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Endpoint:
water solubility
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
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 Suite v4.11

2. MODEL (incl. version number)
WATERNT v1.01

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
Chem: 1,2-Benzenedicarboxylic acid, di-C8-10-alkyl esters
CAS: 71662-46-9
SMILES: CCCCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC;
CCCCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCCCC;
CCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
A reliable QSAR model was used to calculate the water solubility of the isomers of 1,2-Benzenedicarboxylic acid, di-C8-10-alkyl esters (CAS 71662-46-9). The water solubilities were calculated using the WATERNT v1.01 module embedded within the EPISuite computer model. The estimation methodology of the WATERNT Program (estimation of water solubility by fragments) was initially described in a document prepared for the US EPA (Meylan, 1995).
EPISuite and its modules (including WATERNT) 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 WATERNT) 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. WATERNT is listed as one of the QSARs for use in predicting the water solubility of organic compounds (Guidance on information requirements and chemical safety assessment Chapter R.7a: Endpoint specific guidance). In summary, the EPISuite modules (including WATERNT) have had their scientific validity established repeatedly. https://www.epa.gov/tsca-screening-tools/epi-suitetm-estimation-program-interface
- Defined endpoint and unambiguous algorithm:
WATERNT estimates the water solubility of organic compounds at 25oC. WATERNT requires only a chemical structure to estimate a solubility. The estimation methodology is based upon a "fragment constant" method very similar to the method of the KOWWIN Program which estimates octanol-water partition coefficients. WATERNT initially separates a molecule into distinct atom/fragments. In general, 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.
Coefficients for individual fragments and groups in WATERNT were derived by multiple regression of 1000 reliably measured water solubility values.
Results of two successive multiple regressions (first for atom/fragments and second for correction factors) yield the following general equation for estimating water solubility of any organic compound:



log WatSol (moles/L) = Σ(fi * ni) + Σ(cj * nj) + 0.24922

(n = 1128, correlation coef (r2) = 0.940, standard deviation = 0.537, avg deviation = 0.355)
where Σ(fi * ni) 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 Σ(cj * nj) is the summation of cj (the coefficient for each correction factor) times nj (the number of times the correction factor is applied in the molecule).

- Defined domain of applicability:
According to the WATERNT 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 range of the training set compounds and/or 2) 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 (MW only): Number of substances in dataset = 1128, Correlation coef (r2) = 0.940, Std. dev. = 0.537, Avg. dev. = 0.355.
Training Set Estimation Error: within ≤ 0.20 - 47.4%, within ≤0.40 - 73.2%, within ≤ 0.50 – 79.7%, within ≤ 0.60 - 83.7%, within ≤ 0.80 - 90.2%, within ≤ 0.90 - 93.3%.

- Mechanistic interpretation: Preliminary results of multiple-linear regression of fragment constants and correction factors indicate that the methodology from this study (which is analogous to the KOWWIN methodology) can accurately predict water solubility.
5. APPLICABILITY DOMAIN
As described above, according to the WATERNT 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 WATERNT model are 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 30.30 – 627.62, with an average MW of 187.73.
The molecular weight range of the 1,2-Benzenedicarboxylic acid, di-C8-10- alkyl ester isomers is 390 - 447, which falls within the range of the training set.
For each of the three isomers, an experimental water solubility database match was located. For the C8-C8 and the C10-C10 isomers an exact much was retrieved.
The maximum number of each fragment in any of the training set compounds are available in the model documentation. The following (max.) numbers of fragments were found in the target chemical, the respective maximum training set numbers for each fragment are given in the last column:

---------------------------------- WATERNT (v1.01) Results ------------------------
-------+-----+--------------------------------------------+----------+--------- +---------
TYPE | NUM | WATER SOLUBILITY FRAGMENT DESCRIPTION | COEFF | VALUE | Max. NUM training set
-------+-----+--------------------------------------------+----------+--------- +---------
Frag | 2 | -CH3 [aliphatic carbon] |-0.3213 | -0.6425 | 6
Frag | 18 | -CH2- [aliphatic carbon] |-0.5370 | -9.6663 | 14
Frag | 4 | Aromatic Carbon (C-H type) |-0.3359 | -1.3435 | 15
Frag | 2 | -C(=O)O [ester, aromatic attach] | 0.7006 | 1.4012 | 2
Frag | 2 | Aromatic Carbon (C-substituent type) |-0.5400 | -1.0799 | 12
Const | | Equation Constant | | 0.2492
-------+-----+--------------------------------------------+----------+--------- +---------



C8-C10 isomer
SMILES : CCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC
MOL FOR: C26 H42 O4
MOL WT : 418.62
Water Sol (WATERNT v1.01 est): 0.000041114 mg/l

Experimental Database Structure Match:
Name : DINONYL PHTHALATE
CAS Num : 000084-76-4
Exp WSol : 0.00013 mg/L (20 deg C)
Exp Ref : LETINSKI,DJ ET AL. (2002)



C10-C10 isomer
SMILES : CCCCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCCCC
MOL FOR: C28 H46 O4
MOL WT : 446.68
Water Sol (WATERNT v1.01 est): 0.0000036993 mg/L

Experimental Database Structure Match:
Name : DIDECYL PHTHALATE
CAS Num : 000084-77-5
Exp WSol : 0.00022 mg/L (25 deg C)
Exp Ref : ELLINGTON,JJ (1999)


C8-C8 isomer
SMILES : CCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC
MOL FOR: C24 H38 O4
MOL WT : 390.57
Water Sol (WATERNT v1.01 est): 0.00045488 mg/L

Experimental Database Structure Match:
Name : DIOCTYL PHTHALATE
CAS Num : 000117-84-0
Exp WSol : 0.022 mg/L (25 deg C)
Exp Ref : DEFOE,DL ET AL. (1990)

All three isomers are within the MW range of the training set. The number of the “-CH2- [aliphatic carbon]” fragment exceeds the maximum number of this fragment in the raining set compounds for two of the isomers. This is not considered to impact the reliability of the results, as the calculated values are in line with the experimental data for the individual isomers.
As a result 1,2-Benzenedicarboxylic acid, di-C8-10-alkyl esters would not be considered outside the estimation domain. In addition, for two of the three isomers exact structural matches in the experimental database have been found, with water solubility values close to the QSAR results supporting the suitability of this method.

6. ADEQUACY OF THE RESULT
Based on the experimental difficulties for multi component compounds, the WATERNT calculations are fit for the purpose of identifying a certain water solubility range. In case of the underlying target substance, the calculated water solubility values for the individual isomers are in the same range as the obtained experimental results reported in the literature. Hence, the calculations are adequate for the purpose of classification and labelling and/or risk assessment.
The estimated water solubilities were <0.001 mg/l.
The representative SMILES notations used for the predictions were: CCCCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC, CCCCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCCCC, and CCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC.
The WATERNT predicted water solubility values are considered valid and fit for purpose.

7. BIBLIOGRAPHY
Documentation of the WATERNT model is provided in the following references:
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 octanol-water partition coefficients. J. Pharm. Sci. 84: 83-92.
Meylan, W.M. 1995. Preliminary Report: Water Solubility Estimation by Base Compound Modification. prepared for: Gary Thom & Robert S. Boethling, U.S. Environmental Protection Agency, Office of Pollution Prevention and Toxics, Washington, DC, USEPA Contract 68-D2-0141 (Task 3-14), September 1995; prepared by Syracuse Research Corporation, Environmental Science Center, Syracuse, NY 13210 (Charge-F0144-214) [This document (and the training and validation data sets) can be downloaded from the Internet at: http://esc.syrres.com/interkow/EpiSuiteData.htm]
Guideline:
other: REACH Guidance on QSARs R.6
Principles of method if other than guideline:
Meylan, W.M. and P.H. Howard.  1995.  Atom/fragment contribution method for estimating octanol-water partition coefficients.  J. Pharm. Sci. 84: 83-92.
Meylan, W.M.  1995.  Preliminary Report: Water Solubility Estimation by Base Compound Modification.  prepared for: Gary Thom & Robert S. Boethling, U.S. Environmental Protection Agency, Office of Pollution Prevention and Toxics, Washington, DC, USEPA Contract 68-D2-0141 (Task 3-14), September 1995; prepared by Syracuse Research Corporation, Environmental Science Center, Syracuse, NY 13210 (Charge-F0144-214) [This document (and the training and validation data sets) can be downloaded from the Internet at: http://esc.syrres.com/interkow/EpiSuiteData.htm]

 
Specific details on test material used for the study:
SMILES: CCCCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC, CCCCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCCCC, and CCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC.
Key result
Water solubility:
0 mg/L
Conc. based on:
other: Solubility of C8-C10 isomer
Temp.:
25 °C
Remarks on result:
other: QSAR (WATERNT v1.01)
Key result
Water solubility:
0 mg/L
Conc. based on:
other: Solubility of C10-C10 isomer
Temp.:
25 °C
Remarks on result:
other: QSAR (WATERNT v1.01)
Key result
Water solubility:
0 mg/L
Conc. based on:
other: Solubility of C8-C8 isomer
Temp.:
25 °C
Remarks on result:
other: QSAR (WATERNT v1.01)

WATERNT (v1.01) predicted water solubilities for the three isomers as 0.000041114 mg/l (8 -10), 0.0000036993 mg/L (10 -10), and 0.00045488 mg/L (8 -8).

C8 -C10 isomer

Water Sol (WATERNT v1.01 est): 4.1114e-005 mg/l

SMILES : CCCCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC

MOL FOR: C26 H42 O4

MOL WT : 418.62

---------------------------------- WATERNT (v1.01) Results ------------------------

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

TYPE  | NUM |    WATER SOLUBILITY FRAGMENT DESCRIPTION   |  COEFF   |  VALUE  

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

Frag  |  2  |  -CH3    [aliphatic carbon]                |-0.3213   | -0.6425

Frag  | 16  |  -CH2-   [aliphatic carbon]                |-0.5370   | -8.5923

Frag  |  4  |  Aromatic Carbon  (C-H type)               |-0.3359   | -1.3435

Frag  |  2  |  -C(=O)O  [ester, aromatic attach]         | 0.7006   |  1.4012

Frag  |  2  |  Aromatic Carbon  (C-substituent type)     |-0.5400   | -1.0799

Const |     |  Equation Constant                         |          |  0.2492

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

                            Log Water Sol (moles/L) at 25 dec C  =  -10.0078

                            Water Solubility (mg/L) at 25 dec C  =4.1114e-005

----------------Experimental Water Solubility Database Match----------------  

Name     :  DINONYL PHTHALATE  

CAS Num  :  000084-76-4  

Exp WSol :  0.00013 mg/L (20 deg C)  

Exp Ref  :  LETINSKI,DJ ET AL. (2002)

C10 -C10 isomer

Water Sol (WATERNT v1.01 est): 3.6993e-006 mg/L

SMILES : CCCCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCCCC

MOL FOR: C28 H46 O4

MOL WT : 446.68

---------------------------------- WATERNT (v1.01) Results ------------------------

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

TYPE  | NUM |    WATER SOLUBILITY FRAGMENT DESCRIPTION   |  COEFF   |  VALUE  

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

Frag  |  2  |  -CH3    [aliphatic carbon]                |-0.3213   | -0.6425

Frag  | 18  |  -CH2-   [aliphatic carbon]                |-0.5370   | -9.6663

Frag  |  4  |  Aromatic Carbon  (C-H type)               |-0.3359   | -1.3435

Frag  |  2  |  -C(=O)O  [ester, aromatic attach]         | 0.7006   |  1.4012

Frag  |  2  |  Aromatic Carbon  (C-substituent type)     |-0.5400   | -1.0799

Const |     |  Equation Constant                         |          |  0.2492

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

                            Log Water Sol (moles/L) at 25 dec C  =  -11.0819

                            Water Solubility (mg/L) at 25 dec C  =3.6993e-006

----------------Experimental Water Solubility Database Match----------------

Name     :  DIDECYL PHTHALATE  

CAS Num  :  000084-77-5  

Exp WSol :  0.00022 mg/L (25 deg C)  

Exp Ref  :  ELLINGTON,JJ (1999)

C8 –C8 isomer

Water Sol (WATERNT v1.01 est): 0.00045488 mg/L

SMILES : CCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC

MOL FOR: C24 H38 O4

MOL WT : 390.57

---------------------------------- WATERNT (v1.01) Results ------------------------

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

TYPE  | NUM |    WATER SOLUBILITY FRAGMENT DESCRIPTION   |  COEFF   |  VALUE  

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

Frag  |  2  |  -CH3    [aliphatic carbon]                |-0.3213   | -0.6425

Frag  | 14  |  -CH2-   [aliphatic carbon]                |-0.5370   | -7.5183

Frag  |  4  |  Aromatic Carbon  (C-H type)               |-0.3359   | -1.3435

Frag  |  2  |  -C(=O)O  [ester, aromatic attach]         | 0.7006   |  1.4012

Frag  |  2  |  Aromatic Carbon  (C-substituent type)     |-0.5400   | -1.0799

Const |     |  Equation Constant                         |          |  0.2492

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

                             Log Water Sol (moles/L) at 25 dec C  =   -8.9338

                             Water Solubility (mg/L) at 25 dec C  =0.00045488

----------------Experimental Water Solubility Database Match----------------

Experimental Water Solubility Database Match:

 Name     :  DIOCTYL PHTHALATE

 CAS Num  :  000117-84-0

 Exp WSol :  0.022 mg/L (25 deg C)

 Exp Ref  :  DEFOE,DL ET AL. (1990)

Endpoint:
water solubility
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
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 Suite v4.11

2. MODEL (incl. version number)
WSKOWWIN v1.43

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
Chem: 1,2-Benzenedicarboxylic acid, di-C8-10-alkyl esters
CAS: 71662-46-9
SMILES: CCCCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC;
CCCCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCCCC;
CCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
A reliable QSAR model was used to calculate the water solubility of the isomers of 1,2-Benzenedicarboxylic acid, di-C8-10-alkyl esters (CAS 71662-46-9). The water solubilities were calculated using the WSKOWWIN v1.43 module embedded within the EPISuite computer model. WSKOWWIN™ estimates the water solubility (WSol) of an organic compound using the compounds log octanol-water partition coefficient (Kow). EPISuite and its modules (including WSKOWWIN) 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 WSKOWWIN) 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. WSKOWWIN is listed as one of the QSARs for use in predicting the water solubility of organic compounds (Guidance on information requirements and chemical safety assessment Chapter R.7a: Endpoint specific guidance). In summary, the EPISuite modules (including WSKOWWIN) have had their scientific validity established repeatedly. https://www.epa.gov/tsca-screening-tools/epi-suitetm-estimation-program-interface
- Defined endpoint and unambiguous algorithm:
WSKOWWIN estimates water solubility for any compound with one of two possible equations. The equations, given in Meylan and Howard (1994a) and Meylan et al. (1996) are:
log S (mol/L) = 0.796 - 0.854 log Kow - 0.00728 MW + ΣCorrections
log S (mol/L) = 0.693 - 0.96 log Kow - 0.0092(Tm-25) - 0.00314 MW + ΣCorrections

(MW - molecular weight, Tm - melting point in deg C, ΣCorrections -Summation of Corrections)
If a measured melting point is available, that second equation is used; otherwise, the first equation is used.

- Defined domain of applicability:
According to the WSKOWWIN 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, logKow and/or water solubility outside the ranges of the 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 (MW only): Number of substances in dataset = 1450, Correlation coef (r2) = 0.934, Std. dev. = 0.585, Abs. dev. = 0.313.
Training Set Estimation Error: within ≤ 0.20 - 42.0%, within ≤0.40 - 69.5%, within ≤ 0.50 – 79.1%, within ≤ 0.60 - 86.0%, within ≤ 0.80 - 93.9%, within ≤ 0.90 - 97.4%.

- Mechanistic interpretation: At present, the most practical means of estimating water solubility involves regression-derived correlations using log Kow (Yalkowsky and Banerjee, 1992).
5. APPLICABILITY DOMAIN
As described above, according to the WSKOWWIN 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 WSKOWWIN model are the molecular weight of the target substance, the logKow, the water solubility and the identified number of individual fragments in comparison to the training set. The training set molecular weights are within the range of 27.03 – 627.62.
The molecular weight range of the 1,2-Benzenedicarboxylic acid, di-C8-10- alkyl ester isomers is 390 - 447, which falls within the range of the training set.
For each of the three isomers, an experimental water solubility database match was located. For the C8-C8 and the C10-C10 isomers an exact much was retrieved.

C8-C10 isomer
SMILES : CCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC
MOL FOR: C26 H42 O4
MOL WT : 418.62
Water Sol (WSKOWWIN v1.43): 1.735e-005 mg/L
Log Kow(version 1.69 estimate) used for calculation: 9.52

Experimental Database Structure Match:
Name : DINONYL PHTHALATE
CAS Num : 000084-76-4
Exp WSol : 0.00013 mg/L (20 deg C)
Exp Ref : LETINSKI,DJ ET AL. (2002)



C10-C10 isomer
SMILES : CCCCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCCCC
MOL FOR: C28 H46 O4
MOL WT : 446.68
Water Sol (WSKOWWIN v1.43): 2.921e-005 mg/L
Log Kow(version 1.69 estimate) used for calculation: 10.50

Experimental Database Structure Match:
Name : DIDECYL PHTHALATE
CAS Num : 000084-77-5
Exp WSol : 0.00022 mg/L (25 deg C)
Exp Ref : ELLINGTON,JJ (1999)


C8-C8 isomer
SMILES : CCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC
MOL FOR: C24 H38 O4
MOL WT : 390.57
Water Sol (WSKOWWIN v1.43): 0.0001783 mg/L
Log Kow(version 1.69 estimate) used for calculation: 8.54

Experimental Database Structure Match:
Name : DIOCTYL PHTHALATE
CAS Num : 000117-84-0
Exp WSol : 0.022 mg/L (25 deg C)
Exp Ref : DEFOE,DL ET AL. (1990)

All three isomers are within the MW range of the training set and none exceeds the water solubility range of 4 x 10-7 mg/L to completely soluble. No correction factors were applied and all three isomers are outside of the logKow range (-3.89 to 8.27). This is not considered to impact the reliability of the results, as the calculated values are in line with the experimental data for the individual isomers. For two of the three isomers exact structural matches in the experimental database have been found, with water solubility values close to the QSAR results supporting the suitability of this method.As a result 1,2-Benzenedicarboxylic acid, di-C8-10-alkyl esters would not be considered outside the estimation domain.

6. ADEQUACY OF THE RESULT
Based on the experimental difficulties for multi component compounds, the WSKOWWIN calculations are fit for the purpose of identifying a certain water solubility range. In case of the underlying target substance, the calculated water solubility values for the individual isomers are in the same range as the obtained experimental results reported in the literature. Hence, the calculations are adequate for the purpose of classification and labelling and/or risk assessment.
The estimated water solubilities (calculation based on logKow values) were <0.0001 mg/l.
The representative SMILES notations used for the predictions were: CCCCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC, CCCCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCCCC, and CCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC.
The WSKOWWIN predicted water solubility values are considered valid and fit for purpose.
7. BIBLIOGRAPHY
Documentation of the WSKOWWIN model is provided in the following references:

Aldrich. 1992. Aldrich Catalog Handbook of Fine Chemicals. Milwaukee, WI: Aldrich Chemical Co., Inc.
Hansch, C and A. Leo. 1985. MEDCHEM Project. Issue No. 26. Claremont, CA: Pomona College.
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)
Howard, P.H., G.W. Sage, A. LaMacchia and A. Colb. 1982. The development of an environmental fate data base. J. Chem. Inf. Comput. Sci. 22: 38 ... on-line at: http://www.syrres.com/esc/efdb.htm
Howard, P.H., A.E. Hueber, B.C. Mulesky, J.C. Crisman, W.M. Meylan, E. Crosbie, D.A. Gray, G.W. Sage, K. Howard, A.
Kochetkov,A et al. 2001. Air-water partition constants for volatile methyl siloxanes. Environ. Toxicol. Chem. 20:2184-88.
LaMacchia, R. Boethling and R. Troast. 1986. BIOLOG, BIODEG, and fate/expos: new files on microbial degradation and toxcity as well as environmental fate/exposure of chemicals. Environ. Toxicol. Chem 5: 977 ... on-line at: http://www.syrres.com/esc/efdb.htm
Lide, D.R. (editor-in-chief). 1990. CRC Handbook of Chemistry and Physics. 71st edition. Boca Raton, FL: CRC Press.
Meylan, W.M. and P.H. Howard. 1994a. Upgrade of PCGEMS Water Solubility Estimation Method (May 1994 Draft). prepared for Robert S. Boethling, U.S. Environmental Protection Agency, Office of Pollution Prevention and Toxics, Washington, DC; prepared by Syracuse Research Corporation, Environmental Science Center, Syracuse, NY 13210.
Meylan, W.M. and P.H. Howard. 1994b. Validation of Water Solubility Estimation Methods Using Log Kow for Application in PCGEMS & EPI (Sept 1994, Final Report). prepared for Robert S. Boethling, U.S. Environmental Protection Agency, Office of Pollution Prevention and Toxics, Washington, DC; prepared by Syracuse Research Corporation, Environmental Science Center, Syracuse, NY 13210.
Meylan, W.M. and P.H. Howard. 1995. Atom/Fragment contribution method for estimating octanol-water 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.
Sangster, J. 1993. LOGKOW DATABANK. A databank of evaluated octanol-water partition coefficients (Lopg P) on microcomputer diskette. Montreal, Quebec, Canada: Sangster Research Laboratories ... Currently available on-line Internet at: http://logkow.cisti.nrc.ca/logkow/index.jsp
SRC. 1994. PHYSPROP© Database. Physical/chemical property database. Syracuse, NY: Syracuse Research Corp, Environmental Science Center (P.H. Howard) ... on-line at: http://www.syrres.com/esc/databases.htm
SRC. 2000. KOWWIN - The Octanol-Water Partition Coefficient Program, KOWWIN Version 1.67. PC-Computer software. Syracuse Research Corporation, Environmental Chemistry Center, 6225 Running Ridge Road, North Syracuse, NY 13212.
Yalkowsky, S.H and R.M. Dannenfelser. 1990. AQUASOL dATAbASE of Aqueous Solubility. Fifth edition. Tucson, AZ: University of Arizona, College of Pharmacy ... Current book version: Yalkowsky,FH & He,Y. 2003. Handbook of Aqueous Solubility Data. CRC Press, Boca Raton, FL (ISBN 0-8493-1532-8)
Guideline:
other: REACH Guidance on QSARs R.6
Principles of method if other than guideline:
Water Solubility Estimate from Log Kow (WSKOW v1.42)
- Meylan, W.M. and P.H. Howard.    1994a.    Upgrade of PCGEMS Water Solubility Estimation Method (May 1994 Draft).  prepared for Robert S. Boethling, U.S. Environmental Protection Agency, Office of Pollution Prevention and Toxics, Washington, DC;  prepared by Syracuse Research Corporation, Environmental Science Center, Syracuse, NY 13210.
- Meylan, W.M. and P.H. Howard.    1994b.   Validation of Water Solubility Estimation Methods Using Log Kow for Application in PCGEMS & EPI (Sept 1994, Final Report).  prepared for Robert S. Boethling, U.S. Environmental Protection Agency, Office of Pollution Prevention and Toxics, Washington, DC;  prepared by Syracuse Research Corporation, Environmental Science Center, Syracuse, NY 13210.
- 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.
Specific details on test material used for the study:
SMILES: CCCCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC, CCCCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCCCC, and CCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC.
Key result
Water solubility:
0 mg/L
Conc. based on:
other: Solubility of C8-C10 isomer
Temp.:
25 °C
Remarks on result:
other: QSAR (WSKOWWIN v1.43)
Key result
Water solubility:
0 mg/L
Conc. based on:
other: Solubility of C10-C10 isomer
Temp.:
25 °C
Remarks on result:
other: QSAR (WSKOWWIN v1.43)
Key result
Water solubility:
0 mg/L
Conc. based on:
other: Solubility of C8-C8 isomer
Temp.:
25 °C
Remarks on result:
other: QSAR (WSKOWWIN v1.43)

WSKOWWIN (v1.43) predicted water solubilities for the three isomers in the range of 0.00001735 mg/l (C8 -C10), 0.00002921 mg/L (C10 -C10) ,and 0.00045488 mg/L (C8 -C8).

C8 -C10 isomer

Water Sol (WSKOWWIN v1.43): 0.00001735 mg/L  

SMILES : CCCCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC

MOL FOR: C26 H42 O4

MOL WT : 418.62

---------------------------------- WSKOWWIN v1.43 Results ------------------------

Log Kow  (estimated)  :  9.52

Log Kow (experimental):  not available from database

Log Kow used by Water solubility estimates:  9.52

Equation Used to Make Water Sol estimate:

 Log S (mol/L) = 0.796 - 0.854 log Kow - 0.00728 MW + Correction

 No Applicable Correction Factors

 Log Water Solubility  (in moles/L) :  -10.383

 Water Solubility at 25 deg C (mg/L):  1.735e-005

----------------Experimental Water Solubility Database Match----------------  

Name     :  DINONYL PHTHALATE  

CAS Num  :  000084-76-4  

Exp WSol :  0.00013 mg/L (20 deg C)  

Exp Ref  :  LETINSKI,DJ ET AL. (2002)

C10 -C10 isomer

Water Sol (WSKOWWIN v1.43): 0.00002921 mg/L  

SMILES : CCCCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCCCC

MOL FOR: C28 H46 O4

MOL WT : 446.68

---------------------------------- WSKOWWIN v1.43 Results ------------------------

Log Kow  (estimated)  :  10.50

Log Kow (experimental):  9.05

  Cas No: 000084-77-5

  Name  : DIDECYL PHTHALATE

  Refer : ELLINGTON,JJ (1999)

Log Kow used by Water solubility estimates:  9.05

Equation Used to Make Water Sol estimate:

 Log S (mol/L) = 0.796 - 0.854 log Kow - 0.00728 MW + Correction

 No Applicable Correction Factors

 Log Water Solubility  (in moles/L) :  -10.185

 Water Solubility at 25 deg C (mg/L):  2.921e-005

----------------Experimental Water Solubility Database Match----------------

Name     :  DIDECYL PHTHALATE  

CAS Num  :  000084-77-5  

Exp WSol :  0.00022 mg/L (25 deg C)  

Exp Ref  :  ELLINGTON,JJ (1999)

C8 –C8 isomer

Water Sol (WSKOWWIN v1.43): 0.0001783 mg/L

SMILES : CCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC

MOL FOR: C24 H38 O4

MOL WT : 390.57

---------------------------------- WSKOWWIN v1.43 Results ------------------------

Log Kow used by Water solubility estimates:  8.54

Equation Used to Make Water Sol estimate:

  Log S (mol/L) = 0.796 - 0.854 log Kow - 0.00728 MW + Correction

  No Applicable Correction Factors

  Log Water Solubility  (in moles/L) :  -9.340

  Water Solubility at 25 deg C (mg/L):  0.0001783

----------------Experimental Water Solubility Database Match----------------

Experimental Water Solubility Database Match:

 Name     :  DIOCTYL PHTHALATE

 CAS Num  :  000117-84-0

 Exp WSol :  0.022 mg/L (25 deg C)

 Exp Ref  :  DEFOE,DL ET AL. (1990)

Endpoint:
water solubility
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
other: ASTM Standard test method for measurements of aqueous solubility (1987)
Deviations:
yes
Remarks:
The water solubility was determined by turbidity inflection. This solubility determination procedure is similar to one of the methods recommended by ASTM.
Principles of method if other than guideline:
- Principle of test:
The water solubility was determined by turbidity inflection. This solubility determination procedure is similar to one of the methods recommended by ASTM.
- Short description of test conditions:
The turbidity inflection method for determining solubility was based on the Tyndall effect. A 19-liter stainless steel reservoir was filled with type I distilled-deionized water. A stock solution was made by adding chemical and mixing for 5 min with a high-speed router-blender. This stock solution was systematically increased in concentration by adding equal increments of chemical and bliending them for 5 min between each chemical addition. Samples were taken after each chemical addition for turbidity and chemical measurements. Triplicate sample tubes containing 30 ml each were placed in a 2-liter ultrasonic cleaning bath for 2 min to promote uniform mixing of the resulting solutions as well as to disperse molecular aggregates as emulsions began to form. Dissolved gases which interfered with turbidity readings were driven from these solutions using sonification. The samples were then placed in a Hach Turbidity Meter, Model No. 2100A for reading Nephelometric Turbidity Units (NTU).
Type of method:
other: turbidity inflection
Specific details on test material used for the study:
Test material was synthesized for the study at Oak Ridge National Laboratory.
Key result
Water solubility:
0.02 mg/L
Conc. based on:
test mat.
Remarks on result:
other: Solubilty for di-n-octyl phthalate

Description of key information

The experimental value determined by Defoe et al. (1990) is used as key value, as this is the highest reported water solubility for any of the isomers.

Key value for chemical safety assessment

Water solubility:
0.02 mg/L
at the temperature of:
25 °C

Additional information

Standard experimental tests for this endpoint are intended for single substances and are not appropriate for products consisting of various isomers with individual solubilities. The literature values, together with the calculated values for each isomer are hence considered reliable for an overall assessment of the substance.

Available information in the literature for the single isomers and similar structures:

- Dioctyl phtalate: 0.020 mg/l @25°C (Defoe DL et al, 1990)

- Didecyl phtalate: 0.00022 mg/l @25°C (Ellington JJ, 1999)

- Dinonyl phtalate: 0.00013 mg/l @ 20°C (Letinski DJ et al, 2002)

The water solubility was calculated according to EPI Suite v4.11, Water Solubility Estimate from Log Kow (WSKOWWIN v1.43) and from WATERNT (v1.01 est).

WSKOWWIN (v1.43) predicted water solubilities for the three isomers in the range of 0.00001735 mg/l (C8 -C10), 0.00002921 mg/L (C10 -C10) ,and 0.00045488 mg/L (C8 -C8).

WATERNT (v1.01) predicted water solubilities for the three isomers as 0.000041114 mg/l (8 -10), 0.0000036993 mg/L (10 -10), and 0.00045488 mg/L (8 -8).