Registration Dossier

Administrative data

Endpoint:
water solubility
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 (WSKOWWIN v1.42), US EPA

2. MODEL (incl. version number)
WSKOWWIN v1.42 (using the compounds log octanol-water partition coefficient)

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
CC(C)(C)NC[C@H](O)CO

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
A complete description of the estimation methodology used by WSKOWWIN is available in two documents prepared for the U.S. Environmental Protection Agency, Office of Pollution Prevention and Toxics (Meylan and Howard, 1994a,b). A journal article that describes the methodology is also available (Meylan et al., 1996). The WSKOWWIN program estimates the water solubility of an organic compound using the compounds log octanol-water partition coefficient (log Kow). A brief description is given below.
Data Collection
A database of more than 8400 compounds with reliably measured log Kow values had already been compiled from available sources. Most experimental values were taken from a "star-list" compilation of Hansch and Leo (1985) that had already been critically evaluated (see also Hansch et al, 1995) or an extensive compilation by Sangster (1993) that includes many "recommended" values based upon critical evaluation. Other log Kow values were taken from sources located through the Environmental Fate Data Base (EFDB) system (Howard et al, 1982, 1986). A few values were taken from Section 4a, 8d, and 8e submissions the to U.S. EPA under the Toxic Substances Control Act.
Water solubilities were collected from the AQUASOL dATAbASET of the University of Arizona (Yalkowsky and Dannenfelser, 1990), Syracuse Research Corporation's PHYSPROP Database (SRC,1994), and sources located through the Environmental Fate Data Base (EFDB) system (Howard et al, 1982, 1986). Water solubilities were primarily constrained to the 20-25oC temperature range with 25oC being preferred.
Melting points were collected from sources such as AQUASOL dATAbASET, PHYSPROP, and EDFB as well as the Handbook of Chemistry and Physics (Lide, 1990) and the Aldrich Catalog (Aldrich, 1992).
Regression & Results
A dataset of 1450 compounds (941 solids, 509 liquids) having reliably measured water solubility, log Kow and melting point was used as the training set for developing the new estimation algorithms for water solubility. Standard linear regressions were used to fit water solubility (as log S) with log Kow, melting point and molecular weight.

Residual errors from the initial regression fit were examined for compounds sharing common structural features with relatively consistent errors. On that basis, 12 compound classes were initially identified and added to the regression to comprise a multi-linear regression including log Kow, melting point and/or molecular weight plus 12 correction factors. Each correction factor is counted a maximum of once per structure [if applicable], no matter how many times the applicable fragment occurs. For example, the nitro factor in 1,4-dinitrobenzene is counted just once. A compound either contains a correction factor or it doesn't; therefore, the matrix for the multi-linear regression contained either a 0 or 1 for each correction factor. Appendix E of WSKOWWIN User’s guide of describes the correction factors and coefficients used by WSKOWWIN.
WSKOWWIN estimates water solubility for any compound with one of two possible equations. The equations are equations 19 and 20 from Meylan and Howard (1994a) or equations 11 and 12 from the journal article (Meylan et al., 1996). The equations 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
(where MW is molecular weight, Tm is melting point (MP) in deg C [used only for solids]) .
Summation of Corrections (ΣCorrections) are applied as described in Appendix E. When a measured MP is available, that equation is used; otherwise, the equation with just MW is used.


5. APPLICABILITY DOMAIN
Appendix E of WSKOWWIN User’s guide gives the number compounds in the 1450 compound training set containing each of the correction factors. The WSKOWWIN program applies an individual correction factor only once per structure [if at all] regardless of how many instances of the applicable structural feature occur in the structure. The minimum number of instances is zero and the maximum is one.

Range of water solubilities in the Training set:
Minimum = 4 x 10-7 mg/L (octachlorodibenzo-p-dioxin)
Maximum = completely soluble (various)

Range of Molecular Weights in the Training set:
Minimum = 27.03 (hydrocyanic acid)
Maximum = 627.62 (hexabromobiphenyl)

Range of Log Kow values in the Training set:
Minimum = -3.89 (aspartic acid)
Maximum = 8.27 (decachlorobiphenyl)

Currently there is no universally accepted definition of model domain. Water solubility estimates are less accurate for compounds outside the MW range, water solubility range and log Kow range of the training set compounds.
6. ADEQUACY OF THE RESULT
The estimate value has been generated by a valid model. The model is applicable to the substance 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:
WSKOW v1.42 (2015)

Materials and methods

Principles of method if other than guideline:
- Software tool(s) used including version: WSKOW v1.4
- Model description: see field 'Justification for non-standard information'
GLP compliance:
no
Type of method:
other: QSAR

Test material

Reference
Name:
Unnamed
Test material form:
solid: particulate/powder

Results and discussion

Water solubility
Water solubility:
1 000 g/L
Temp.:
25 °C
Remarks on result:
other: QSAR predicted value
Details on results:
Estimated from Log Kow (WSKOW v1.4) water solubility: 1x10^6 mg/l a 25°C

Applicant's summary and conclusion

Conclusions:
WSKOW v 1.42 predicted that the substance has a water solubility = 1x10^6 mg/l at 25 °C.