Structure-Toxicity Relationships for Aminoalkanols: A Comparison with Alkanols and Alkanamines

Abstract

The relative toxicity (logIGC^?1 ₅₀) of 49 selected aliphatic amines and aminoalkanols was evaluated in the static Tetrahymena pyriformis population growth impairment assay. Excess toxicity, indicated by potency greater than predicted for non-polar narcotic alkanols, was associated with both classes of test chemicals. Moreover, the aminoalkanols were found to be more toxic than the corresponding alkanamines. A high quality 1-octanol/water partition coefficient (log K _ow) dependent quantitative structure-activity relationship (QSAR), logIGC^?1 ₅₀ = 0.78 (log K _ow)-1.42; r ² = 0.934, was developed for alkanamines. This QSAR represented the amine narcosis mechanism of toxic action. No quality QSAR was developed for the aminoalkanols. However, several structure-toxicity features were observed for this class of chemicals. Two-amino-1-hydroxy derivatives being more toxic than the corresponding derivatives, where the amino and hydroxy moieties were separated by methylene groups. Hydrocarbon branching next to the amino moiety resulted in decreased toxicity. Aminoalkanol alters lipid metabolism in T. pyriformis.     

Joint QSAR Analysis Using the Free-Wilson Approach and Quantum Chemical Parameters

Abstract

A new quantitative structure-activity relationship (QSAR) technique combining the Free-Wilson method and constructed quantum chemical parameters was used to simulate the aqueous solubility (S _w), 1-octanol/water partition coefficient (K _ow) of 14 new synthesized benzanilide derivatives and their 96 h acute toxicity (EC₅₀) to Daphnia magna. The mode of action of the 14 selected compounds to Daphnia magna was shown to be a complex process involving a physical partition stage and a biochemical reaction stage. The results also indicated that the joint (QSAR) analysis was much effective than the original Free-Wilson method and Hansch method not only in predicting properties/toxicity, but also in investigating the mode of action of chemicals.     

A Novel QSAR Approach for Estimating Toxicity of Phenols

Abstract

Toxicity values (log IGC^?1 ₅₀) for 60 phenols tested in the 2-d static population growth inhibition assay with the ciliate Tetrahymena pyriformis were tabulated. Each chemical was selected so the series formed uniform coverage of the hydrophobicity/ionization surface. A high quality hydrophobicity-dependent (log K _ow) structure-toxicity relationship (log IGC^?1 ₅₀ = 0.741 (log K_ow) ?1.433; n = 17; r² = 0.970; s = 0.134; F = 486.55; Pr > F = 0.0001) was developed for phenols with pK_a values > 9.8. Similarly, separate hydrophobicity-dependent relationships were developed for phenols with pK_a values of 4.0, 5.1, 6.3, 7.5, and 8.7. Comparisons of intercepts and slopes, respectively, revealed phenols with pK_a values of 6.3 to be the most toxic and the least influenced by hydrophobicity. These relationships were reversed for the more acidic and basic phenols. Plots of toxicity versus pK_a for nitro-substituted phenols and phenols with log K_ow values of either 1.75 or 2.50 further demonstrated bilinearity between toxicity and ionization. In an effort to more accurately model the relationship between toxicity and ionization, the absolute value function |6.3-pK_a| was used to model ionization affects for derivatives with pK_a values between 0 and 9.8. For derivatives with pK_a value > 9.8, a value of 3.50 was used to quantitate ionization effects. The use of log K_ow in conjunction with this modified pK_a (ΔpK_a) resulted in the structure-toxicity relationship (log IGC^?1 ₅₀ = 0.567 (log K_ow)-0.226 (ΔpK_a-0.079; n = 54; r² = 0.926; s = 0.215; F = 321.06; Pr > F = 0.0001). Derivatives with a nitro group in the 4-position typically did not model well with the above equation.     

Retention prediction and hydrophobicity estimation of weak acidic compounds by reversed-phase liquid chromatography using acetic and perchloric acids as ion suppressors

Simple acids are usually applied to suppress the ionization of weakly ionizable acidic analytes in reversed-phase liquid chromatography. The purpose of this study is to investigate the retention behavior of various weak acidic compounds (monoprotic, diprotic, triprotic, and tetraprotic acids) using acetic or perchloric acid as ion suppressor in a binary hydroorganic mobile phase. The apparent n-octanol–water partition coefficient (K _ow ″) was proposed to calibrate the n-octanol–water partition coefficient (K _ow) of weak acidic compound. LogK _ow ″ was found to have a better linear correlation with logk _w, the logarithm of the retention factor obtained by extrapolating to neat aqueous fraction of the mobile phase, for all weakly ionizable acidic compounds. This straightforward relationship offers a potential medium for direct measurement of K _ow data of weak acidic analytes and can be used to predict retention behavior of these compounds in the ion suppression reversed-phase liquid chromatographic mode.     

Assessment of Centrifugal Partition Chromatography for Determination of Octanol-Water Partition Coefficients

Abstract

Centrifugal partition chromatography (CPC) has been assessed as a convenient automated method for the determination of octanol-water partition coefficients (K_OW) over the range of -0.5 to 2.5 log units. The stationary (V_s) and mobile phase (V_m) volumes, which are needed for the calculation of K_ow, are determined in situ by injecting four compounds with known K_ow. V3 and V_m were also determined by independent analytical means to demonstrate that this is a direct measurement of K_ow from fundamental chromatographic principles with no unexplained fitted parameters. Propagation of error shows that a single four-component calibration with duplicate injections of each unknown is sufficient to determine log K_ow with a precision of less than 0.1 log units.     

Water solubility and octanol/water-partitioning of hydrophobic chlorinated organic substances determined by using SPME/GC

The critical step in the determination of water solubilitiy (S _w) and octanol-water partition coefficient (K _ow) of hydrophobic organic chemicals by using the generator-column technique and the slow-stirring procedure, respectively, is the exact quantification of the low water-phase concentrations of the substances under investigation. We have tested the applicability of solid-phase microextraction (SPME) and gas chromatography with seven chlorinated organic compounds. The substances cover a S _w range from 500 mg/L to 7 ng/L and a log K _ow range from 3 to 8. The results show that SPME can be a valuable alternative to common preconcentration techniques in the quantification of hydrophobic organics in pure and octanol-saturated water. The apparent SPME distribution constants K _SPME (obtained with the 100 μm-PDMS fiber for analyte’s partitioning between fiber coating and aqueous sample) do not correlate directly with octanol/water partition coefficients and thus cannot be recommended as a surrogate parameter for K _ow. Received: 15 January 1997 / Revised: 2 May 1997 / Accepted: 8 May 1997     

Nonlinear Dependence of Bioconcentration Factors on n-Octanol-Water Partition Coefficients of Chlorinated Dibenzofurans and Dibenzo-p-Dioxins

Abstract

A nonlinear thermodynamic model is applied to the prediction of both the bioconcentration factor (K_bw) in the guppy (Poecilia reticulata) and the n-octanol-water partition coefficient (K_ow) of chlorinated dibenzofurans and dibenzo-p-dioxins. To this end molar liquid volumes, heats of vaporization and empirically fitted parameters of the pertinent solute and solvents are used. Calculated log K_bw and log K_ow values are obtained with correlation coefficients (r = 0.85 and 0.992) and mean deviations (< dev > = 0.19 and 0.17), which compare favourably with experimental data.

In addition the model enables an explanation of the well-known nonlinear log-log relationship between the two properties for compounds with high K_ow values on the basis of differences between the properties of biotic lipid and n-octanol. It is suggested that the breakdown of the linear relationship is caused by entropic effects related to the number of chlorine atoms in the solute molecules and to the structures of the lipid and n-octanol.     

Determination of Octanol–Water Partition Coefficients,Water Solubility and Vapour Pressures of Alkyl-lead Compounds

Physico-chemical properties of alkyl-lead compounds, namely aqueous solubility, octanol–water partition coefficient ( K _ow), vapour pressure and Henry's Law constant, have been determined. Vapour pressures of trialkyl-lead salts at different temperatures were measured by a gas-saturation technique in which air was passed slowly through a glass column packed with pure solid alkyl-lead compounds. K _ow of tetra-alkyl-lead (TAL) and trialkyl-lead (TriAL) were determined under different salinity and pH conditions, and the latter were related to the species (R₃Pb⁺, R₃PbOH⁰ or R₃PbCl⁰) dominating under a particular set of conditions. Regression calculations incorporating melting point corrections relate water solubility to K _ow, and provide a means of estimating either parameter for a wider range of compounds.     

Determination of the n‐octanol/water partition coefficients of weakly ionizable basic compounds by reversed‐phase high‐performance liquid chromatography with neutral model compounds

A strategy to utilize neutral model compounds for lipophilicity measurement of ionizable basic compounds by reversed‐phase high‐performance liquid chromatography is proposed in this paper. The applicability of the novel protocol was justified by theoretical derivation. Meanwhile, the linear relationships between logarithm of apparent n‐octanol/water partition coefficients (logK_ow′′) and logarithm of retention factors corresponding to the 100% aqueous fraction of mobile phase (logk_w) were established for a basic training set, a neutral training set and a mixed training set of these two. As proved in theory, the good linearity and external validation results indicated that the logK_ow′′–logk_w relationships obtained from a neutral model training set were always reliable regardless of mobile phase pH. Afterwards, the above relationships were adopted to determine the logK_ow of harmaline, a weakly dissociable alkaloid. As far as we know, this is the first report on experimental logK_ow data for harmaline (logK_ow = 2.28 ± 0.08). Introducing neutral compounds into a basic model training set or using neutral model compounds alone is recommended to measure the lipophilicity of weakly ionizable basic compounds especially those with high hydrophobicity for the advantages of more suitable model compound choices and convenient mobile phase pH control.     

Sorption and partitioning parameters of benzotriazole compounds

Benzotriazole compounds have major commercial applications as anticorrosive agents in automotive antifreeze and airplane deicer fluids. This study assesses the sorption of benzotriazole (BT), 5-methylbenzotriazole (MBT), and 5-chlorobenzotriazole (CBT) from aqueous solutions to four top soils. The concentration range of 10-500 mg l⁻¹ was used with soils differing in total organic carbon content from 0.27 to 1.72%. Batch systems facilitated the equilibrium sorption with analysis by HPLC. The sorption of these compounds was as much as 60% by mass to a soil with 0.33% Org. C. The log octanol-water partition coefficients (log K_ow) were determined to be 1.23 for BT, 1.89 for MBT, and 2.17 for CBT. The relationship between the log of the sorption partition coefficient, log K_oc and log K_ow differed from previous correlations because hydrophobicity was not the only factor affecting sorption. These compounds have substantial permanent dipole moments as well as being hydrophobic. At high pH where CBT molecules approach their pK_a, sorption was approximately 50% less (by mass) than that of relatively non-ionized CBT molecules.     

Equilibrium and kinetic solid-phase microextraction determination of the partition coefficients between polychlorinated biphenyl congeners and dissolved humic acid

A conventional solid-phase microextraction (SPME) method combined with liquid–liquid extraction was applied under equilibrium and nonequilibrium conditions to determine the partition coefficients (K_doc) of 25 polychlorinated biphenyl congeners (PCBs) between Sigma–Aldrich humic acid (HA) and water. The values of log K_doc determined with equilibrium SPME were linearly correlated with the logarithm of the octanol–water partition coefficients (K_ow) for PCB congeners at log K_ow < ∼7.2, but the trends were disrupted for log K_ow from ∼7.2 to 8.18. In addition, short-term (5 min to 4 days) and long-term (5–44 days) uptake profiles of PCBs were established, from which a pseudo-equilibrium for sorption of PCBs was revealed at ∼4 days of extraction. To understand this phenomenon, the uptake profiles were fitted with two equations (one equation is often used for pure water samples and the other one is applicable for samples containing complex matrices) derived from a first-order kinetics model. Subsequently, K_doc values obtained through kinetic approaches were compared with those acquired from equilibrium SPME. The comparison of K_doc values indicated that the pseudo-equilibrium was caused by the slow desorption of PCBs from HA rather than the biphasic desorption mechanism.     

Water solubility and octanol/water-partitioning of hydrophobic chlorinated organic substances determined by using SPME/GC

The critical step in the determination of water solubilitiy (S _w) and octanol-water partition coefficient (K _ow) of hydrophobic organic chemicals by using the generator-column technique and the slow-stirring procedure, respectively, is the exact quantification of the low water-phase concentrations of the substances under investigation. We have tested the applicability of solid-phase microextraction (SPME) and gas chromatography with seven chlorinated organic compounds. The substances cover a S _w range from 500 mg/L to 7 ng/L and a log K _ow range from 3 to 8. The results show that SPME can be a valuable alternative to common preconcentration techniques in the quantification of hydrophobic organics in pure and octanol-saturated water. The apparent SPME distribution constants K _SPME (obtained with the 100 μm-PDMS fiber for analyte’s partitioning between fiber coating and aqueous sample) do not correlate directly with octanol/water partition coefficients and thus cannot be recommended as a surrogate parameter for K _ow.     

Predicting 1-octanol-water partition coefficient by high-performance liquid chromatography gradient elution

The method to predict 1-octanol-water partition coefficients (K _ow) from capacity factors (k) obtained by Reversed-Phase High-Performance Liquid Chromatography (RP-HPLC) has been extended to use gradient elution rather than isocratic elution. The mobile phase has been changed either linearly or exponentially with time. The initial composition of the mobile phase and its rate of change affected the log K _ow versus log k relation. This relation was exponential in linear gradient experiments. For non-linear gradient elution in which the water fraction of the mobile phase decreased exponentially from 100% to approach 0% asymptotically, a physically-based equation describing the dependence of log K _ow on log k has been derived. Without any preliminary estimation, RP-HPLC gradient elution allows a precise prediction of log K _ow over a range of nearly six orders of magnitude.     

Reversed phase liquid chromatography of PCBs as a basis for the calculation of water solubility and log Kow for polychlorobiphenyls

Summary Water solubility (S _w) and log K _ow values have been determined for 154 possible polychlorobiphenyls using the retention indices obtained by RP-HPLC and structurally selected PCB congeners with known log K _ow values for the regression lines. The water solubility data are melting point corrected.

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Umkehrphasen-Flüssig-Chromatographie von PCBs als Grundlage zur Berechnung der Wasserlöslichkeit und des log K _ow für Polychlorbiphenyle

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Dedicated to Prof. Dr. W. Fresenius on the occasion of his 75th birthday     

Determination of bioconcentration factors of isomeric polycyclic aromatic hydrocarbons in polychaete worms by HRGC on selective liquid crystalline stationary phases

The bioconcentration factors (K_b) of parent and alkylated PAHs isolated from polychaete worms collected in coastal sediments were determined for the first time. Capillary gas chromatography using a polymeric liquid crystalline (MPMS) and SE-54 stationary phases coupled to FID, MS and concurrent elution with authentic standards permitted positive identifications of parent PAHs. The K_b values of 18 compounds were accurately determined on the liquid crystalline column and the those of mono- and dialkyl-phenathrene, -pyrene and -chrysene were determined by GC-MS on a SE-54 coated column. The experimental K_b values exhibited a moderate correlation (r=0.7–0.8) with the reported octanol-water partition coefficients (K_ow) for these compounds. Consequently, kinetic considerations, i.e. biouptake-release and enzymatic activity seem to be relevant, in addition of biota-media equilibrium. Therefore, integrated bioconcentration models are needed.     

Evaluation of low-cost disposable polymeric materials for sorptive extraction of organic pollutants in water samples

The capabilities of four commercially available and low cost polymeric materials for the extraction of polar and non-polar contaminants (log K_ow = −0.07–6.88, from caffeine to octocrylene, respectively) from water samples was compared. Tested sorbents were polyethersulphone, polypropylene and Kevlar, compared to polydimethylsiloxane as reference material. Parameters that affect the extraction process such as pH and ionic strength of the sample, extraction time and desorption conditions were thoroughly investigated. A set of experimental partition coefficients (K_pw), at two different experimental conditions, was estimated for the best suited materials and compared with the theoretical octanol–water (K_ow) partition coefficients of the analytes. Polyethersulphone displayed the largest extraction yields for both polar and non-polar analytes, with higher K_pw and lower matrix effects than polydimethylsiloxane and polypropylene. Thus, a sorptive microextraction method, followed by large volume injection (LVI) gas chromatography–tandem mass spectrometry (GC–MS/MS), was proposed using the former sorbent (2 mg) for the simultaneous determination of model compounds in water samples. Good linearity (>0.99) was obtained for most of the analytes, except in the case of 4-nonylphenol (0.9466). Precision (n = 4) at 50 and 500 ng L⁻¹ levels was in the 2–24% and limits of detection (LODs) were in the 0.6–25 ng L⁻¹ range for all the analytes studied.     

Validation of pH-Metric Technique for Measurement of pKa and log Pow of Ionizable Herbicides

Abstract

Knowing the values of pK_a and partition coefficients between 1-octanol and water (P_ow) of ionizable herbicides helps us to understand the movement of these compounds in plants and soil. However, shake-flask and high-pressure liquid chromatography (HPLC) techniques. though valuable for measurement of log P_ow of herbicide molecules that do not ionize in aqueous solution, are difficult to use for ionizable molecules; this is especially so for molecules that form ion pairs having appreciable log P_ow values, those with multiple ionizations and for bases with high pK_a values. Our aim in this study was to validate the use of the pH-metric technique (based on potentiometric titration) for measurements of pK_a and log P_ow of ionizable standard substances and herbicides. The values obtained show good correlation with results from other techniques, including shake-flask and HPLC. The OECD Guideline for Testing of Chemicals 117, adopted 30th March 1989, describes the use of HPLC for the measurement of log P_ow. It is hoped that these studies and further testing of this technique will permit it to be included in these OECD guidelines.     

Volume and enthalpy relaxation in a-PMMA after temperature up-jumps

the volume and enthalpy relaxation in a-PMMA subjected to temperature jumps in t_g region has been analysed. The measured H and V data were compared with respect to aging time and proportionality between them as a slope of (∂H/∂V)_T dependencies has been found. According to previous works the slope was identified as an apparent bulk modulus, K _a. This method is applied to aging following temperature up-jumps after consolidation periods of varying lengths. the main finding is a marked increase of K _a with consolidation time, approaching a limiting value in an asymptotic fashion. This revised version was published online in July 2006 with corrections to the Cover Date.