Quantitative analysis of molecular interaction potentials of ionic liquid anions using multi-functionalized stationary phases in HPLC.

The molecular interaction potentials, including S (dipolarity/polarizability), A (hydrogen bonding acidity), and B (hydrogen bonding basicity), of anions are experimentally determined using multi-functionalized stationary phases in high-performance liquid chromatography (HPLC) systems. We employ three different multi-functionalized stationary phase columns (Obelisc R, Obelisc N, and Acclaim Trinity-P1) combined with two ingredients, namely, acetonitrile (ACN) and methanol (MeOH). These conditions can cause neutral, cationic, and anionic compounds to be retained. By using the retention characteristics of calibration compounds, including cations, anions, and neutral compounds, system parameters including the ionic interaction terms (zc Zc , za Za ) are evaluated using multiple linear regression, resulting in a standard deviation (SD) of 0.090-0.158 log units. Based on the system parameters and retention characteristics of the anions of interest, their molecular interaction potentials are characterized on the same scale for neutral and cationic molecules. Furthermore, to verify the determined molecular interaction potentials, we predict anion hydrophobicity. The results show that the determined S, A, and B, together with the computable descriptors E (excess molar refraction) and V (McGowan volume), can predict anion hydrophobicity with R(2) =0.982 and SD=0.167 (dimensionless).

Determination of LFER descriptors of 30 cations of ionic liquids--progress in understanding their molecular interaction potentials.

In order to understand molecular interaction potentials of 30 cations of ionic liquids (ILs), the well-known linear free energy relationship concept (LFER) was applied. The LFER descriptors for the excess molar refractivity and the molar volume were calculated in silico and for hydrogen-bonding acidity and basicity, and the polarizability/dipolarity of IL cations were experimentally determined through high performance liquid chromatography (HPLC) measurements. For the study, three different columns (RP-select B, Cyan, and Diol) and buffered mobile phases, based on two organic solvents acetonitrile (ACN) and methanol (MeOH), were selectively combined to the HPLC separation systems RP-select B-ACN, RP-select B-MeOH, Cyan-MeOH, Diol-ACN, and Diol-MeOH. By measuring the retention factors of 45 neutral calibration compounds and calculating LFER descriptors of three cations in the HPLC systems, the system parameters, including an ionic z coefficient, were determined. Conversely, the LFER descriptors of 30 ionic liquid cations were determined, based on the parameters of five systems and their retention factors in the HPLC systems. The results showed that the type of head group, alkyl chain length and further substituents of the cation have a significant influence on the dipolarity/polarizability and the hydrogen-bonding acidity, and functionalized groups (hydroxyl, ether, and dimethylamino) lead to hydrogen-bonding basicity of the cation. The characterization of cationic LFER descriptors opens up the chance for a more quantitative understanding of molecular interaction potentials and physicochemical properties of ILs.

Analyzing cytotoxic effects of selected isothiazol-3-one biocides using the toxic ratio concept and structure-activity relationship considerations.

To demonstrate how baseline toxicity can be separated from other more specific modes of toxic action and to address possible pitfals when dealing with hydrophobic substances, the four isothiazol-3-one biocides N-methylisothiazol-3-one (MIT), 5-chloro-N-methylisothiazol-3-one (CIT), N-octylisothiazol-3-one (OIT), and 4,5-dichloro-N-octylisothiazol-3-one (DCOIT) as an example for reactive electrophilic xenobiotics were tested for their cytotoxic effects on the human hepatoblastoma cell line Hep G2, on the marine bacterium Vibrio fischeri, and on the limnic green alga Scenedesmus vacuolatus. In each of the three test systems, toxic effects were observed in a consistent pattern. The two chlorinated compounds and OIT were found to be significantly more toxic than MIT. As compared to baseline toxicants, the small and polar MIT and CIT exhibited pronounced excess toxicity in each of the three test systems that is presumably triggered by their intrinsic reactivity toward cellular thiols. In contrast, OIT and DCOIT showed mainly toxicities that could be explained by their hydrophobicity. Analyzing and comparing these results using the toxic ratio concept and with data that indicate a dramatic depletion of cellular glutathione levels after incubation with DCOIT reveals that for highly hydrophobic substances, baseline level toxicity in an assay for acute toxicity can lead to an oversight of other more specific modes of toxic action that may cause significant effects that might be less reversible than those caused by unreactive baseline toxicants. This possibility should be taken into account in the hazard assessment of chemicals that are both hydrophobic and reactive.

Explaining ionic liquid water solubility in terms of cation and anion hydrophobicity.

The water solubility of salts is ordinarily dictated by lattice energy and ion solvation. However, in the case of low melting salts also known as ionic liquids, lattice energy is immaterial and differences in hydrophobicity largely account for differences in their water solubility. In this contribution, the activity coefficients of ionic liquids in water are split into cation and anion contributions by regression against cation hydrophobicity parameters that are experimentally determined by reversed phase liquid chromatography. In this way, anion hydrophobicity parameters are derived, as well as an equation to estimate water solubilities for cation-anion combinations for which the water solubility has not been measured. Thus, a new pathway to the quantification of aqueous ion solvation is shown, making use of the relative weakness of interactions between ionic liquid ions as compared to their hydrophobicities.

Structure-activity relationships for the impact of selected isothiazol-3-one biocides on glutathione metabolism and glutathione reductase of the human liver cell line Hep G2.

To investigate the toxic mode of action of isothiazol-3-one biocides the four compounds N-methylisothiazol-3-one (MIT), 5-chloro-N-methylisothiazol-3-one (CIT), N-octylisothiazol-3-one (OIT) and 4,5-dichloro-N-octylisothiazol-3-one (DCOIT) were purified and tested as single chemical entities for their effects on the human hepatoblastoma cell line Hep G2 and on isolated and cellular glutathione reductase GR). The two chlorinated substances CIT and DCOIT significantly decreased the amount of total cellular glutathione (GSx) in a dose and time dependent manner. Concomitantly, an increase in the level of oxidised glutathione (GSSG) was observed. The resulting shift in the GSH/GSSG ratio entailing the breakdown of the cellular thiol reduction potential was accompanied by necrotic morphological changes like swelling of the plasma membrane and subsequent lysis of the cells. Additionally, CIT and DCOIT were found to inhibit cellular GR in the cells in a concentration dependent manner. The T-SAR-based (thinking in terms of structure-activity relationships) comparison of the chlorine-substituted structures CIT and DCOIT with their non-chlorinated and less active analogues MIT and OIT identified the chlorine substituents and the resulting reaction mechanisms to be the key structural mediators of the observed toxic effects. Furthermore, differences in the activity of both chlorinated substances could be explained using the T-SAR approach to link the lipophilicity and the intrinsic glutathione-reactivity of the compounds to the expected target site concentrations inside the cells.

Risk assessment of biocides in roof paint. Part 1: experimental determination and modelling of biocide leaching from roof paint.

BACKGROUND, AIM AND SCOPE: Many surface coatings, including roof paints, contain biocides. It is generally not known to what extent roof paint biocides leach from the paint, and consequently, what concentration the biocide may attain in a rainwater collection system. To this end the leaching of specific biocides from a variety of German roof paints was investigated and the resulting concentrations in collected rain water were estimated. MATERIALS AND METHODS: A laboratory simulation was used to determine the time dependant leaching rate of the biocide from the paint into synthetic rainwater. The concentrations of biocide in the leachate were quantified using HPLC. The course of the leachate concentrations over time was fitted using a simple mathematical model. This was then used to estimate concentrations of biocides in a typical household rainwater collection system over time. RESULTS: Surprisingly, the biocides found in the paints did not always concur with the declared biocides. Concerning the modelling of runoff concentrations, it was found that--under the model assumptions--the rain intensity and cumulative raining time after application are the dominant factors influencing the concentration of the biocide. At the highest modelled rain intensity of 40 mm/hour it only takes about 2 hours to reach peak concentrations lower than 0.1 mg/L, at 0.3 mm/hour it takes about 10 hours to reach peak concentrations of 1.3, 0.9, 5.2 and 1.1 mg/L for terbutryn from Emalux paint, terbutryn from Südwest paint, carbendazim from Emalux paint, and carbendazim from MIPA paint, respectively. DISCUSSION: The results confirm that biocides leached from roof paint will be present in roof runoff. The highest estimated peak concentrations are close to the water solubility of the respective biocides. This indicates that the model assumption of a concentration independent leaching rate will tendentially lead to an overestimation of the leached concentrations under these circumstances. However, under most circumstances such as higher rain intensities, and longer time after peak concentrations have been reached, the runoff concentrations are far from the solubility limit, and therefore it is proposed that the model assumptions are tenable. CONCLUSIONS: The leaching of biocides from roof paints can be roughly assessed using a relatively simple approach. The declaration of biocidal ingredients in roof paints should be improved and information on their biocide leaching behaviour should be made available. Furthermore, the estimations should be evaluated by a field study. RECOMMENDATIONS AND PERSPECTIVES: The leaching study indicated that the concentrations of selected biocides can reach significant levels, especially after low intensity rainfall. Taking into account the inherent biological activity of the substances under scrutiny, it can already be concluded that it is not advisable to use runoff water from roofs freshly painted with biocide containing roof paints. These results have been complemented by a literature search of biological effects of the investigated biocides, ecotoxicological tests with several species and a risk analysis for organisms exposed to runoff water. This will be presented in Part 2 of this contribution.

Comparison of software tools for kinetic evaluation of chemical degradation data.

BACKGROUND: For evaluating the fate of xenobiotics in the environment, a variety of degradation or environmental metabolism experiments are routinely conducted. The data generated in such experiments are evaluated by optimizing the parameters of kinetic models in a way that the model simulation fits the data. No comparison of the main software tools currently in use has been published to date. This article shows a comparison of numerical results as well as an overall, somewhat subjective comparison based on a scoring system using a set of criteria. The scoring was separately performed for two types of uses. Uses of type I are routine evaluations involving standard kinetic models and up to three metabolites in a single compartment. Evaluations involving non-standard model components, more than three metabolites or more than a single compartment belong to use type II. For use type I, usability is most important, while the flexibility of the model definition is most important for use type II. RESULTS: Test datasets were assembled that can be used to compare the numerical results for different software tools. These datasets can also be used to ensure that no unintended or erroneous behaviour is introduced in newer versions. In the comparison of numerical results, good agreement between the parameter estimates was observed for datasets with up to three metabolites. For the now unmaintained reference software DegKinManager/ModelMaker, and for OpenModel which is still under development, user options were identified that should be taken care of in order to obtain results that are as reliable as possible. Based on the scoring system mentioned above, the software tools gmkin, KinGUII and CAKE received the best scores for use type I. Out of the 15 software packages compared with respect to use type II, again gmkin and KinGUII were the first two, followed by the script based tool mkin, which is the technical basis for gmkin, and by OpenModel. CONCLUSIONS: Based on the evaluation using the system of criteria mentioned above and the comparison of numerical results for the suite of test datasets, the software tools gmkin, KinGUII and CAKE are recommended for use type I, and gmkin and KinGUII for use type II. For users that prefer to work with scripts instead of graphical user interfaces, mkin is recommended. For future software evaluations, it is recommended to include a measure for the total time that a typical user needs for a kinetic evaluation into the scoring scheme. It is the hope of the authors that the publication of test data, source code and overall rankings foster the evolution of useful and reliable software in the field.

Reversed-phase liquid chromatographic method for the determination of selected room-temperature ionic liquid cations.

The separation of selected 1-alkyl- and 1-aryl-3-methylimidazolium-based room temperature ionic liquid cations has been performed using reversed-phase high-performance liquid chromatography with electrospray ionization mass detection. The RP-HPLC method development started with the selection of a column taking into account especially the resolution of low molecular congeners of the selected group. Mobile phase composition was optimized for peak resolution, sensitivity and high reproducibility of retention values. The results of the method development were applied to the determination of exemplary ionic liquid species present in the medium used in cytotoxicity studies.

Ionic liquids: predictions of physicochemical properties with experimental and/or DFT-calculated LFER parameters to understand molecular interactions in solution.

In this article, we present evolutionary models to predict the octanol-water partition coefficients (log P), water solubilities, and critical micelle concentrations (CMCs) of ionic liquids (ILs), as well as the anionic activity coefficients and hydrophobicities in pure water and octanol-water. They are based on a polyparameter linear free energy relationship (LFER) using measured and/or DFT-calculated LFER parameters: hydrogen-bonding acidity (A), hydrogen-bonding basicity (B), polarizability/dipolarity (S), excess molar refraction (E), and McGowan volume (V) of IL ions. With both calculated or experimental LFER descriptors of IL ions, the physicochemical parameters were predicted with an errors of 0.182-0.217 for the octanol-water partition coefficient and 0.131-0.166 logarithmic units for the water solubility. Because experimentally determined solute parameters of anions are not currently available, the CMC, anionic activity coefficient, and hydrophobicity were predicted with quantum-chemical methods with R(2) values of at least 0.99, as well as errors below 0.168 logarithmic units. These new approaches will facilitate the assessment of the technical applicability and environmental fate of ionic compounds even before their synthesis.

Lipophilicity parameters for ionic liquid cations and their correlation to in vitro cytotoxicity.

Regarding the great structural variability of the currently expanding group of ionic liquids, it is highly desirable to understand the basic factors affecting their toxicity in different biological systems. The present study of a set of 74 ionic liquids with imidazolium, pyrrolidinium, pyridinium, quinolinium, quaternary phosphonium and quaternary ammonium cations and the comparatively small anions Cl(-), Br(-), BF(4)(-), or PF(6)(-) demonstrates the influence of the cation lipophilicity on the cytotoxicity in IPC-81 leukemia cells from rats. The scope of this correlation is limited to ionic liquids with these or similarly small anions that are sufficiently nonreactive under physiological and chromatographic conditions and whose cation lipophilicity does not exceed a certain threshold.

Persistence of antifouling agents in the marine biosphere.

Risk indicators provide an interesting way to compare chemical substances with respect to the risks of their large-scaled release. The present study implies that, for antifouling agents used in commercial shipping, residence times in the marine biosphere are especially suitable to represent their inherent potential to cause exposure of organisms. A simple box model is described providing the possibility to estimate residence times in the marine biosphere from water-particle equilibrium partitioning constants and half-lives in water and sediment. Resulting residence times in the marine biosphere range from about 5 d (4,5-dichloro-2-n-octyl-4-isothiazolin-3-one) up to about 40,000 yr (copper). For an evaluation of the validity of the model, calculated values are compared with measured environmental concentrations. Remaining uncertainties are also discussed. The main purpose of the presented residence times is to serve as a basis for decisions in antifouling paint development or environmentally conscious purchasing of antifouling paints.