Reaction products of tetrazotized 5-amino-2-[(E)-2-(4-amino-2-sulfophenyl)ethenyl]benzenesulfonic acid with 6-amino-4-hydroxynaphthalene-2-sulfonic acid and 4-amino-5-hydroxynaphthalene-2,7-disulfonic acid in 2-[bis(2-hydroxyethyl)amino]ethanol

Partition coefficient

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

partition coefficient

Type of information:

(Q)SAR

Adequacy of study:

key study

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
Individual model KOWWIN included in the Estimation Programs Interface (EPI) Suite.

2. MODEL (incl. version number)
KOWWIN v1.68 included in EPISuite v 4.11, ©2000 - 2012

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
A SMILES NOTATION/CAS NUMBER was entered in the initial data entry screen. In the structure window, the molecular weight, structural formula and the structure of the input SMILES notation is shown.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL

a. Defined Endpoint: Octanol-water partition coefficient

b. Explicit algorithm:
The program methodology is known as an Atom/Fragment Contribution (AFC) method. KOWWIN uses a "fragment constant" methodology to predict log P. In a "fragment constant" method, a structure is divided into fragments (atom or larger functional groups) and coefficient values of each fragment or group are summed together to yield the log P estimate.
The equation is as follows: Log Kow = Sum (fini) + Sum (cjnj) + 0.229, where Sum (fini) is the summation of fi (the coefficient for each atom/fragment) times ni (the number of times the atom/fragment occurs in the structure), and (cjnj) is the summation of cj (the coefficient for each correction factor) times nj (the number of times the correction factor occurs (or is applied) in the molecule). The program requires only a chemical structure to estimate a log P. KOWWIN initially separates a molecule into distinct atom/fragments. For various types of structures, that log P estimates made from atom/fragment values alone could or needed to be improved by inclusion of substructures larger or more complex than "atoms"; hence, correction factors were added to the AFC method.

c. Descriptor selection:
As the program requires only a chemical structure to estimate a log P, KOWWIN initially separates a molecule into distinct atom/fragments. Each non-hydrogen atom (e.g. carbon, nitrogen, oxygen, sulfur, etc.) in a structure is a "core" for a fragment; the exact fragment is determined by what is connected to the atom. Several functional groups are treated as core "atoms". Connections to each core "atom" are either general or specific. For example, aromatic carbon, aromatic oxygen and aromatic sulfur atoms have nothing but general connections; i.e., the fragment is the same no matter what is connected to the atom. In contrast, the aliphatic carbon atom does not matter what is connected to -CH3, -CH2-, or -CH<, the fragment is the same; however, an aliphatic carbon with no hydrogens has two possible fragments: (a) if there are four single bonds with 3 or more carbon connections and (b) any other not meeting the first criteria. Additionally, for various types of structures, need to be improved by inclusion of substructures larger or more complex than "atoms" by adding correction factors. The correction factors have two main groupings: first, factors involving aromatic ring substituent positions and second, miscellaneous factors. In general, the correction factors are values for various steric interactions, hydrogen-bondings, and effects from polar functional substructures. Individual correction factors were selected through a tedious process of correlating the differences (between log P estimates from atom/fragments alone and measured log P values) with common substructures.

d. Defined domain of applicability: For each fragment the maximum number of instances of that fragment in any of the 2447 training set compounds and 10946 validation set compounds is located in Appendix D of the help menu of the EPISuite data entry page. The minimum and the maximum values for molecular weight are the following:
Training Set Molecluar Weights: 18.02-719.92 g/mol
Validation Set Molecular Weights: 27.03-991.15 g/mol

e. Statistical characteristics: Correlation coefficient of the total training set r² = 0.982; Correlation coefficient of the total validation set r² = 0.943.
KOWWIN has been tested on an external validation dataset of 10,946 compounds. The validation set includes a diverse selection of chemical structures that rigorously test the predictive accuracy of any model. It contains many chemicals that are similar in structure to chemicals in the training set, but also many chemicals that are different from and structurally more complex than chemicals in the training set. The average molecular weight of compounds in the validation set is 258.98 versus 199.98 for the training set.
(Training dataset includes a total of 2447 compounds)
(Validation dataset includes a total of 10946 compounds)

f. Mechanistic interpretation: The structural fragments used as descriptors reflect the lipophilic or hydrophobic properties of the substances, and so the octanol-water partition coefficient.

5. APPLICABILITY DOMAIN
a. Descriptor domains:
i. Molecular weights: With a molecular weight of 870 g/mol the substance is not within the range of the training set (18.02 - 719.92 g/mol) but in the range of the validation set (27.03 - 991.15 g/mol).
ii. Structural fragment domain: Regarding the structure of 2-Naphthalenesulfonic acid 3,3'-[1,2-ethenediylbis[(3-sulfo-4,1-phenylene)azo]]bis[6-amino-4-hydroxy- compound with 2,2',2''-nitrilotris[ethanol] (1:4), the fragment descriptors found by the program are complete and listed in Appendix D (KOWWIN Fragment and Correction Factor descriptors). Additionally the substance is not listed in Appendix F (Compounds that exceed the Fragment & Molecular Weight Domains).
iii. Mechanism domain: NO INFORMATION AVAILABLE
iv. Metabolic domain, if relevant: NOT RELEVANT
b. Structural analogues: NO INFORMATION AVAILABLE
i. Considerations on structural analogues: NO INFORMATION AVAILABLE

6. ADEQUACY OF THE RESULT
a. Regulatory purpose: The data may be used under any regulatory purpose.
b. Approach for regulatory interpretation of the model result: If no experimental data are available, the estimated value is used to fill data gaps needed for hazard and risk assessment, classification and labelling and PBT / vPvB assessment. Further the value can be used for other calculations.
c. Outcome: The prediction of the logarithmic octanol-water partition coefficient yields a useful result for further evaluation.
d. Conclusion: The result is considered as useful for regulatory purposes.

Guideline:

other: REACH guidance QSARs R6, May/July 2008

Principles of method if other than guideline:

Estimation Program Interface EPI-Suite version 4.11: KOWWIN for estimating the logarithmic octanol-water partition coefficient (log Kow).
The Estimation Programs Interface was developed by the US Environmental Agency's Office of Pollution Prevention and Toxics and Syracuse Research Corporation (SRC).© 2000 - 2012 U.S. Environmental Protection Agency for EPI SuiteTM (Published online in November 2012).

GLP compliance:

no

Type of method:

other: QSAR

Partition coefficient type:

octanol-water

Specific details on test material used for the study:

CAS number: 75701-34-7
EC number: 278-293-1
Empirical formula: C34H26N6O14S4
SMILES: N(=Nc3ccc(c(c3)S(=O)(=O)O)C=Cc4c(cc(cc4)N=Nc5c(c6c(ccc(c6)N)cc5S(=O)(=O)O)O)S(=O)(=O)O)c1c(c2c(ccc(c2)N)cc1S(=O)(=O)O)O
Molecular weight: 870 g/mole

Key result

Type:

log Pow

Partition coefficient:

<= 0

Temp.:

20 °C

pH:

>= 4 - <= 9

Remarks on result:

other: at environmental pH

Validity of model:

1. Defined Endpoint: Octanol-water partition coefficient

2. Unambiguous algorithm: The molecule is separated into distinct atom/fragments using an Atom/Fragment Contribution method. Based on structure of the molecule, the following fragments were applied: Olefin carbon, Aromatic Carbon, hydroxy, aromatic attach, sulfonic, Azol, Ring reaction -> -OH ortho to Azo. The number of times of the fragments that occur in the structure of the substance applied by the program is verified.

3. Applicability domain: With a molecular weight of 870 g/mol the substance is not within the range of the training Aromatic Carbonset (18.02 - 719.92) but in the range of the validation set (27.03 - 991.15).

4. Statistical characteristics: Correlation coefficient of the total training set r² = 0.982; Correlation coefficient of the total validation set r² = 0.943.

5. Mechanistic interpretation: The structural fragments used as descriptors reflect the lipophilic or hydrophobic properties of the substances, and so the octanol-water partition coefficient.

6. Adequacy of prediction: The result for 2-Naphthalenesulfonic acid 3,3'-[1,2-ethenediylbis[(3-sulfo-4,1-phenylene)azo]]bis[6-amino-4-hydroxy- compound with 2,2',2''-nitrilotris[ethanol] (1:4) falls within the applicability domain described above and the estimation rules applied for the substance appears appropriate. Therefore the predicted value can be considered reliable yielding a useful result for further assessment.

Conclusions:

The QSAR determination of the logarithmic octanol-water partition coefficient for 2-Naphthalenesulfonic acid 3,3'-[1,2-ethenediylbis[(3-sulfo-4,1-phenylene)azo]]bis[6-amino-4-hydroxy- compound with 2,2',2''-nitrilotris[ethanol] (1:4) using the model KOWWIN included in the Estimation Program Interface (EPI) Suite v4.11 revealed a value of 3.7178 of the substance. Additionally, measured octanol-water partition coefficient values of ionized structural analogues show, that the log Kow of these substances is significantly < 0. Therefore, a value of ≤ 0 is a realistic estimation of octanol-water partition coefficient of the substance 2-Naphthalenesulfonic acid 3,3'-[1,2-ethenediylbis[(3-sulfo-4,1-phenylene)azo]]bis[6-amino-4-hydroxy- compound with 2,2',2''-nitrilotris[ethanol] (1:4). The predicted value can be considered reliable yielding a useful result for further assessment.

Executive summary:

The QSAR determination of the  logarithmic octanol-water partition coefficient for 2-Naphthalenesulfonic acid 3,3'-[1,2-ethenediylbis[(3-sulfo-4,1-phenylene)azo]]bis[6-amino-4-hydroxy- compound with 2,2',2''-nitrilotris[ethanol] (1:4) using the model KOWWIN included in the Estimation Program Interface (EPI) Suite v4.11 revealed a value of 3.7178 of the substance. The prediction of the logarithmic octanol-water partition coefficient yields a useful result for further evaluation. However, KOWWIN estimates apply to compounds that are predominantly in a non-ionized form. For ionizable compounds, log Kow measurements can vary greatly with pH. In general, log Kow values of a compound are lower (sometimes significantly) when it exists predominantly in the ionized form as compared to existing primarily in the non-ionized form. At environmental relevant pH, the substance 2-Naphthalenesulfonic acid 3,3'-[1,2-ethenediylbis[(3-sulfo-4,1-phenylene)azo]]bis[6-amino-4-hydroxy- compound with 2,2',2''-nitrilotris[ethanol] (1:4) exists predominantly in the dissociated form. At pH 4 to 9, the substance will be deprotonated resulting in the corresponding anion. Therefore, it can be assumed that the realistic log Kow value of the substance is significantly lower than the value calculated by KOWWIN. Additionally, measured octanol-water partition coefficient values of ionized structural analogues show, that the log Kow of these substances is significantly < 0. Therefore, a value of ≤ 0 is a realistic estimation of octanol-water partition coefficient of the substance 2-Naphthalenesulfonic acid 3,3'-[1,2-ethenediylbis[(3-sulfo-4,1-phenylene)azo]]bis[6-amino-4-hydroxy- compound with 2,2',2''-nitrilotris[ethanol] (1:4). The predicted value can be considered reliable yielding a useful result for further assessment.

Reference 2

Endpoint:

partition coefficient

Type of information:

(Q)SAR

Adequacy of study:

key study

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
Individual model KOWWIN included in the Estimation Programs Interface (EPI) Suite.

2. MODEL (incl. version number)
KOWWIN v1.68 included in EPISuite v 4.11, ©2000 - 2012

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
A SMILES NOTATION/CAS NUMBER was entered in the initial data entry screen. In the structure window, the molecular weight, structural formula and the structure of the input SMILES notation is shown.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL

a. Defined Endpoint: Octanol-water partition coefficient

b. Explicit algorithm:
The program methodology is known as an Atom/Fragment Contribution (AFC) method. KOWWIN uses a "fragment constant" methodology to predict log P. In a "fragment constant" method, a structure is divided into fragments (atom or larger functional groups) and coefficient values of each fragment or group are summed together to yield the log P estimate.
The equation is as follows: Log Kow = Sum (fini) + Sum (cjnj) + 0.229, where Sum (fini) is the summation of fi (the coefficient for each atom/fragment) times ni (the number of times the atom/fragment occurs in the structure), and (cjnj) is the summation of cj (the coefficient for each correction factor) times nj (the number of times the correction factor occurs (or is applied) in the molecule). The program requires only a chemical structure to estimate a log P. KOWWIN initially separates a molecule into distinct atom/fragments. For various types of structures, that log P estimates made from atom/fragment values alone could or needed to be improved by inclusion of substructures larger or more complex than "atoms"; hence, correction factors were added to the AFC method.

c. Descriptor selection:
As the program requires only a chemical structure to estimate a log P, KOWWIN initially separates a molecule into distinct atom/fragments. Each non-hydrogen atom (e.g. carbon, nitrogen, oxygen, sulfur, etc.) in a structure is a "core" for a fragment; the exact fragment is determined by what is connected to the atom. Several functional groups are treated as core "atoms". Connections to each core "atom" are either general or specific. For example, aromatic carbon, aromatic oxygen and aromatic sulfur atoms have nothing but general connections; i.e., the fragment is the same no matter what is connected to the atom. In contrast, the aliphatic carbon atom does not matter what is connected to -CH3, -CH2-, or -CH<, the fragment is the same; however, an aliphatic carbon with no hydrogens has two possible fragments: (a) if there are four single bonds with 3 or more carbon connections and (b) any other not meeting the first criteria. Additionally, for various types of structures, need to be improved by inclusion of substructures larger or more complex than "atoms" by adding correction factors. The correction factors have two main groupings: first, factors involving aromatic ring substituent positions and second, miscellaneous factors. In general, the correction factors are values for various steric interactions, hydrogen-bondings, and effects from polar functional substructures. Individual correction factors were selected through a tedious process of correlating the differences (between log P estimates from atom/fragments alone and measured log P values) with common substructures.

d. Defined domain of applicability: For each fragment the maximum number of instances of that fragment in any of the 2447 training set compounds and 10946 validation set compounds is located in Appendix D of the help menu of the EPISuite data entry page. The minimum and the maximum values for molecular weight are the following:
Training Set Molecluar Weights: 18.02-719.92 g/mol
Validation Set Molecular Weights: 27.03-991.15 g/mol

e. Statistical characteristics: Correlation coefficient of the total training set r² = 0.982; Correlation coefficient of the total validation set r² = 0.943.
KOWWIN has been tested on an external validation dataset of 10,946 compounds. The validation set includes a diverse selection of chemical structures that rigorously test the predictive accuracy of any model. It contains many chemicals that are similar in structure to chemicals in the training set, but also many chemicals that are different from and structurally more complex than chemicals in the training set. The average molecular weight of compounds in the validation set is 258.98 versus 199.98 for the training set.
(Training dataset includes a total of 2447 compounds)
(Validation dataset includes a total of 10946 compounds)

f. Mechanistic interpretation: The structural fragments used as descriptors reflect the lipophilic or hydrophobic properties of the substances, and so the octanol-water partition coefficient.

5. APPLICABILITY DOMAIN
a. Descriptor domains:
i. Molecular weights: With a molecular weight of 1030 g/mol the substance is not within the range of the training set (18.02 - 719.92 g/mol) and not within the range of the validation set (27.03 - 991.15 g/mol).
ii. Structural fragment domain: Regarding the structure of SUBSTANCE, the fragment descriptors found by the program are complete and listed in Appendix D (KOWWIN Fragment and Correction Factor descriptors). Additionally the substance is not listed in Appendix F (Compounds that exceed the Fragment & Molecular Weight Domains).
iii. Mechanism domain: NO INFORMATION AVAILABLE
iv. Metabolic domain, if relevant: NOT RELEVANT
b. Structural analogues: NO INFORMATION AVAILABLE
i. Considerations on structural analogues: NO INFORMATION AVAILABLE

6. ADEQUACY OF THE RESULT
a. Regulatory purpose: The data may be used under any regulatory purpose.
b. Approach for regulatory interpretation of the model result: If no experimental data are available, the estimated value is used to fill data gaps needed for hazard and risk assessment, classification and labelling and PBT / vPvB assessment. Further the value can be used for other calculations.
c. Outcome: The prediction of the logarithmic octanol-water partition coefficient yields a useful result for further evaluation.
d. Conclusion: The result is considered as useful for regulatory purposes.

Guideline:

other: REACH guidance QSARs R6, May/July 2008

Principles of method if other than guideline:

Estimation Program Interface EPI-Suite version 4.11: KOWWIN for estimating the logarithmic octanol-water partition coefficient (log Kow).
The Estimation Programs Interface was developed by the US Environmental Agency's Office of Pollution Prevention and Toxics and Syracuse Research Corporation (SRC).© 2000 - 2012 U.S. Environmental Protection Agency for EPI SuiteTM (Published online in November 2012).

GLP compliance:

no

Type of method:

other: QSAR

Partition coefficient type:

octanol-water

Specific details on test material used for the study:

CAS number: 75701-36-9
EC number: 278-294-7
Empirical formula: C34H26N6O20S6
SMILES: N(=Nc3cc(c(cc3)C=Cc4ccc(cc4S(=O)(=O)O)N=Nc5c(c6c(cc5S(=O)(=O)O)cc(cc6N)S(=O)(=O)O)O)S(=O)(=O)O)c1c(c2c(cc1S(=O)(=O)O)cc(cc2N)S(=O)(=O)O)O
Molecuar weight: 1030 g/mole

Key result

Type:

log Pow

Partition coefficient:

<= 0

Temp.:

20 °C

pH:

>= 4 - <= 9

Remarks on result:

other: at environmental relevant pH

Validity of model:

1. Defined Endpoint: Octanol-water partition coefficient

2. Unambiguous algorithm: The molecule is separated into distinct atom/fragments using an Atom/Fragment Contribution method. Based on structure of the molecule, the following fragments were applied: Olefin carbon; aromatic carbon; hydroxy, aromatic attach; aliphatic N, one aromatic attach; sulfonic; azol; Ring reaction -> OH-ortho to azo. The number of times of the fragments that occur in the structure of the substance applied by the program is verified.

3. Applicability domain: With a molecular weight of 1030 g/mol the substance is not within the range of the training set (18.02 - 719.92) and not in the range of the validation set (27.03 - 991.15).

4. Statistical characteristics: Correlation coefficient of the total training set r² = 0.982; Correlation coefficient of the total validation set r² = 0.943.

5. Mechanistic interpretation: The structural fragments used as descriptors reflect the lipophilic or hydrophobic properties of the substances, and so the octanol-water partition coefficient.

6. Adequacy of prediction: The prediction of the logarithmic octanol-water partition coefficient yields a useful result for further evaluation. However, KOWWIN estimates apply to compounds that are predominantly in a non-ionized form. For ionizable compounds, log Kow measurements can vary greatly with pH. In general, log Kow values of a compound are lower (sometimes significantly) when it exists predominantly in the ionized form as compared to existing primarily in the non-ionized form. At environmental relevant pH, the substance 2,7 Naphthalenedisulfonic acid, 3,3'-[1,2-ethenediylbis[(3-sulfo-4,1-  phenylene) azo]]bis[5-amino-4-hydroxy-, compound with 2,2',2''-nitrilotris[ethanol] (1:6) exists predominantly in the dissociated form. At pH 4 to 9, the substance will be deprotonated resulting in the corresponding anion. Therefore, it can be assumed that the realistic log Kow value of the substance is significantly lower than the value calculated by KOWWIN. Additionally, measured octanol-water partition coefficient values of ionized structural analogues show, that the log Kow of these substances is significantly < 0 (see table 2). Therefore, a value of ≤ 0 is a realistic estimation of octanol-water partition coefficient of the substance 2,7 Naphthalenedisulfonic acid, 3,3'-[1,2-ethenediylbis[(3-sulfo-4,1-  phenylene) azo]]bis[5-amino-4-hydroxy-, compound with 2,2',2''-nitrilotris[ethanol] (1:6).Therefore the predicted value can be considered reliable yielding a useful result for further assessment.

Conclusions:

The QSAR determination of the logarithmic octanol-water partition coefficient for 2,7-Naphthalenedisulfonic acid, 3,3'-[1,2-ethenediylbis[(3-sulfo-4,1-phenylene)azo]]bis[5-amino-4-hydroxy-, compound with 2,2',2''-nitrilotris[ethanol] (1:6) using the model KOWWIN included in the Estimation Program Interface (EPI) Suite v4.11 revealed a value of 1.8230 of the substance. Additionally, measured octanol-water partition coefficient values of ionized structural analogues show, that the log Kow of these substances is significantly < 0. Therefore, a value of ≤ 0 is a realistic estimation of octanol-water partition coefficient of the substance 2,7-Naphthalenedisulfonic acid, 3,3'-[1,2-ethenediylbis[(3-sulfo-4,1-phenylene)azo]]bis[5-amino-4-hydroxy-, compound with 2,2',2''-nitrilotris[ethanol] (1:6). The predicted value can be considered reliable yielding a useful result for further assessment.

Executive summary:

The QSAR determination of the  logarithmic octanol-water partition coefficient for 2,7-Naphthalenedisulfonic acid, 3,3'-[1,2-ethenediylbis[(3-sulfo-4,1-phenylene)azo]]bis[5-amino-4-hydroxy-, compound with 2,2',2''-nitrilotris[ethanol] (1:6) using the model KOWWIN included in the Estimation Program Interface (EPI) Suite v4.11 revealed a value of 1.8230 of the substance. The prediction of the logarithmic octanol-water partition coefficient yields a useful result for further evaluation. However, KOWWIN estimates apply to compounds that are predominantly in a non-ionized form. For ionizable compounds, log Kow measurements can vary greatly with pH. In general, log Kow values of a compound are lower (sometimes significantly) when it exists predominantly in the ionized form as compared to existing primarily in the non-ionized form. At environmental relevant pH, the substance

2,7-Naphthalenedisulfonic acid, 3,3'-[1,2-ethenediylbis[(3-sulfo-4,1-phenylene)azo]]bis[5-amino-4-hydroxy-, compound with 2,2',2''-nitrilotris[ethanol] (1:6)

exists predominantly in the dissociated form. At pH 4 to 9, the substance will be deprotonated resulting in the corresponding anion. Therefore, it can be assumed that the realistic log Kow value of the substance is significantly lower than the value calculated by KOWWIN. Additionally, measured octanol-water partition coefficient values of ionized structural analogues show, that the log Kow of these substances is significantly < 0. Therefore, a value of ≤ 0 is a realistic estimation of octanol-water partition coefficient of the substance

2,7-Naphthalenedisulfonic acid, 3,3'-[1,2-ethenediylbis[(3-sulfo-4,1-phenylene)azo]]bis[5-amino-4-hydroxy-, compound with 2,2',2''-nitrilotris[ethanol] (1:6)

. The predicted value can be considered reliable yielding a useful result for further assessment.

Reference 3

Endpoint:

partition coefficient

Type of information:

(Q)SAR

Adequacy of study:

key study

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
Individual model KOWWIN included in the Estimation Programs Interface (EPI) Suite.

2. MODEL (incl. version number)
KOWWIN v1.68 included in EPISuite v 4.11, ©2000 - 2012

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
A SMILES NOTATION/CAS NUMBER was entered in the initial data entry screen. In the structure window, the molecular weight, structural formula and the structure of the input SMILES notation is shown.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL

a. Defined Endpoint: Octanol-water partition coefficient

b. Explicit algorithm:
The program methodology is known as an Atom/Fragment Contribution (AFC) method. KOWWIN uses a "fragment constant" methodology to predict log P. In a "fragment constant" method, a structure is divided into fragments (atom or larger functional groups) and coefficient values of each fragment or group are summed together to yield the log P estimate.
The equation is as follows: Log Kow = Sum (fini) + Sum (cjnj) + 0.229, where Sum (fini) is the summation of fi (the coefficient for each atom/fragment) times ni (the number of times the atom/fragment occurs in the structure), and (cjnj) is the summation of cj (the coefficient for each correction factor) times nj (the number of times the correction factor occurs (or is applied) in the molecule). The program requires only a chemical structure to estimate a log P. KOWWIN initially separates a molecule into distinct atom/fragments. For various types of structures, that log P estimates made from atom/fragment values alone could or needed to be improved by inclusion of substructures larger or more complex than "atoms"; hence, correction factors were added to the AFC method.

c. Descriptor selection:
As the program requires only a chemical structure to estimate a log P, KOWWIN initially separates a molecule into distinct atom/fragments. Each non-hydrogen atom (e.g. carbon, nitrogen, oxygen, sulfur, etc.) in a structure is a "core" for a fragment; the exact fragment is determined by what is connected to the atom. Several functional groups are treated as core "atoms". Connections to each core "atom" are either general or specific. For example, aromatic carbon, aromatic oxygen and aromatic sulfur atoms have nothing but general connections; i.e., the fragment is the same no matter what is connected to the atom. In contrast, the aliphatic carbon atom does not matter what is connected to -CH3, -CH2-, or -CH<, the fragment is the same; however, an aliphatic carbon with no hydrogens has two possible fragments: (a) if there are four single bonds with 3 or more carbon connections and (b) any other not meeting the first criteria. Additionally, for various types of structures, need to be improved by inclusion of substructures larger or more complex than "atoms" by adding correction factors. The correction factors have two main groupings: first, factors involving aromatic ring substituent positions and second, miscellaneous factors. In general, the correction factors are values for various steric interactions, hydrogen-bondings, and effects from polar functional substructures. Individual correction factors were selected through a tedious process of correlating the differences (between log P estimates from atom/fragments alone and measured log P values) with common substructures.

d. Defined domain of applicability: For each fragment the maximum number of instances of that fragment in any of the 2447 training set compounds and 10946 validation set compounds is located in Appendix D of the help menu of the EPISuite data entry page. The minimum and the maximum values for molecular weight are the following:
Training Set Molecluar Weights: 18.02-719.92 g/mol
Validation Set Molecular Weights: 27.03-991.15 g/mol

e. Statistical characteristics: Correlation coefficient of the total training set r² = 0.982; Correlation coefficient of the total validation set r² = 0.943.
KOWWIN has been tested on an external validation dataset of 10,946 compounds. The validation set includes a diverse selection of chemical structures that rigorously test the predictive accuracy of any model. It contains many chemicals that are similar in structure to chemicals in the training set, but also many chemicals that are different from and structurally more complex than chemicals in the training set. The average molecular weight of compounds in the validation set is 258.98 versus 199.98 for the training set.
(Training dataset includes a total of 2447 compounds)
(Validation dataset includes a total of 10946 compounds)

f. Mechanistic interpretation: The structural fragments used as descriptors reflect the lipophilic or hydrophobic properties of the substances, and so the octanol-water partition coefficient.

5. APPLICABILITY DOMAIN
a. Descriptor domains:
i. Molecular weights: With a molecular weight of 950 g/mol the substance is not within the range of the training set (18.02 - 719.92 g/mol) but in the range of the validation set (27.03 - 991.15 g/mol).
ii. Structural fragment domain: Regarding the structure of 2,7-Naphthalenedisulfonic acid, 5-amino-3-((4-(2-(4-((7-amino-1-hydroxy-3-sulfo-2-naphthalenyl)azo)-2-sulfophenyl)ethenyl)-3-sulfophenyl)azo)-4-hydroxy-, potassium salt, compound with 2,2',2''-nitrilotris(ethanol), the fragment descriptors found by the program are complete and listed in Appendix D (KOWWIN Fragment and Correction Factor descriptors). Additionally the substance is not listed in Appendix F (Compounds that exceed the Fragment & Molecular Weight Domains).
iii. Mechanism domain: NO INFORMATION AVAILABLE
iv. Metabolic domain, if relevant: NOT RELEVANT
b. Structural analogues: NO INFORMATION AVAILABLE
i. Considerations on structural analogues: NO INFORMATION AVAILABLE

6. ADEQUACY OF THE RESULT
a. Regulatory purpose: The data may be used under any regulatory purpose.
b. Approach for regulatory interpretation of the model result: If no experimental data are available, the estimated value is used to fill data gaps needed for hazard and risk assessment, classification and labelling and PBT / vPvB assessment. Further the value can be used for other calculations.
c. Outcome: The prediction of the logarithmic octanol-water partition coefficient yields a useful result for further evaluation. However, KOWWIN estimates apply to compounds that are predominantly in a non-ionized form. For ionizable compounds, log Kow measurements can vary greatly with pH. In general, log Kow values of a compound are lower (sometimes significantly) when it exists predominantly in the ionized form as compared to existing primarily in the non-ionized form. At environmental relevant pH, the substance 2,7-Naphthalenedisulfonic acid, 5-amino-3-((4-(2-(4-((7-amino-1-hydroxy-3-sulfo-2-naphthalenyl)azo)-2-sulfophenyl)ethenyl)-3-sulfophenyl)azo)-4-hydroxy-, potassium salt, compound with 2,2',2''-nitrilotris(ethanol) exists predominantly in the dissociated form. At pH 4 to 9, the substance will be deprotonated resulting in the corresponding anion. Therefore, it can be assumed that the realistic log Kow value of the substance is significantly lower than the value calculated by KOWWIN. Additionally, measured octanol-water partition coefficient values of ionized structural analogues show, that the log Kow of these substances is significantly < 0 (see table 2). Therefore, a value of ≤ 0 is a realistic estimation of octanol-water partition coefficient of the substance 2,7-Naphthalenedisulfonic acid, 5-amino-3-((4-(2-(4-((7-amino-1-hydroxy-3-sulfo-2-naphthalenyl)azo)-2-sulfophenyl)ethenyl)-3-sulfophenyl)azo)-4-hydroxy-, potassium salt, compound with 2,2',2''-nitrilotris(ethanol).
d. Conclusion: The result is considered as useful for regulatory purposes.

Guideline:

other: REACH guidance QSARs R6, May/July 2008

Principles of method if other than guideline:

Estimation Program Interface EPI-Suite version 4.11: KOWWIN for estimating the logarithmic octanol-water partition coefficient (log Kow).
The Estimation Programs Interface was developed by the US Environmental Agency's Office of Pollution Prevention and Toxics and Syracuse Research Corporation (SRC).© 2000 - 2012 U.S. Environmental Protection Agency for EPI SuiteTM (Published online in November 2012).

GLP compliance:

no

Type of method:

other: QSAR

Partition coefficient type:

octanol-water

Specific details on test material used for the study:

CAS number: 85269-32-5
EC number: 286-556-7
Empirical formula: C34H26N6O17S5
SMILES: Oc1c2c(N)cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)c1N=Nc3cc(S(=O)(=O)O)c(cc3)C=Cc4c(S(=O)(=O)O)cc(cc4)N=Nc5c(S(=O)(=O)O)cc6ccc(N)cc6c5O
Molecular weight: 950 g/mole

Type:

log Pow

Partition coefficient:

<= 0

Temp.:

20 °C

pH:

>= 4 - <= 9

Remarks on result:

other: environmental relevant pH

Validity of model:

1. Defined Endpoint: Octanol-water partition coefficient

2. Unambiguous algorithm: The molecule is separated into distinct atom/fragments using an Atom/Fragment Contribution method. Based on structure of the molecule, the following fragments were applied: Olefin carbon; Aromatic carbon; hydroxy, aromatic attach; aliphatic N, one aromatic attach; sulfonic; azol; Ring reaction -> -OH ortho to azo.The number of times of the fragments that occur in the structure of the substance applied by the program is verified.

3. Applicability domain: With a molecular weight of 950 g/mol the substance is not within the range of the training set (18.02 - 719.92) but in the range of the validation set (27.03 - 991.15).

4. Statistical characteristics: Correlation coefficient of the total training set r² = 0.982; Correlation coefficient of the total validation set r² = 0.943.

5. Mechanistic interpretation: The structural fragments used as descriptors reflect the lipophilic or hydrophobic properties of the substances, and so the octanol-water partition coefficient.

6. Adequacy of prediction: The result for

2,7-Naphthalenedisulfonic acid, 5-amino-3-((4-(2-(4-((7-amino-1-hydroxy-3-sulfo-2-naphthalenyl)azo)-2-sulfophenyl)ethenyl)-3-sulfophenyl)azo)-4-hydroxy-, potassium salt, compound with 2,2',2''-nitrilotris(ethanol)

falls within the applicability domain described above and the estimation rules applied for the substance appears appropriate. Therefore the predicted value can be considered reliable yielding a useful result for further assessment.

Conclusions:

The QSAR determination of the logarithmic octanol-water partition coefficient for 2,7-Naphthalenedisulfonic acid, 5-amino-3-((4-(2-(4-((7-amino-1-hydroxy-3-sulfo-2-naphthalenyl)azo)-2-sulfophenyl)ethenyl)-3-sulfophenyl)azo)-4-hydroxy-, potassium salt, compound with 2,2',2''-nitrilotris(ethanol) using the model KOWWIN included in the Estimation Program Interface (EPI) Suite v4.11 revealed a value of 2.7704 of the substance. Additionally, measured octanol-water partition coefficient values of ionized structural analogues show, that the log Kow of these substances is significantly < 0. Therefore, a value of ≤ 0 is a realistic estimation of octanol-water partition coefficient of the substance 2,7-Naphthalenedisulfonic acid, 5-amino-3-((4-(2-(4-((7-amino-1-hydroxy-3-sulfo-2-naphthalenyl)azo)-2-sulfophenyl)ethenyl)-3-sulfophenyl)azo)-4-hydroxy-, potassium salt, compound with 2,2',2''-nitrilotris(ethanol) . The predicted value can be considered reliable yielding a useful result for further assessment.

Executive summary:

The QSAR determination of the  logarithmic octanol-water partition coefficient for 2,7-Naphthalenedisulfonic acid, 5-amino-3-((4-(2-(4-((7-amino-1-hydroxy-3-sulfo-2-naphthalenyl)azo)-2-sulfophenyl)ethenyl)-3-sulfophenyl)azo)-4-hydroxy-, potassium salt, compound with 2,2',2''-nitrilotris(ethanol) using the model KOWWIN included in the Estimation Program Interface (EPI) Suite v4.11 revealed a value of 2.7704 of the substance. The prediction of the logarithmic octanol-water partition coefficient yields a useful result for further evaluation. However, KOWWIN estimates apply to compounds that are predominantly in a non-ionized form. For ionizable compounds, log Kow measurements can vary greatly with pH. In general, log Kow values of a compound are lower (sometimes significantly) when it exists predominantly in the ionized form as compared to existing primarily in the non-ionized form. At environmental relevant pH, the substance

2,7-Naphthalenedisulfonic acid, 5-amino-3-((4-(2-(4-((7-amino-1-hydroxy-3-sulfo-2-naphthalenyl)azo)-2-sulfophenyl)ethenyl)-3-sulfophenyl)azo)-4-hydroxy-, potassium salt, compound with 2,2',2''-nitrilotris(ethanol)

exists predominantly in the dissociated form. At pH 4 to 9, the substance will be deprotonated resulting in the corresponding anion. Therefore, it can be assumed that the realistic log Kow value of the substance is significantly lower than the value calculated by KOWWIN. Additionally, measured octanol-water partition coefficient values of ionized structural analogues show, that the log Kow of these substances is significantly < 0. Therefore, a value of ≤ 0 is a realistic estimation of octanol-water partition coefficient of the substance 2,7-Naphthalenedisulfonic acid, 5-amino-3-((4-(2-(4-((7-amino-1-hydroxy-3-sulfo-2-naphthalenyl)azo)-2-sulfophenyl)ethenyl)-3-sulfophenyl)azo)-4-hydroxy-, potassium salt, compound with 2,2',2''-nitrilotris(ethanol). The predicted value can be considered reliable yielding a useful result for further assessment.

Description of key information

The partition coefficient was estimated from QSAR calculations for the three main components of the substance and determined to be in the range of 1.82 - 3.72.  KOWWIN estimates apply to compounds that are predominantly in a non-ionized form. However, at environmental relevant pH, the substance 2-Naphthalenesulfonic acid 3,3'-[1,2-ethenediylbis[(3-sulfo-4,1-phenylene)azo]]bis[6-amino-4-hydroxy- compound with 2,2',2''-nitrilotris[ethanol] (1:4) exists predominantly in the dissociated form. In general, log Kow values of a compound are lower (sometimes significantly) when it exists predominantly in the ionized form as compared to existing primarily in the non-ionized form. Therefore, three structural analogues with experimental determined octanol-water partition coefficients were assessed.  The experimental measurements of the octanol-water partition coefficients were made at pH were the substances are ionized. Measured octanol-water partition coefficient values of these structural analogues show, that the log Kow is significantly < 0.  The log Kow was estimated to be ≤ 0 based on experimental measured values of structural analogues (ionized form at environmental relevant pH).

Key value for chemical safety assessment

Log Kow (Log Pow):

0

at the temperature of:

20 °C

Additional information

The substance is a brown-violet, crystalline solid, however, the substance is marketed in a liquid form in aqueous solution for stabilisation. The three main components add up to 70.1% (HPLC-UV analysis).

The substance consists of three main components that were used for the log Kow estimation:

Component 1: CAS 75701-34-7; 2-Naphthalenesulfonic acid 3,3'-[1,2-ethenediylbis[(3-sulfo-4,1-phenylene)azo]]bis[6-amino-4-hydroxy- compound with 2,2',2''-nitrilotris[ethanol] (1:4): LogPow = 3.7178 (calculated)

.

Component 2: CAS 75701 -36 -9; 2,7-Naphthalenedisulfonic acid, 3,3'-[1,2-ethenediylbis[(3-sulfo-4,1-phenylene)azo]]bis[5-amino-4-hydroxy-, compound with 2,2',2''-nitrilotris[ethanol] (1:6): LogPow = 1.8230 (calculated)

.

Component 3: CAS 85269-32-5; 2,7-Naphthalenedisulfonic acid, 5-amino-3-((4-(2-(4-((7-amino-1-hydroxy-3-sulfo-2-naphthalenyl)azo)-2-sulfophenyl)ethenyl)-3-sulfophenyl)azo)-4-hydroxy-, potassium salt, compound with 2,2',2''-nitrilotris(ethanol): LogPow = 2.7704 (calculated).

The log Kow of the three main components is estimated to be in the range of 1.82 - 3.72. The log Kow was estimated to be ≤ 0 based on experimental measured values of structural analogues (ionized form at environmental relevant pH).