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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:
accepted calculation method
Justification for type of information:
1. Substance
This section is aimed at defining the substance for which the (Q)SAR prediction is made.

1.1 CAS number: N/A. Related CAS numbers: 91770-24-0 (Mentha spicata, ext.) and 84696-51-5 (Spearmint, ext.). Common name: Spearmint oil. Spearmint oil is an UVCB/NCS the following constituents:
(-)-β-Bourbonene (CAS 5208-59-3) (EC -) (C15H24)
1,8-Cineole (CAS 470-82-6) (EC 207-431-5) (C10H18O)
3-Octanol (CAS 589-98-0) (EC 209-667-4) (C8H18O)
Germacrene D (CAS 37839-63-7) (EC -) (C15H24)
L-Carvone (CAS 6485-40-1) (EC 229-352-5) (C10H14O)
Linalool (CAS 78-70-6) (EC 201-134-4) (C10H18O)
L-Limonene (CAS 5989-54-8) (EC 227-815-6) (C10H16)
para-Cymene (CAS 99-87-6) (EC 202-796-7) (C10H14)
Sabinene hydrate (CAS 546-79-2) (EC 208-911-7) (C10H18O)
Terpinen-4-ol (CAS 562-74-3) (EC 209-235-5) (C10H18O)
trans-Dihydrocarvone (CAS 5524-05-0) (EC 226-872-4) (C10H16O)
α-Pinene (CAS 80-56-8) (EC 201-291-9) (C10H16)
β-Myrcene (CAS 123-35-3) (EC 204-622-5) (C10H16)
β-Pinene (CAS 127-91-3) (EC 204-872-5) (C10H16)
γ-Terpinene (CAS 99-85-4) (EC 202-794-6) (C10H16)

1.2 EC numbers: N/A. Related EC numbers: 294-809-8 (Mentha spicata, ext.) and 283-656- 2 (Spearmint, ext.). For constituents see 1.1
1.3 Chemical name: Essential oil of Spearmint obtained from the aerial part of Mentha spicata and/or Mentha cardiaca (Lamiaceae) obtained by distillation, Common name spearmint oil. The NCS/UVCB consists of the constituents specified in 1.1.
1.4 Structural formula: See 1.1
1.5 Structure codes:
a. SMILES:
(-)-β-Bourbonene:
SMILES: C=C1C2C(C3(C2C(C(C)C)CC3)C)CC1
InCHI: 1S/C15H24/c1-9(2)11-7-8-15(4)12-6-5-10(3)13(12)14(11)15/h9,11-14H,3,5-8H2,1-2,4H3/t11-,12+,13-,14+,15-/m0/s1

1,8-Cineole:
SMILES: O(C(CCC1C2)(C2)C)C1(C)C
InCHI: 1S/C10H18O/c1-9(2)8-4-6-10(3,11-9)7-5-8/h8H,4-7H2,1-3H3

3-Octanol:
SMILES: OC(CCCCC)CC
InCHI: 1/C8H18O/c1-3-5-6-7-8(9)4-2/h8-9H,3-7H2,1-2H3

Germacrene D
SMILES: CC(C)C1CCC(C)=CCCC(=C)C=C1
InCHI: 1S/C15H24/c1-12(2)15-10-8-13(3)6-5-7-14(4)9-11-15/h7-8,10,12,15H,3,5-6,9,11H2,1-2,4H3/b10-8+,14-7-

L-Carvone:
SMILES: O=C(C(=CCC1C(=C)C)C)C1
InCHI: 1S/C10H14O/c1-7(2)9-5-4-8(3)10(11)6-9/h4,9H,1,5-6H2,2-3H3

Linalool:
SMILES: OC(C=C)(CCC=C(C)C)C
InCHI: 1S/C10H18O/c1-5-10(4,11)8-6-7-9(2)3/h5,7,11H,1,6,8H2,2-4H3

L-Limonene
SMILES: C(=CCC(C(=C)C)C1)(C1)C
InCHI: 1S/C10H16/c1-8(2)10-6-4-9(3)5-7-10/h4,10H,1,5-7H2,2-3H3/t10-/m1/s1

para-Cymene
SMILES: c(ccc(c1)C)(c1)C(C)C
InCHI: 1S/C10H14/c1-8(2)10-6-4-9(3)5-7-10/h4-8H,1-3H3

Sabinene hydrate
SMILES: OC(C(C1(C2)C(C)C)C1)(C2)C
InCHI: 1S/C10H18O/c1-7(2)10-5-4-9(3,11)8(10)6-10/h7-8,11H,4-6H2,1-3H3

Terpinen-4-ol
SMILES: OC(CCC(=C1)C)(C1)C(C)C
InCHI: 1/C10H18O/c1-8(2)10(11)6-4-9(3)5-7-10/h4,8,11H,5-7H2,1-3H3

trans-Dihydrocarvone
SMILES: O=C1CC(C(=C)C)CCC1C
InCHI: 1/C10H16O/c1-7(2)9-5-4-8(3)10(11)6-9/h8-9H,1,4-6H2,2-3H3/t8-,9-/m1/s1

α-Pinene
SMILES: C(C(CC1C2)C1(C)C)(=C2)C
InCHI: 1S/C10H16/c1-7-4-5-8-6-9(7)10(8,2)3/h4,8-9H,5-6H2,1-3H3

β-Myrcene
SMILES: C(C=C)(=C)CCC=C(C)C
InCHI: 1S/C10H16/c1-5-10(4)8-6-7-9(2)3/h5,7H,1,4,6,8H2,2-3H3

β-Pinene
SMILES: C(C(CC1C2)C1(C)C)(C2)=C
InCHI: 1S/C10H16/c1-7-4-5-8-6-9(7)10(8,2)3/h8-9H,1,4-6H2,2-3H3

γ-Terpinene
SMILES: C=1(C(C)C)CC=C(C)CC1
InCHI: 1S/C10H16/c1-8(2)10-6-4-9(3)5-7-10/h4,7-8H,5-6H2,1-3H3

b. InChI: See 1.5a, not used for prediction
c. Other structural representation: Not available
d. Stereochemical features: not relevant for this endpoint

2. General information
General information about the compilation of the current QPRF is provided in this section.
2.1 Date of QPRF: February 18, 2016
2.2 QPRF author and contact details:
A.C. Belfroid (Angelique); P. Englebienne (Pablo)
HaskoningDHV Nederland B.V.
P.O. Box 151
6500 AD Nijmegen, The Netherlands
angelique.belfroid@rhdhv.com; pablo.englebienne@rhdhv.com
http://www.royalhaskoningdhv.com

3. Prediction
3.1 Endpoint (OECD Principle 1)
a. Endpoint: Solubility in water
b. Dependent variable: Solubility in water in mg/l at 25°C

3.2 Algorithm (OECD Principle 2)
a. Model or submodel name: WATERNT
b. Model version: Version 1.01
c. Reference to QMRF: QSAR for water solubility in mg/l at 25°C
drafted 21.07.2011 by P.S. Schoep (Piet); A.C. Belfroid (Angelique)
d. Predicted value (model result):
Sw (mg/L @ 25 °C)
(-)-β-Bourbonene (CAS 5208-59-3): 0.022729
1,8-Cineole (CAS 470-82-6): 551.66
3-Octanol (CAS 589-98-0): 1285.3
Germacrene D (CAS 37839-63-7): 0.81945
L-Carvone (CAS 6485-40-1): 135.17
Linalool (CAS 78-70-6): 709.26
L-Limonene (CAS 5989-54-8): 44.388
para-Cymene (CAS 99-87-6): 28.93
Sabinene hydrate (CAS 546-79-2): 742.39
Terpinen-4-ol (CAS 562-74-3): 1767.3
trans-Dihydrocarvone (CAS 5524-05-0): 897.09
α-Pinene (CAS 80-56-8): 3.4834
β-Myrcene (CAS 123-35-3): 17.814
β-Pinene (CAS 127-91-3): 2.6192
γ-Terpinene (CAS 99-85-4): 59.034
e. Predicted value (comments):No comments
f. Input for prediction: 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.
g. Descriptor values: Coefficients for individual fragments and groups in WATERNT were derived by
multiple regression of 1000 reliably measured water solubility values. In total 117 different types of fragments exist.

3.3 Applicability domain (OECD principle 3)
a. Domains: Discuss whether the query chemical falls in the applicability domain of the model as defined in the corresponding QMRF (section 5 of QMRF, Defining the applicability domain – OECD Principle 3). If additional software/methods were used to assess the applicability domain then they should also be documented in this section. Include a discussion about:
i. descriptor domain: All molecular weights of the substances for which solubility in water is predicted fall within the applicability domain (range of molecular weight for the training set substances).
ii. structural fragment domain: All chemicals are chemically similar to the training and validation set substances. All molecular groups that are present in the substances for which predictions are made are covered by the model.
iii. mechanism domain: Not relevant
iv. metabolic domain: Not relevant
b. Structural analogues: As this is a bulk set of structural similar constituents, the ‘validation’ of the QSAR for the data mentioned in chapter 1.1 is based on experimental values for those constituents for which experimental data were available in the training set.
An overview is provided below.
c. Considerations on structural analogues: In the calculation method based on fragments, 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. In the calculation method based on fragments, some measured values are lower than the estimated values, with the exception of the minor constituents linalool, eugenol and 1,8- cineol which are higher. For all constituents, the fragments calculation method is considered applicable and will therefore be used to estimate the water solubility of the NCS constituents.

3.4 The uncertainty of the prediction (OECD principle 4)
The training set data and validation set are not from one lab, but a collection. The sets are nevertheless considered robust as they are very large: 1128 and 4636 chemicals respectively. For more information on the quality of these datasets we refer to the Help file of MPBPVPWIN v1.43.

3.5 The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5). A mechanistic interpretation is not relevant. The underlying principle of the model is that substances with more hydrophobic fragments are less soluble while hydrophilic fragments may contribute to the solubility in water.

4. Adequacy (Optional)
4.1 Regulatory purpose: The predictions are used to gather the required data for filling the Water solubility data gap in the REACH dossier for a UVCB substance.
4.2 Approach for regulatory interpretation of the model result: REACH accepts and encourages the use of QSARs to fill data gaps. The requirements for REACH are met as:
- a robust study summary and endpoint summary are included in the dossier;
- a QMRF for the QSAR model is included in the dossier;
- a QPRF for the predictions is included in the dossier.
4.3 Outcome: The model results (water solubility in mg/l at 25 °C) is compatible with the requirements of REACH for the water solubility endpoint.
4.4 Conclusion: As all criteria for the application of QSARs under REACH are met, the predictions for the water solubility endpoint are considered to be adequate and fit-for-purpose.
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
other:
Principles of method if other than guideline:
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
Key result
Water solubility:
12.6 mg/L
Temp.:
25 °C
pH:
7
Remarks on result:
other: pH was not reported (7 included as default)

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.

Conclusions:
The substance Ethyllinalyl acetate has a water solubility of 12.6 mg/L.
Executive summary:

The water solubility of Ethyllinalyl acetate was estimated by calculation using the QSAR WATERNT v1.01 according to the fragment method.

The water solubility for Ethyllinalyl acetate was found to be 12.6 mg/L at 25°C

Description of key information

The substance Ethyllinalyl acetate has a water solubility of 12.6 mg/L.

Key value for chemical safety assessment

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

Additional information