cis-4-tert-butylcyclohexyl acetate

Water solubility

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

water solubility

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

March 23rd, 2020

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:

1. SOFTWARE
iSafeRat® toolbox – in Silico Algorithms For Environmental Risk And Toxicity version 2.4

2. MODEL (incl. version number)
iSafeRat® holistic HA-QSAR v1.9

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
CC(=O)O[C@@H]1CC[C@@H](CC1)C(C)(C)C
experimental log Kow (4.8) used as input value for the QSAR model

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached QMRF

5. APPLICABILITY DOMAIN
See attached QPRF

6. ADEQUACY OF THE RESULT
See attached QPRF

Reason / purpose for cross-reference:

reference to other study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 105 (Water Solubility)

Deviations:

not applicable

Remarks:

QSAR model

Principles of method if other than guideline:

The purpose of the in silico study was to determine the water solubility of test item in pure water at 25°C.
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 the Guideline for Testing of Chemicals No. 105, "Water Solubility" (OECD, 1995). The determination was performed using a regression method in which validated log Kow values are plotted against the log of sub-cooled liquid water solubility from studies of high quality. These have been carried out using one of the methods recommended in the OECD guideline 105 or an adaptation of these.

GLP compliance:

no

Type of method:

other: QSAR model

Specific details on test material used for the study:

log Kow (experimental) = 4.8;; read-across from non-differentiated isomers

Key result

Water solubility:

4.16 mg/L

Temp.:

25 °C

Remarks on result:

other: pH not relevant by QSAR calculation

Details on results:

Applicability Domain

Descriptor domain
The log Kow (4.8) given as the input to the iSafeRat® WatSol model falls within the descriptor domain of the model between a log Kow of 0.03 to 5.52. The test item falls within the response domain of the training set between a SLWS (in log (mol/L)) of -5.92 to 0.01.

Structural fragment domain
All chemical groups within the molecular structure are represented within the datasets of the model.

Mechanism domain
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 HA-QSAR includes the following submodels:
· Water Solubility submodel for Non-Polar Organic compounds:
for compounds which are neither donors, nor acceptors for hydrogen bonds (e.g. alkanes, halides, alkenes, thiols… etc.)
· Water Solubility submodel for Oxygenated, Non-Hydroxylated compounds (classical):
for hydrogen bond acceptor compounds which are not donors (e.g. ethers, mono-esters, ketones, aldehydes, epoxides, lactones, carbonates, (meth)acrylates)
· Water Solubility submodel for Oxygenated, Non-Hydroxylated compounds (diesters):
specific submodel for diester compounds.
· Water Solubility submodel for Oxygenated, Hydroxylated compounds:
for hydrogen bond acceptor and donor compounds (i.e. alcohols, ethoxylated alcohols, lactates and carboxylic acids).
· Water Solubility model for Alkyl-/Alkoxy-phenols:
for hydrogen bond acceptor and donor compounds which can participate in strong hydrogen bonds.
· Water Solubility model for Amino compounds:
for hydrogen bond acceptor and donor compounds which can be ionised (i.e. primary, secondary and tertiary amines).
Given the molecular structure of the substance (ester), the submodel used to predict its water solubility is the one dedicated to Oxygenated, Non-Hydroxylated compounds (classical), which are hydrogen bond acceptors but not donors.

95% confidence interval (α = 0.05): 3.36 – 5.15 mg/L.

QSAR statistical parameters are given in the QMRF and the QPRF

Executive summary:

A validated Quantitative Structure-Property Relationship (QSPR) model was used to calculate the water solubility of the test item.

The determination was performed using a regression method in which validated log Kow values are plotted against the log of sub-cooled liquid water solubility from studies of high quality.

The experimentally determined log Kow was used as input.

The test item falls within the applicability domain of the model and was therefore reliably predicted for its water solubility. Therefore, this endpoint value can be considered valid and fit for purpose.

The water solubility at 25°C of the test item was determined as 4.16 mg/L.

95% confidence interval (α = 0.05): 3.36 – 5.15 mg/L.

Reference 2

Endpoint:

water solubility

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

From 21/01/2013 to 04/02/2013

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

The study was conducted according to an internationally recognised method, and under GLP. Substance ID is adequately specified with purity. However, due to analytical limitation, the result was completed with a qsar estimation. Therefore validation applies, but with restrictions.

Qualifier:

according to guideline

Guideline:

OECD Guideline 105 (Water Solubility)

Deviations:

yes

Remarks:

equilibration time and temperature

Qualifier:

according to guideline

Guideline:

EU Method A.6 (Water Solubility)

GLP compliance:

yes (incl. QA statement)

Remarks:

signed on 12 March 2012

Type of method:

flask method

Specific details on test material used for the study:

Storage condition of test material: Refrigerator (between 0 and 10°C under nitrogen).

Water solubility:

< 39.6 mg/L

Temp.:

20 °C

pH:

4.9

Remarks on result:

not determinable because of methodological limitations

Remarks:

< LOQ

Water solubility:

3.55 mg/L

Temp.:

25 °C

Remarks on result:

other: QSAR estimated value

Preliminary test

The preliminary test estimate of water solubility was <1 g/L.

QSAR estimated water solubility: 3.55 mg/L at 25°C.

Definitive test

No peak was detected for the test material in all samples (A, B, C).

The limit of quantification by this method is too high in this case to allow detection of the test material. In the calibration curve, the peak for standard 2 (39.6 mg/l) is near the detection limit; hence to ensure a reliable quantification, the concentration can’t be lowered.

Typical chromatograms for standards and sample are available in the study report.

Executive summary:

The water solubility of the test substance was determined according to the OECD 105/EU A6 guideline, flask method, with HPLC analysis.

Samples were found to be below the limit of detection, the result was therefore expressed as a limit value compared to the lowest quantifiable standard.

The estimated value calculated from WSKow model is retained as additional information.

Water solubility: < 39.6 mg/L (LOQ) (experimental); 3.55 mg/L (QSAR estimation)

Description of key information

Calculated water solubility = 4.16 mg/L at 25°C.

pH ca 4.9 at expected saturation (exp)

Key value for chemical safety assessment

Water solubility:

4.16 mg/L

at the temperature of:

25 °C

Additional information

A reliable experimental study, conducted according to a recognized OECD/EC method and under GLP, is available. However, due to analytical limitations (no substance detected at the LOQ), only a limit value could be obtained (< 39.6 mg/L). The report was completed with a QSAR estimation (3.55 mg/L), but no validation parameters were provided. The pH of the resulting solution was included as supporting scientific information of interest.

Thanks to the dossier update, a new, fully reliable prediction was released, using a validated QSAR and the experimental logKow as input, and is considered as the key data.