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Water solubility

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Reference
Endpoint:
water solubility
Type of information:
(Q)SAR
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: 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:
See QMRF document "WaterNT.pdf" attached to this record.
Qualifier:
no guideline followed
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 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, a number of measured values are higher than the estimated values. In the calculation method based on fragments, almost all measured values are lower than the estimated values, with the exception of linalool which is slightly higher. Therefore, the fragments calculation method can be considered applicable and will therefore be used to estimate the water solubility of the NCS constituents.
GLP compliance:
no
Type of method:
other: Estimation by calculation
Key result
Water solubility:
>= 3.48 - <= 1 767.3 mg/L
Temp.:
25 °C
Remarks on result:
other: concern lowest and highest value for water solubility. 80% of the NCS has a ws of 44.4mg/L
Details on results:
No data
Substance CAS Estimated water solubility (mg/l at 25ºC )
D-limonene 5989-27-5 44.388
Citral 5392-40-5 1101
beta-Myrcene 123-35-3 17.814
Linalool 78-70-6 709.26
Alpha-Terpineol 98-55-5 1767.3
Alpha-pinene 7785-70-8 3.4834
Citronellal 106-23-0 514.22
Decanal  112-31-2 85.498
Octanal 124-13-0 831.88

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 multipleregression 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 an 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.

Conclusions:
Interpretation of results (migrated information): other: constituents Sw varies from slightly soluble to soluble
The range of water solubilities of the known constituents of orange oil is 3.48 - 1767.3 mg/l at 25ºC.
Executive summary:

The water solubility of orange oil 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 of the known constituents of orange oil was found to be 3.48 - 1767.3 mg/l at 25 ºC.

Description of key information

Water solubility: The range of water solubilities of the known constituents of orange oil was found to be 3.48 - 1767.3 mg/l at 25ºC.

Key value for chemical safety assessment

Additional information

In a key study, the water solubility of orange oil was estimated by calculation in line with the NCS protocol. Water solubilities for the known constituents were estimated using the QSAR WATERNT v1.01 according to the fragment method. The range of water solubilities of the known constituents of orange oil was found to be 3.48 - 1767.3 mg/l at 25 ºC.