- Remarks:
- General Mechanistic
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- DPRA less than 9% (DPRA 13%) >> No protein binding alert
- Run / experiment:
- other: Keratinocyte gene expression
- Parameter:
- other: OECD QSAR Toolbox v4.2 Profilers for Skin Sensitisation
- Remarks:
- Endpoint Specific
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- not determinable
- Remarks:
- Not possible to classify according to these rules
- Run / experiment:
- other: Protein binding alerts for skin sensitization by OASIS
- Parameter:
- other: OECD QSAR Toolbox v4.2 Profilers for Skin Sensitisation
- Remarks:
- Endpoint Specific
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- No alert found
- Run / experiment:
- other: Protein binding alerts for skin sensitization according to GHS
- Parameter:
- other: OECD QSAR Toolbox v4.2 Profilers for Skin Sensitisation
- Remarks:
- Endpoint Specific
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- No alert found
- Run / experiment:
- other: Respiratory sensitisation
- Parameter:
- other: OECD QSAR Toolbox v4.2 Profilers for Skin Sensitisation
- Remarks:
- Endpoint Specific
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- No alert found
- Run / experiment:
- other: Protein Binding Potency h-CLAT
- Parameter:
- other: OECD QSAR Toolbox v4.2 Profilers for Skin Sensitisation
- Remarks:
- Endpoint Specific
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- No alert found
- Parameter:
- other: Nexus DEREK
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- No structural alerts were triggered for skin sensitisation
- Other effects / acceptance of results:
- Results with OECD QSAR Toolbox v4.2
As per the profiling results, the query substance will be predicted as non-sensitising to the skin.
Results with Nexus DEREK
No structural alerts were triggered for skin sensitisation. - Interpretation of results:
- other: GHS criteria not met by structural analogue
- Conclusions:
- The final consensus result predicted assigned based on the above results:
trisodium 8-hydroxypyrene-1,3,6-trisulfonate is predicted as a non-sensitising to the skin.
Klimisch score assigned by the study investigator for the final prediction: K2
Referenceopen allclose all
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (not sensitising)
- Additional information:
Both structures for the substancesTetrasodium 1,3,6,8-pyrenetetrasulfonate and8-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 sensitization.
Respiratory sensitisation
Endpoint conclusion
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
Multiple Quantitative Structure Activity Relationship (QSAR) models were used to predict the Skin Sensitisation potential 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 Chemicals No. 429: Skin Sensitisation.
Based on multiple QSAR models applied, Tetrasodium 1,3,6,8-pyrenetetrasulfonate was predicted as non-sensitising to the skin and as such does not meet the criteria for classification.
The final QSAR result can be associated with a Klimisch score: K2
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
