Registration Dossier

Administrative data

Endpoint:
water solubility
Type of information:
(Q)SAR
Adequacy of study:
key study
Study period:
2018
Reliability:
1 (reliable without restriction)
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:
SOFTWARE
As the holistic approach followed simple modelling techniques (fragment contribution method and simple linear regression), no additional packages or tools were involved. All the descriptors (independent variables) and endpoint values (dependent variables) were experimentally derived and retrieved from various literature resources including some publicly disseminated databases as well as some confidential data available within iSafeRat database.

MODEL
- Name: Model iSafeRat® High-Accuracy-Quantitative Structure-Activity Relationship (HA-QSAR) based on a holistic approach for predicting physicochemical and ecotoxicological endpoints: Water solubility
- Version: iSafeRat® holistic HA-QSAR v1.8

SMILES USED AS INPUT FOR THE MODEL
C(C(C(C(C=O)O)O)O)O

SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
[Explain how the model fulfils the OECD principles for (Q)SAR model validation. Consider attaching the QMRF or providing a link]
- Data used as the input: log KOW = -2.32
- Unambiguous algorithm:
- Defined domain of applicability:
- Appropriate measures of goodness-of-fit and robustness and predictivity:
- Mechanistic interpretation:

APPLICABILITY DOMAIN
[Explain how the substance falls within the applicability domain of the model]
- Descriptor domain: The log KOW used as the descriptor for this prediction does not fall within the descriptor domain of the model between a log KOW of 0.79 to 6.03. Therefore, the prediction is considered as an extrapolation.
- Structural and mechanistic domains: All chemical groups within the molecular structure are represented within the datasets used by the model. Water solubility of the substance is determined using log KOW as the descriptor. The submodel used is dependent on the capability of the substance to participate in hydrogen bonding with water and octanol. iSafeRat® Holistic HAQSAR includes the following submodels:
* Water Solubility submodel for NonPolar Organic compounds;
* Water Solubility submodel for Oxygenated, NonHydroxylated compounds (classical);
* Water Solubility submodel for Oxygenated, NonHydroxylated compounds (diesters);
* Water Solubility submodel for Oxygenated, Hydroxylated compounds;
* Water Solubility model for Alkyl/Alkoxyphenols;
* Water Solubility model for Amino compounds.
- Limits of applicability: See QMRF - page 15 - table 9

ADEQUACY OF THE RESULT
Water solubility is a required regulatory endpoint under REACH (Annex VII) as part of the suite of required physicochemical properties. It is also necessary for ecotoxicity study validation to verify that the toxicity value determined was not greater than the solubility limit, which may occur in studies on certain poorly soluble substances due to physical interactions between the test substance and the test organism.
The model result can be used to interpret whether an ecotoxicity study value (E/LC50) from an experimental study is greater than the water solubility of the test substance (based on pure water). It can also be used to predict the expected solubility-toxicity cut-off value of acute aquatic toxicity studies (and therefore predictions).
In the case of the iSafeRat® QSAR, the water solubility value can be used to determine all other related endpoints (log KOW; aquatic toxicity) which are driven by thermodynamically based relationships.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report Date:
2018

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 105 (Water Solubility)
Deviations:
no
Principles of method if other than guideline:
This QSPR model has been validated as a QSAR model to be compliant with the OECD recommendations for QSAR modeling (OECD, 2004) and predicts the endpoint value which would be expected when testing the substance under experimental conditions in a laboratory following Guideline for Testing of Chemicals No. 105, "Water Solubility".
In the majority of cases data were obtained from shake flask experiments in which approximately 5 times the quantity of test substance expected to saturate the desired water volume is added to ultra-pure water solubility in three appropriate vessels, closed and agitated using fairly high energy (head-over-heels shaker, or other forms of vigorous mixing) at 30 °C for 24, 48 and 72 hours. Each flask is allowed 24 hours of further equilibration at 20 or 25°C and the contents generally centrifuged and the concentration of test substance measured.
Instead of high energy agitation, flasks containing a tap close to the bottom are nearly filled by ultra-pure water, covered by a thin layer of the test item and slow stirred (approximately 100 RPM or less). The aim of this method is to prevent the formation of emulsions that can occur with the shake flask method and lead to a solubility overestimation. The water solubility is given by the mass concentration in water when this has reached a plateau as a function of time.
In rare cases data has been taken from studies performed using a second method described in OECD guideline 105 (2), the column elution method (recommended for solids with water solubility below 10 mg.L-1) in which the substance is coated onto beads in a column generator and water circulated in an attempt to saturate the circulating water. The solution is passed through the column at different flow rates such that the degree of saturation can be ascertained.
Type of method:
other: QSAR modelization

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
Dry powder, white to slightly yellow
Specific details on test material used for the study:
SMILES USED AS INPUT FOR THE MODEL
C(C(C(C(C=O)O)O)O)O

Results and discussion

Water solubility
Key result
Water solubility:
> 1 000 g/L
Temp.:
25 °C
Remarks on result:
completely miscible
Remarks:
The water solubility was estimated by calculation to 103 kg/L at 25°C

Applicant's summary and conclusion

Conclusions:
The test item is completely miscible according to the QSPR model adapted from OECD test guideline 105 (water solubility).