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ECO 38: Cross-validation for improving determinations of water solubility for difficult to test substances

Principal Investigator

Prof. Philipp Mayer

Technical University of Denmark

Bygningstorvet B115, 2800 Kgs. Lyngby, Denmark

Telephone: +45 4525 1569


Daniel J. Letinski, ExxonMobil Biomedical Sciences, Inc



Water solubility is a fundamental parameter for the environmental risk assessment of organic chemicals. It is critical for understanding and predicting the environmental fate of substances, and also has relevance for their effect assessment. While water solubility is relatively easy to determine for some substances, it is much more difficult for other substances. In the present project we will address these difficulties in a systematic manner, with the overall goals to (1) facilitate progress within solubility research and testing, (2) develop and optimize methodology for determining solubility of difficult to test substances and (3) conduct ring testing and cross validations of existing and new methods.

It is important to realize that there are challenges on the technical, analytical and scientific level, and several of these challenges will be addressed in the proposed project.

Technically, it can be very challenging to generate a saturated aqueous solution of a chemical while ensuring the absence of the pure substance in crystal or liquid form and also the absence of substance bound to a third phase in the solution. The best way to address this issue is the careful selection and optimization of the physical principle to introduce the chemical into the solution. The proposed project will include a number of established and novel principles for introducing the test substance and saturating the water. The latest developments within passive dosing will be applied, and particularly the simple saturation of polymer by swelling in pure liquid phase and accelerated passive dosing that can provide equilibrated solutions within a few minutes.

Analytically, it can be very challenging to measure aqueous concentrations in relatively small water volumes particularly for the most hydrophobic chemicals. We will address this challenge by a careful alignment of the solubility experiments and the subsequent analytical measurement of the aqueous concentration.

Scientifically, there are several critical issues. (1) While solubility is well defined for single chemicals, many chemicals are produced, used and released into the environment as mixtures. Special attention will be given to how to address and determine solubility parameters for UVCBs, isomeric mixtures and enantiomeric mixtures. (2) For surfactants, the upper concentration limit for the dissolved molecules is given by the critical micelle concentration (CMC). CMCs of surfactants will be determined with a new analytical principle, which takes advantage of that free surfactant molecules behave as co-solute while micelles act as a third binding phase. (3) The existence of a well-defined solubility that sets the upper limit for aqueous concentrations in the environment can even be challenged, since super-saturated aqueous solutions are physically possible. While supersaturation of organic substances is a rare and less important phenomena within the environment, it is more likely to occur when spiking substances using water miscible solvents. We will not study supersaturation in detail, but rather aim for confirming the absence of supersaturation in our experiments.

Aqueous solubility at a given condition should be physically and chemically defined, rather than by the method that was applied to measure it. However, since there are differences between experimental methods and also between prediction methods, aqueous solubilities will sometimes become operationally defined. Comparisons between different methods will be applied for studying and quantifying differences and hopefully cross validating the best methods. Ring testing will be applied to test the reproducibility and repeatability of selected methods.

The objectives of this project are:

(1) to bundle existing expertise on determinations of aqueous solubility for difficult to test substances,

(2) to improve, apply and compare the best methods for single compounds as well as for UVCBs and

(3) to facilitate progress in this area on the technical, analytical and scientific level.

The short-term expected outcomes are (1) scientific and technical progress regarding solubility testing of poorly soluble substances, surfactants and UVCBs, (2) providing the basis for and actively contributing to the updating of the OECD 105 guideline, (3) a knowledge gain from experimental ring testing of the slow stirring method and (4) a new level of confidence in solubility data based on cross-validations of different methods. The long-term benefit of the project will be higher quality in future solubility testing and thus an improved basis for future environmental risk assessment.

Timeline: February 2017 > January 2020

LRI funding: 301.807€


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