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Administrative data

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
EPI v.4.11 (KOWWIN v1.68), US EPA

2. MODEL (incl. version number)
KOWWIN v1.68 (Atom/Fragment Contribution (AFC) method)

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
OC(c1ccccc1)CCNC

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
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. KOWWIN’s methodology is known as an Atom/Fragment Contribution (AFC) method. Coefficients for individual fragments and groups were derived by multiple regression of 2447 reliably measured log P values. KOWWIN’s "reductionist" fragment constant methodology (i.e. derivation via multiple regression) differs from the "constructionist" fragment constant methodology of Hansch and Leo (1979) that is available in the CLOGP Program (Daylight, 1995). See the Meylan and Howard (1995) journal article for a more complete description of KOWWIN’s methodology.
To estimate log P, KOWWIN initially separates a molecule into distinct atom/fragments.
It became apparent, 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. The term "correction factor" is appropriate because their values are derived from the differences between the log P estimates from atoms alone and the measured log P values. 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.

Estimation Accuracy
To be effective an estimation method must be capable of making accurate predictions for chemicals not included in the training set. Currently, KOWWIN has been tested on an external validation dataset of 10,946 compounds (compounds not included in the training set). 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.


5. APPLICABILITY DOMAIN
Currently there is no universally accepted definition of model domain. Appendix D of KOWWIN User’s Guide lists (for each fragment) the maximum number of instances of that fragment in any of the 2447 training set compounds and 10946 validation set compounds (the minimum number of instances is of course zero, since not all compounds had every fragment). The minimum and maximum values for molecular weight are the following:

Training Set Molecular Weights:
Minimum MW: 18.02
Maximum MW: 719.92
Average MW: 199.98

Validation Molecular Weights:
Minimum MW: 27.03
Maximum MW: 991.15
Average MW: 258.98

6. ADEQUACY OF THE RESULT
The estimate value has been generated by a valid model. The model is applicable to α-[2-(methylamino)ethyl]benzyl alcohol with the necessary level of reliability and is sufficiently relevant for the regulatory purpose.

Data source

Reference
Reference Type:
other: QSAR
Title:
EPI Suite Version 4.11
Year:
2012
Bibliographic source:
KOWIN v1.68 (2015)

Materials and methods

Principles of method if other than guideline:
- Software tool(s) used including version: EPI v.4.11 (KOWWIN v1.68), US EPA
- Model(s) used: KOWWIN v1.68 (Atom/Fragment Contribution (AFC) method)
- Model description: see field 'Justification for non-standard information'
GLP compliance:
no
Type of method:
other: QSAR
Partition coefficient type:
octanol-water

Test material

1
Chemical structure
Reference substance name:
α-[2-(methylamino)ethyl]benzyl alcohol
EC Number:
255-679-8
EC Name:
α-[2-(methylamino)ethyl]benzyl alcohol
Cas Number:
42142-52-9
Molecular formula:
C10H15NO
IUPAC Name:
3-(methylamino)-1-phenylpropan-1-ol

Results and discussion

Partition coefficient
Type:
log Pow
Partition coefficient:
0.98
Remarks on result:
other: QSAR predicted data

Applicant's summary and conclusion