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Partition coefficient

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Reference
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 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 194.19 g/mol the substance is within the range of the training set (18.02 - 719.92 g/mol) as well as in the range of the validation set (27.03 - 991.15 g/mol).
ii. Structural fragment domain: Regarding the structure of 1,3-Diacetoxybenzene, 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.
Qualifier:
according to
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
Type:
log Pow
Partition coefficient:
1.87
Remarks on result:
other: Calculated value is based on ambient temperature and neutral pH conditions

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: -CH3 [aliphatic carbon]; Aromatic carbon; -C(=O)O [ester, aliphatic attach]; Ring reaction --> -O-CO/-O-CO. 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 194.19 g/mol the substance is within the range of the training set (18.02 - 719.92) as well as 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 1,3-Diacetoxybenzene 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 1,3-Diacetoxybenzene using the model KOWWIN included in the Estimation Program Interface (EPI) Suite v4.11 revealed a value of 1.87 of the substance. The predicted value can be considered reliable yielding a useful result for further assessment.
Executive summary:

The logarithmic octanol-water partition coefficient (log Kow) for 1,3-Diacetoxybenzene was predicted using the QSAR calculation of the Estimation Program Interface (EPI) Suite v 4.11. The log Kow was estimated to be 1.87. The predicted value can be considered reliable yielding a useful result for further assessment.

Description of key information

The logarithmic octanol-water partition coefficient (log Kow) for 1,3-Diacetoxybenzene was predicted using the QSAR calculation of the Estimation Program Interface (EPI) Suite v 4.11. The log Kow was estimated to be 1.87. The predicted value can be considered reliable yielding a useful result for further assessment.

Key value for chemical safety assessment

Log Kow (Log Pow):
1.87

Additional information

Calculated value is based on ambient temperature and neutral pH conditions