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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
EPISuite (v4.11)

2. MODEL (incl. version number)
KOWWIN v1.68

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
OCC(CCCCCCCCCC)CCCCCCCC
CAS No. 5333-42-6

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
A reliable QSAR model was used to calculate the partition coefficient of 2-octyldodecan-1-ol. The logKow value was calculated using the KOWWIN v1.68 module embedded within the EPISuite computer model. KOWWIN™ estimates the log octanol-water partition coefficient, log Kow, of chemicals using an atom/fragment contribution method. EPISuite and its modules (including KOWWIN) have been utilized by the scientific community for prediction of phys/chem properties and environmental fate and effect properties since the 1990’s. The program underwent a comprehensive review by a panel of the US EPA’s independent Science Advisory Board (SAB) in 2007. The SAB summarized that the EPA used sound science to develop and refine EPISuite. The SAB also stated that the property estimation routines (PERs) satisfy the Organization for Economic Cooperation and Development (OECD) principles established for quantitative structure-activity relationship ((Q)SAR) validation.
The EPISuite modules (including KOWWIN) have been incorporated into the OECD Toolbox. Inc lusion in the OECD toolbox requires specific documentation, validation and acceptability criteria and subjects EPISuite to international use, review, providing a means for receiving additional and ongoing input for improvements. KOWWIN is listed as one of the QSARs for use in predicting partition coefficient (Kow) of organic compounds values in the literature referenced in Guidance on information requirements and chemical safety assessment Chapter R.7a: Endpoint specific guidance. In summary, the EPISuite modules (including KOWWIN) have had their scientific validity established repeatedly.
https://www.epa.gov/tsca-screening-tools/epi-suitetm-estimation-program-interface

- Defined endpoint and unambiguous algorithm:
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 com plete description of KOWWIN’s methodology.

- Defined domain of applicability:
According to the KOWWIN documentation, there is currently no universally accepted definition of model domain. However, the documentation does provide information for reliability of the calculations. Estimates will possibly be less accurate for compounds that 1) have a MW outside the ranges of the training set compounds and 2) and/or that have more instances of a given fragment than the maximum for all training set compounds. It is also possible that a compound may have a functional group(s) or other structural features not represented in the training set, and for which no fragment coefficient was developed.

- Appropriate measures of goodness-of-fit and robustness and predictivity:
Total Training Set Statistics: Number of substances in dataset = 2447, Correlation coef (r2) = 0.982,
Standard deviation = 0.217, Absolute deviation = 0.159, Avg. Molecular Weight = 199.98.
Training Set Estimation Error: within ≤ 0.10 - 45.0%, within ≤0.20 - 72.5%, within ≤ 0.40 - 92.4%, with in ≤ 0.50 - 96.4%, within ≤ 0.60 - 98.2%.

5. APPLICABILITY DOMAIN
As described above, according to the KOWWIN documentation, there is currently no universally accepted definition of model domain. In general, the intended application domain for all models embedded in EPISuite is organic chemicals. Specific compound classes, besides organic chemicals, require additional correction factors. Indicators for the general applicability of the KOWWIN model a re the molecular weight of the target substance and the identified number of individual fragments in comparison to the training set. The training set molecular weights are within the range of 18.02 - 719.92 with an average molecular weight of 199.98 (Validation set molecular weights: 27.03 - 991.15 a nd average of 258.98).
The molecular weight of 2-octyldodecan-1-ol is 298.56 , which falls within the range of both, the training set and the validation set.
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) are available in the model documentation. The following numbers of fragments were found in the target chemical, the respective maximum training set numbers for each fragment are given in the last column:

TYPE | NUM | LOGKOW FRAGMENT DESCRIPTION | COEFF | VALUE | MAx. number training set (validation set)
-------+-----+--------------------------------------------+---------+--------
Frag | 2 | -CH3 [aliphatic carbon] | 0.5473 | 1.0946 | 13 (20)
Frag | 17 | -CH2- [aliphatic carbon] | 0.4911 | 8.3487 | 18 (28)
Frag | 1 | -CH [aliphatic carbon] | 0.3614 | 0.3614 | 16 (23)
Frag | 1 | -OH- [hydoxy, aliphatic attach] | -1.4086 | -1.4086 | 6 (9)
Const Equation Constant | 0.2290

Out of the four identified fragments, none did exceed the maximum number found in the training set substances, as well as in the validation set.
In addition to the fragment identification, no correction factors had to be applied. As a result 2-octyldodecan-1-ol would not be considered outside the estimation domain.

6. ADEQUACY OF THE RESULT
Based on the experimental difficulties for certain compound classes, the KOWWIN calculations are fit for the purpose of identifiying a certain partition coefficient range. In case of the underlying target substance, the calculated logKow is in a similar range (>8) as the obtained experimental results and, hence, adequate for the purpose of classification and labelling and/or risk assessment.
The estimated logKow (calculation based on fragment contribution) was 8.63.
The representative SMILES notation used for the predictions was: OCC(CCCCCCCCCC)CCCCCCCC
The KOWWIN predicted partition coefficient value is considered valid and fit for purpose.

7. BIBLIOGRAPHY
Documentation of the KOWWIN model is provided in the following references:
Akamatsu, M., Y. Yoshida, H. Nakamura, M. Asao, H. Iwamura and T. Fujita. 1989. Hydrophobicity of di- and tripeptides having un-ionizable side-chains and correlation with substituent and structural parameters. Quant. Struct.-Act. Relat. 8: 195-203.
Akamatsu, M., S.I. Okutani, K. Nakao, N.J. Hong and T. Fujita. 1990. Hydrophobicity of N-acetyl, di and tripeptide amides having unionizable side chains and correlation with substituent and structural parameters. Quant. Struct.Act. Relat., 9: 189-194.
Akamatsu, M. and T. Fujita. 1992. Quantitative analyses of hydrophobicity of di- to pentapeptides having nonionizable side chains with substituent and structural parameters, J. Pharm. Sci. 81: 164-174.
Barbato, F., G. Caliendo, M.I. LaRotonda, P. Morrica, C. Silipo and A. Vittoria. 1990. Relationships between octanol-water partition data, chromatographic indexes and their dependence on pH in a set of beta-adrenoceptor blocking agents. Farmaco, 45:, 647-663.
Daylight. 1995. CLOGP Program. Daylight Chemical Information Systems. Von Karman Ave.,Irvine, CA 92715. (web-site as of March 2008: http://www.daylight.com/)
Hansch, C and Leo, A.J. 1979. Substituent Constants for Correlation Analysis in Chemistry and Biology; Wiley: New York, 1979.
Hansch. C., A. Leo and D. Hoekman. 1995. Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Professional Reference Book. Washington, DC: American Chemical Society.
Howard, P.H. and M. Neal. 1992. Dictionary of Chemical Names and Synonyms. Lewis Publishers, Chelsea, MI (ISBN 0-87371-396-6)
Meylan, W.M. and P.H. Howard. 1995. Atom/fragment contribution method for estimating octanolwater partition coefficients. J. Pharm. Sci. 84: 83-92.
Meylan, W.M. P.H. Howard and R.S. Boethling. 1996. Improved method for estimating water solubility from octanol/water partition coefficient. Environ. Toxicol. Chem. 15: 100-106.
Meylan, WM, Howard, PH, Boethling, RS et al. 1999. Improved Method for Estimating Bioconcentration / Bioaccumulation Factor from Octanol/Water Partition Coefficient, Environ. Toxicol. Chem. 18(4): 664-672.
Meylan, W.M. and P.H. Howard. 2005. Estimating octanol-air partition coefficients with octanol-water partition coefficients and Henry's law constants. Chemosphere 61:640-644.
Morrison, R.T. and R.N. Boyd. 1973. Organic Chemistry. Third Ed., Boston, MA: Allyn and Bacon, Inc. p. 1133-38.
Nieder, M., W. Stroesser and J. Kappler. 1987. Octanol/buffer partition coefficients of different betablockers", Arzneim.- Forsch., 37: 549-550.
Ribo, J.M. 1988. The octanol/water partition coefficient of the herbicide chlorsulfuron as a function of pH. Chemosphere 17: 709-15.

Principles of method if other than guideline:
log octanol-water partition coefficient (log KOW) estimation using an atom/fragment contribution method
GLP compliance:
no
Type of method:
other: calculation
Partition coefficient type:
octanol-water
Key result
Type:
log Pow
Partition coefficient:
8.63
Temp.:
20 °C
pH:
ca. 7

Description of key information

Log Pow = 8.63 (calculated with KOWWIN from EPI Suite)

Key value for chemical safety assessment

Log Kow (Log Pow):
8.63
at the temperature of:
20 °C

Additional information

Due to its hydrophobic structure the experimental determination of the logPow of 2-octyldodecan-1-ol is not possible as no sufficiently sensitive analytical method is available.

According to REACH Guidance on information requirements and chemical safety assessment Chapter R.7.1.8 highly accurate measurements of high log Pow are not possible and no standard method is available for log Pow > 8.3.

To determine a reliable logPow the value was calculated using the KOWWIN v1.68 software from EPI Suite. With the molecular weight of 298.56 2-octyldodecan-1-ol falls within the ranges of the log KOWWIN model is valid for of 18.02 to 719.92 (for the training set) and 27.03 to 991.15 (for the validation set).

For 2-octyldodecan-1-ol, the model accounts for each fragment, therefore also for this aspect the substance fits within the domain:

-------+-----+--------------------------------------------+---------+----------------------------------------------------

TYPE | NUM | LOGKOW FRAGMENT DESCRIPTION | COEFF | VALUE

-------+-----+--------------------------------------------+---------+----------------------------------------------------

Frag | 2 | -CH3 [aliphatic carbon] | 0.5473 | 1.0946

Frag | 17 | -CH2- [aliphatic carbon] | 0.4911 | 8.3487

Frag | 1 | -CH [aliphatic carbon] | 0.3614 | 0.3614

Frag | 1 | -OH [hydroxy, aliphatic attach] |-1.4086 | -1.4086

Const | | Equation Constant | | 0.2290

-------+-----+--------------------------------------------+---------+---------------------------------------------------

Log Kow = 8.6251

The calculated logPow for 2-octaldodecan-1-ol is 8.63.