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
Remarks:
Values for individual constituents of this natural complex substance (NCS) were calculated using a validated QSAR. All constituents fall within the applicability domain of the QSAR.
Justification for type of information:
1. The software used: see attached QMRF
2. The model(s) used: see attached QPRF

1. SOFTWARE
WATERNT v 1.01 QSAR for water solubility in mg/l at 25°C Dr. Robert
Boethling, U.S. Environmental Protection Agency, 1200 Pennsylvania Ave.,
N.W. (Mail Code 7406M) Washington, DC 20460, USA, Phone: # (202) 564-
8 5 3 3 , e - m a i l : b o e t h l i n g . b o b @ e p a . g o v
h t t p : / / w w w . e p a . g o v / o p p t / e x p o s u r e / p u b s / e p i s u i t e d l . h t m

2. MODEL (incl. version number)
Model or Submodel name: WATERNT
Model Version: Version 1.01
Reference to QMRF: QSAR for water solubility in mg/L at 25ºC
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
other: QSAR model
Title:
WATERNT v1.01a
Author:
U.S. Environmental Protection Agency
Year:
2010
Bibliographic source:
US EPA. [2008]. Estimation Programs Interface Suite™ for Microsoft® Windows, v 4.00. United States Environmental Protection Agency, Washington, DC, USA

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: REACH Guidance on QSARs R.6
Version / remarks:
Replaces OECD Guideline 105 (Water Solubility)
Deviations:
not applicable
Principles of method if other than guideline:
NCSs, consisting of a number of constituents, do not have one single water solubility value (Sw). The range of Sw can be given from calculated or measured values of the individual constituents. Calculated and measured data on the constituents are obtained from the QSAR WaterNT v1.01 from US-EPA.
For Sw, two calculation methods are available in Wskowwin: by log Kow and by fragments of the molecule. In the calculation method based on log Kow, the estimated log Kow value is used as input for the estimation of the water solubility. As this method consists of building QSAR on QSAR preference is given to the next method based on fragments. In this method, the calculation is based on the "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 solubility estimate.
The relevance and reliability of the used QSAR for these constituents is shown in the attached QMRF and QPRF.
GLP compliance:
no
Type of method:
other: Estimation by calculation / QSAR

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: not applicable for in silico study
Details on test material:
- Name of test material (as cited in study report): Ceadrwood Texas oil distilled - Cedrol
- Commercially available test material - not applicable for in silico study

Results and discussion

Water solubility
Key result
Water solubility:
>= 0.03 - <= 29.25 mg/L
Temp.:
25 °C
Remarks on result:
other: Data concern lowest and highest value for water solubility for the individual constituents.
Details on results:
No data

Any other information on results incl. tables

Constituent CAS Estimated water solubility (mg/L at 25ºC)
 Widdrol  6892-80-4  29.254
 Cedrol  77-53-2  8.7229
 Bergamotene alpha  17699-05-7  0.27926
 Himachalene beta  1461-03-6  1.1378
 Chamigrene alpha  19912-83-5  1.0168
 Himachalene gamma  53111-25-4  0.72174
 Himachalene alpha  3853-83-6  0.54268
 Cuparene  16982-00-6  0.50078

 Thujopsene

 470-40-6

 0.059998

 cedrene alpha

 469-61-4

 0.042587

 cedrene beta  546-28-1  0.032021

 diepi-alpha-cedrene

 50894-66-1

 0.042587

WaterNT v1.01 model details

Reference to the type of model used

WATERNT uses a "fragment constant" methodology to predict water solubility. 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 solubility estimate. The WATERNT™s methodology is further referred to as the Atom/Fragment Contribution (AFC) method. Coefficients for individual fragments and groups in WATERNT were derived by multiple regression of 1000 reliably measured water solubility values.

Description of the applicability domain

The applicability domain is based on the maximum number of instances of that a fragment can be used in a chemical (based on the training and validation set, summarized in appendix D) and on molecular weight. The minimum and maximum values for molecular weight are the following:

 

Training Set Molecular Weights:

Minimum MW: 30.30

Maximum MW: 627.62

Average MW: 187.73

Currently there is no universally accepted definition of model domain. However, users may wish to consider the possibility that water solubility estimates are less accurate for compounds outside the MW range of the training set compounds, 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. These points should be taken into consideration when interpreting model results.

 

Description and results of any possible structural analogues of the substance to assess reliability of the prediction

External validation with a dataset containing 4636 substances resulted in a correlation coefficient (r2) of 0.815, a standard deviation of 1.045 and an absolute deviation of 0.796. The external 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.

 

Uncertainty of the prediction

All constituents for which estimations were made fall within the applicability domain of the model.

Mechanistic domain

WATERNT uses a "fragment constant" methodology to predict water solubility. 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 solubility estimate.

 

It became apparent, for various types of structures, that water solubility 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 water solubility estimates from atoms alone and the measured water solubility 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 solubility estimates from atom/fragments alone and measured solubility values) with common substructures. Results of two successive multiple regressions (first for atom/fragments and second for correction factors) yield the QSAR. In total 117 different types of fragments exist.

 

To estimate water solubility, 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. Several functional groups are treated as core "atoms"; these include carbonyl (C=O), thiocarbonyl (C=S), nitro (-NO2), nitrate (ONO2), cyano (-C/N), and isothiocyanate (-N=C=S). Connections to each core "atom" are either general or specific; specific connections take precedence over general connections.

 

As all regular and common fragments are included in this method, and the constituents for which this method was applied do not contain exotic fragments, there are no limits to the mechanistic domain.

Applicant's summary and conclusion

Conclusions:
The range of water solubilities for the known constituents of Cedarwood Texas oil distilled - Cedrol is 0.03-29.25 mg/L at 25°C. The main constituent Cedrol has a solubility < 10 mg/L, 100% of the NCS has a water solubility < 100 mg/L.
Executive summary:

The water solubility of Cedarwood Texas oil distilled - Cedrol was estimated by calculation. Water solubilities for the known constituents were estimated using the QSAR WATERNT v1.01 according to the fragment method.

The range of water solubilities for the known constituents of Cedarwood Texas oil distilled - Cedrol was found to be 0.03-29.25 mg/L at 25°C. The main constituent Cedrol has a water solubility < 10 mg/L, 100% of the NCS has a water solubility < 100 mg/L.