Calcium 1,4-bis(2-ethylhexyl) bis(2-sulphosuccinate)

Water solubility

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

water solubility

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 105 (Water Solubility)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Type of method:

flask method

Specific details on test material used for the study:

Batch FPAC1822263.
Substance tested is a 56%wt solution of calcium docusate in corn oil. Attempts were made to obtain neat/pure test material but the substance is extremely difficult to handle in the neat form. The form of the substance tested reflects how the substance will be supplied and placed on the market.

Key result

Water solubility:

ca. 6 g/L

Conc. based on:

test mat. (dissolved fraction)

Loading of aqueous phase:

8 other: %w/w

Incubation duration:

ca. 24 h

Temp.:

20 °C

pH:

7.8

Water solubility:

ca. 0.6 g/L

Conc. based on:

test mat. (dissolved fraction)

Loading of aqueous phase:

8 other: %w/w

Incubation duration:

ca. 72 h

Temp.:

30 °C

pH:

7.8

Details on results:

Preliminary Experiment

Upon standing overnight, the 10% and 20% samples remained as a milky white suspension, however a few drops of a yellow oil were observed on the surface of the suspension. The 30,40 and 50% samples contained an off white / pale yellow semi solid with a clear supernatant liquid. The samples were filtered through a 0.2 um syringe filter and analysed by HPLC. The 10% sample was opaque after filtration. The 20% sample was slightly cloudy after filtration and 30%, 40% and 50% sample were clear after filtration. HPLC analysis showed the greatest concentration at 10%, decreasing further at 20%.

Experiment 2

Upon standing overnight, the samples remained as milky white suspensions, however a few drops of yellow oil were observed on the surface of the 6%, 8% and 10% w/w samples. A thin layer of a fine white solid was present at the base of the vials. The samples were centrifuged, filtered through a 0.2 um syringe filter and analysed by HPLC.The centrifuged samples showed some heavier white material at the base of all samples, with the 8 and 10% w/w samples having some oil floating on the surface. The Docusate Calcium concentration increased proportionally over the 2-10% w/w sample range (subsequent review following further data analysis showed the maximum concentration of docusate calcium was achieved at about 8%).

Experiment 3

Upon standing overnight, the 15% and 20% samples remained as a milky white suspension, with a yellow oil floating on the surface around the edges. A small amount of white solid was noticed on the base of the vial. The 25 % w/w sample was less milky in appearance but still had yellow oil floating on the surface around the edges. The 30 % w/w sample had separated to a lower white / pale yellow gel / solid at the bottom of the vial, an almost clear middle layer and an upper white / pale yellow gel /solid.

A further review of the data obtained for the samples prepared over the 2 to 30 %w/w range showed that the maximum concentration obtained for the docusate calcium was obtained at around 8%. N.B Sample concentrations were obtained against a single point calibration of a supplied Docusate Calcium reference sample.

A yellow oil on top of an off white solid / gel was observed around the edge of the vial of the 7%, 8% and 9% w/w samples. A layer of a fine white solid was also observed on the base of the vials. The samples at concentrations of 7, 8 and 9 % w/w were equilibrated at room temperature for an hour and a middle liquid portion of the samples was centrifuged for 30 minutes. All three samples had some white solid in the base of the centrifuge tube along with a slightly cloudy supernatant liquid. Upon filtration of the supernatant liquid through a 0.2 um syringe filter the samples remained slightly cloudy. The samples were analysed by HPLC. The HPLC analysis showed that 8% solution was the maximum concentration. It was noted that the response was approximately a tenth of what was observed during the previous analysis of an 8% sample. It is possible that the sample either underwent a degree of decomposition during the 72 hours shaking at 30 °C or that the increased temperature changed the partition coefficient and an hour of equilibration at room temperature was insufficient to re-establish the correct partition coefficient. Two successive methods of sample preparation have shown that an 8% w/w preparation of Docusate Calcium USP 50% Corn oil NF 50% in water results in a maximum solubilisation of Docusate Calcium in the aqueous layer.

Conclusions:

The registered substance was found to have an estimated solubility of 6 g/L at a temperature of 20°C when left to equilibrate over a period of 24h.
In a seperate experiment within the same study the registered substance was found to have an estimated solubility of 0.6 g/L at a temperature of 30°C over a 72h equilibration period.

The reason for the discrepancy between the solubility at different temperatures and incubation times is unknown. However, since the test item was a mixture of the registration substance docusate calcium (56%w/w) in corn oil (44%w/w) the partitioning characteristics of the surface active registration substance is likely to be sensitive to these experimental condition variables.

Executive summary:

An attempt to determine the experimental water solubility of docusate calcium in water was carried out in a GLP study in accordance with OECD 105.

Ideally the study should have been carried out on a neat/pure form of the registered substance. However, despite several attempts it was not possible to isolate the substance to produce a representative sample for testing making practical determination of the water solubility very difficult. Water solubility testing was therefore conducted on the sample as typically placed on the market (i.e. as mixture in USP corn oil).

The registered substance was found to have an estimated solubility of 6 g/L at a temperature of 20°C when left to equilibrate over a period of 24h.

In a seperate experiment within the same study the registered substance was found to have an estimated solubility of 0.6 g/L at a temperature of 30°C over a 72h equilibration period.

The reason for the discrepancy between the solubility at different temperatures and incubation times is unknown. However, since the test item was a mixture of the registration substance docusate calcium (56%w/w) in corn oil (44%w/w) the partitioning characteristics of the surface active registration substance is likely to be sensitive to these experimental condition variables.

It is worth noting that the estimated bulk solubility of calcium docusate determined in this study (~6g/L at 20°C) is very close to the result of 8.17 g/L obtained for docusate sodium (577 -11 -7) in an OECD 105 guideline study. See read-across justification in section 13 and the REACH dossier for docusate sodium for additional details.

Reference 2

Endpoint:

water solubility

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

May 2018

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a (Q)SAR model, with limited documentation / justification, but validity of model and reliability of prediction considered adequate based on a generally acknowledged source

Justification for type of information:

Results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Qualifier:

no guideline followed

Principles of method if other than guideline:

The test substance is a surfactant. The established methods for the determination of the water solubility as described in EC A.6 and OECD 105 are not applicable to surfactants. Therefore, in the absence of experimental data the water solubility has been predicted using the US EPA EPI Suite software model WATERNT v1.01.

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.   We call WATERNT’s methodology 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.

The exact same methodology is used in the KOWWIN Program (estimation of octanol water partition coefficient ... see the Meylan and Howard (1995) journal article and the KOWWIN Help file for a more complete description of KOWWIN’s methodology).

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.

GLP compliance:

no

Remarks:

QSAR Prediction

Key result

Water solubility:

0.019 mg/L

Temp.:

20 °C

pH:

7

Details on results:

The water solubility of docusate calcium using the WATERNT V1.01 model was predicted to be low with a value of 0.019 mg/L at 20°C

Conclusions:

Interpretation of results: insoluble (<1 mg/L)
The predicted water solubility is 0.019 mg/L

Executive summary:

The US EPA EPI Suite QSAR model software package (WATERNT v1.01) was used to predict the water solubility of docusate calcium.

The following SMILES string was used as input to the model:

[Ca]CCCCC(CC)COC(=O)CC(C(=O)OCC(CC)CCCC)S([O-])(=O)=OCCCCC(CC)COC(=O)CC(C(=O)OCC(CC)CCCC)S([O-])(=O)=O

The water solubility of docusate calcium was predicted to be extremely low with a value of 0.019 mg/L at 20°C. The accuracy of this calculated water solubility value is questionable as the substance has surface-active properties and the structrually analagous monovalent sodium docusate salt has a much higher solubility in water (>1 g/L at 20°C)

Reference 3

Endpoint:

water solubility

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a (Q)SAR model, with limited documentation / justification, but validity of model and reliability of prediction considered adequate based on a generally acknowledged source

Justification for type of information:

Results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Qualifier:

no guideline followed

Principles of method if other than guideline:

The test substance is a surfactant. The established methods for the determination of the water solubility as described in EC A.6 and OECD 105 are not applicable to surfactants. Therefore, in the absence of experimental data the water solubility has been predicted using the US EPA EPI Suite software model WSKOWWIN v1.42

WSKOWWIN estimates water solubility for any compound with one of two possible equations. The equations are:

    log S (mol/L)  =  0.796 - 0.854 log Kow - 0.00728 MW + ΣCorrections

    log S (mol/L)  =  0.693 - 0.96 log Kow - 0.0092(Tm-25) - 0.00314 MW + ΣCorrections

(where MW is molecular weight, Tm is melting point (MP) in deg C [used only for solids]) ... Summation of Corrections (ΣCorrections) are applied as described in Appendix E of the WSKOWWIN user guide.   When a measured MP is available, that equation is used; otherwise, the equation with just MW is used.

GLP compliance:

no

Key result

Water solubility:

0 mg/L

Temp.:

20 °C

pH:

7

Details on results:

The water solubility of docusate calcium using the WSKOWWIN v1.42 model was predicted to be extremely low with a value of 3.1 x10 -9 mg/L at 20°C

Conclusions:

Interpretation of results: insoluble (<1 mg/L)
The predicted water solubility is 3.1x10-9 mg/L

Executive summary:

The US EPA EPI Suite QSAR model software package (WSKOWWIN v1.42) was used to predict the water solubility of docusate calcium.

The following SMILES string was used as input to the model:

[Ca]CCCCC(CC)COC(=O)CC(C(=O)OCC(CC)CCCC)S([O-])(=O)=OCCCCC(CC)COC(=O)CC(C(=O)OCC(CC)CCCC)S([O-])(=O)=O

The water solubility of docusate calcium was predicted to be extremely low with a value of 3.1 x10 -9 mg/L at 20°C. The accuracy of this calculated water solubility value is questionable as the substance has surface-active properties and the structrually analagous monovalent sodium docusate salt has a much higher solubility in water (>1 g/L at 20°C)

Description of key information

Experimental Study

An attempt to determine the experimental water solubility of docusate calcium in water was carried out in a GLP study in accordance with OECD 105.

Ideally the study should have been carried out on a neat/pure form of the registered substance. However, despite several attempts it was not possible to isolate the substance to produce a representative sample for testing making practical determination of the water solubility very difficult. Water solubility testing was therefore conducted on the sample as typically placed on the market (i.e. as mixture in USP corn oil).

The registered substance was found to have an estimated solubility of 6 g/L at a temperature of 20°C when left to equilibrate over a period of 24h.

In a seperate experiment within the same study the registered substance was found to have an estimated solubility of 0.6 g/L at a temperature of 30°C over a 72h equilibration period.

The reason for the discrepancy between the solubility at different temperatures and incubation times is unknown. However, since the test item was a mixture of the registration substance docusate calcium (56%w/w) in corn oil (44%w/w) the partitioning characteristics of the surface active registration substance is likely to be sensitive to these experimental condition variables.

It is worth noting that the estimated bulk solubility of calcium docusate determined in this study (~6g/L at 20°C) is very close to the result of 8.17 g/L obtained for docusate sodium (577 -11 -7) in an OECD 105 guideline study. See read-across justification in section 13 and the REACH dossier for docusate sodium for additional details.

In Silico QSAR predictions

Two of the US EPA EPI Suite QSAR model software packages (WATERNT v1.01 and WSKOWWIN v1.42) have been used to predict the water solubility of docusate calcium.

The following SMILES string was used as input to both models:

[Ca]CCCCC(CC)COC(=O)CC(C(=O)OCC(CC)CCCC)S([O-])(=O)=OCCCCC(CC)COC(=O)CC(C(=O)OCC(CC)CCCC)S([O-])(=O)=O

The water solubility of docusate calcium was predicted to be extremely low with values of 0.019 mg/L and 3.1E-9 mg/L at 20°C using both of the WATERNT and WSKOWWIN models, respectively. The accuracy of these QSAR calculated water solubility values is questionable as the substance has surface-active properties and the available experimental data for the substance itself and the structrually equivalent monovalent sodium salt exhibit much higher solubility in water (>1 g/L at 20°C)

Key value for chemical safety assessment

Water solubility:

6 g/L

at the temperature of:

20 °C