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Abstract

Chemicals possessing persistence (P) and high mobility (M) can present a hazard to drinking water resources by traversing natural barriers like riverbanks and artificial barriers found in water treatment plants. If the chemical is also toxic (T), i.e. classifiable as a PMT, the agent might be of particular concern as a potential drinking water contaminant. During routine water sampling, detection and quantitation of polar substances with high mobility can be problematic. The German Environment Agency (UBA) is considering the use of the Log Koc value as a proxy for mobility (M). Log Koc is related to Log P by the equation Log Koc = 0.69 Log P + 0.22. In this study, we demonstrate that chemicals with log P values at or very close to 2.0, 3.0 or 4.0 (and their concomitant log Koc values) can vary significantly in their chemical structures, molecular weights, molar volumes, and calculated molar refractivity (CMR), which is related to the mean polarizability of a molecule. The large degree of potential diversity in chemical structure and molecular parameters related to chemical behavior at a particular log P or log Koc value suggests that log Koc might not contain enough information to function as a standalone surrogate for the mobility (M) of a chemical, i.e. as related to its ability to move from a drinking water resource through the water plant purification process.

Keywords

Chemical mobility log Koc log P QSAR water quality

Introduction

Certain persistent (P) and mobile (M) chemicals inadvertently released into the environment can pass through natural barriers like riverbanks and soil layers above aquifers, and through artificial barriers found in water plants, eventually working their way into drinking water.¹ The time required for an environmental chemical to traverse a particular natural barrier and make its way to a water treatment plant varies greatly, from a few days for surface water runoff, 1 to 2 weeks to percolate through a riverbank, or up to the scale of years to enter groundwater wells.¹ Several factors can influence the time lag between a chemical’s release into the environment and its entry into drinking water. First, higher quantity emissions increase the probability of downstream contamination. Second, persistent chemicals (P) have a longer half-life thereby increasing the chance of eventually entering drinking water. Third, chemicals with higher mobility (M) are more likely to complete the journey from point of environmental entry to drinking water.¹

The German Environment Agency (UBA) is considering the use of the Log Koc value as a proxy for mobility (M).^2

–6 The Soil Adsorption Coefficient is denoted by either Kd or Kf. The Soil Adsorption Coefficient (Kd or Kf) measures the amount of a chemical adsorbed onto soil per amount of water. [The Kf designation comes from the Freundlich solid-water distribution coefficient.] Soil Adsorption Coefficient values vary greatly because the organic chemical compositional percentage of soil varies greatly. Adsorption of chemicals onto soil occurs predominantly by partition into the soil organic matter. Therefore, the Kd or Kf is normalized to the amount of organic carbon in a soil and is expressed as either Koc or Kfoc, which are interchangeable for practical purposes. The Koc is known as the organic carbon-water partition coefficient.^7,8 Log Koc is related to Log P (Log of the octanol/water partition coefficient) by the equation Log Koc = 0.69 Log P + 0.22.^9,10

In this study, we demonstrate that 3 sets of 25 chemicals with log P values at or very close to 2.0, 3.0 or 4.0 (and their concomitant log Koc values), respectively, can vary significantly in their Hansch Quantitative Structure-Activity Relationship (QSAR) parameters. The parameters examined in this study are the calculated base 10 logarithm of the octanol–water partition coefficient (ClogP), the McGowan molecular volume (MgVol), and the calculated molar refractivity (CMR). These QSAR parameters represent hydrophobic (ClogP) effects, steric/size (MgVol) considerations, and the total polarizability (CMR) of a mole of the substance of a chemical on its biological activity. These parameters have proven extremely useful in developing QSAR models describing the quantitative relationships between the biological activity of chemicals and their physicochemical characteristics.

Previously, Smith et al. ¹¹ showed that smaller molecular volumes were found to be associated with higher levels of tumorigenicity. Lower rather than higher levels of lipophilicity were found to be associated with higher levels of tumorigenicity. Positive Ames test results were positively correlated with overall tumorigenicity and with possession of structural alerts of carcinogenicity. Since larger organic molecules have more chemical reaction centers, it was not surprising that higher ClogP values were positively correlated with the number of structural alerts of carcinogenicity. The results from this earlier study¹¹ demonstrated the ability to devise rational rules for relative tumorigenicity in rodents that correlated with known parameters of toxicity.

Log P values of 2.0 represent 100-fold more solubility in lipid than in water, log P values of 3.0 represent 1000-fold more lipid solubility, and log P values of 4.0 represent 10,000-fold more lipid solubility. Thus, the 75 molecules (3 sets of 25 molecules) examined in this study span a wide range of lipid solubility. As log Koc is linearly related to log P, the range of log Koc values spanned in this study is also very large. The large degree of potential diversity in chemical structure and molecular parameters related to chemical behavior at a particular log P or log Koc value suggests that log Koc might not contain enough information to function as a standalone surrogate for the mobility (M) of a chemical as related to its ability to move from a drinking water resource through the water plant purification process.

Methods

The octanol-water partition coefficients (P) for the 75 chemicals were reported in the literature and located by developing a web scraper searching for chemicals from the Super Natural II Database (http://bioinf-applied.charite.de/supernatural_new/index.php) with log P values of 2.0, 3.0 and 4.0.¹² Super Natural II is a highly curated online database for natural products. Initially designed in 2006, the database contains 325,508 natural products extracted from various resources, including vendor information. Natural II offers both search and analysis options. It provides the toxicity prediction for the database compounds.¹² The log Koc values were calculated from the literature values for log P using the equation¹⁰:

$Log Koc = 0.69 Log P + 0.22$

Calculation of Clog P, CMR and MgVol

Bio-Loom (version 1.6; Biobyte Corp., Claremont, CA, USA)¹³ was used to compute the three parameters used in our QSAR analysis from the simplified molecular input line entry system representation of each chemical compound: ClogP, CMR, and MgVol (Online Appendix 4). The utility of Bio-Loom for comparative QSAR (C-QSAR) analysis in comparative correlation analysis has been discussed in Hansch and Leo.¹⁴ The parameters used in this study are also discussed in detail in Hansch and Leo.¹⁴ In brief, ClogP is the calculated logarithm of the partition coefficient in octanol/water and is a measure of hydrophobicity (or lipophilicity) of a chemical.^14,15 MgVol is the molar volume calculated by the method of Abraham and McGowan ^16,17 and CMR is the calculated molar refractivity (MR) for the whole molecule. MR is calculated as follows:

MR = [(n^{2} - 1) / (n^{2} + 2)] \times [MW / d]

where n is the refractive index, MW is the molecular weight, and d is the density of a substance. Since there is very little variation in n,¹⁸ MR is largely a measure of volume with a small correction for polarizability. The MR values are scaled by 0.1. MR can be used for a substituent or for the whole molecule. Clog P and CMR are for the neutral form of partially ionized chemicals. CMR values obtained are calculated using the same program as that used to calculate ClogP.¹³ Note that the Clog P values are for the neutral form of acids and bases that may be partially ionized. If the degree of ionization is about the same for a set of congeners, the ionization factor can be neglected; otherwise, good correlation can be obtained using electronic terms.^14,18 The correlation between experimental Log P and Clog P values for 13,815 chemicals in the CLOG program, which is a part of Bio-Loom,¹³ is 0.98 (experimental Log P = 1:00 Clog P − 0:03 (n = 13,815, r = 0.98, s = 0.35)). Clog P parameter that was used in this study has been widely used and cited by the QSAR community, both for environmental studies and for drug design.^{19

–30} A very high correlation (r = 0.98) between experimental Log P and Clog P gives confidence in using Clog P values whenever experimental Log P values are not available.

Statistical methods

Analysis of variance (ANOVA) for one factor³⁰

The following scenario is considered. A set of data consisting of N scores x’s composed of n groups of equal size k each so that N = nk. Index these scores as x_{i, j}, 1 ≤ i ≤ n, 1 ≤ j ≤ k. The score x_{i, j} falls in the i’th group and index j is for the j’th score x in the i’th group.

$Let {\bar{x}}_{i} = (\sum_{j = 1}^{k} x_{i, j}) / k be the mean for the x ’s in group i.$

$Let \bar{x} = (\sum_{i = 1}^{n} \sum_{j = 1}^{k} x_{i, j}) / N be the mean for all the x ’s.$

A test for the statistical significance of differences in the means $\bar{x}$ _i is requested. In section 40, Intraclass Correlation as an Example of the Analysis of Variance in Statistical Methods for Research Workers, by RA Fisher (Fifth Edition 1934), the following reasoning is employed.³¹

$First \sum_{i = 1}^{n} \sum_{j = 1}^{k} {(x_{i, j} - \bar{x})}^{2} = k \sum_{i = 1}^{n} {({\bar{x}}_{i} - \bar{x})}^{2} + \sum_{i = 1}^{n} \sum_{j = 1}^{k} {(x_{i, j} - \bar{x})}^{2}$

Thus, the Total sum of squares $\sum_{i = 1}^{n} \sum_{j = 1}^{k} {(x_{i, j} - \bar{x})}^{2}$ can be written as the Between families k $k \sum_{i = 1}^{n} {({\bar{x}}_{i} - \bar{x})}^{2}$ plus the Within families $\sum_{i = 1}^{n} \sum_{j = 1}^{k} {(x_{i, j} - {\bar{x}}_{i})}^{2}$ sums of squares.

Under the assumption (Null Hypothesis) that all the x’s are independent observations taken from the same population with a normal distribution (fixed mean and standard deviation) the Total, Between families, and Within families sum of squares after each being divided by the variance of this normal distribution will have $χ$ ² distributions with nk $-$ 1, n $-$ 1, and n(k $-$ 1) degrees of freedom, respectively.³¹

Fisher goes on to define the correlation $ρ$ = A / (A+B), where A = $A = (\sum_{i = 1}^{n} {(x_{i} - {\bar{x}}_{i})}^{2}) / (n - 1) - B / k$ and B = $B = (\sum_{i = 1}^{n} \sum_{j = 1}^{k} {(x_{i, j} - {\bar{x}}_{i})}^{2}) / (n (k - 1))$ .³¹

The modification $F (n - 1, N - n) = ((\sum_{i = 1}^{n} k ({\bar{x}}_{i} - \bar{x}) 2) / (n - 1)) / ((\sum_{i = 1}^{n} \sum_{j = 1}^{k} {(x_{i, j} - \bar{x})}^{2}) / (N - n))$ is used by Excel ANOVA.

Results

For the chemicals with log P values at or near 2.0 (for log P of 2, concomitant log Koc value is 1.6), the molecular weights vary widely from a low value of 150.104 to a high of 888.451 (Table 1). In ascending order, the molecular weights of the chemicals with log P values at or near 2.0 are as follows: 150.104; 163.124;164.131; 220.085; 256.167; 260.105; 270.183; 288.16; 288.171; 308.116; 328.058; 348.157; 350.19; 354.067; 358.069; 376.225; 404.255; 420.19; 432.323; 480.183; 482.217; 483.226; 486.262; 594.377; and 888.451. For the chemicals with log P values at or near 3.0 (for log P of 3, concomitant log Koc value is 2.29), the molecular weights range from 125.12 to 694.263 (Table 1). In ascending order, the molecular weights of the chemicals with log P values at or near 3.0 are as follows: 125.12; 156.151; 198.068; 203.095; 222.126; 250.157; 252.173; 317.128; 328.067; 330.183; 334.214; 342.194; 352.154; 356.126; 385.213; 389.257; 395.185; 398.137; 424.271; 436.163; 476.241; 489.154; 493.273; 530.324; and 694.263. For the chemicals with log P values at or near 4.0 (for log P of 4, concomitant log Koc value is 2.98), the molecular weights range from 216.151 to 839.555 (Table 1). In ascending order, the molecular weights of the chemicals with log P values at or near 4.0 are as follows: 216.151; 218.167; 228.115; 250.063; 254.094; 259.194; 260.095; 266.182; 304.167; 320.046; 324.184; 339.183; 351.147; 357.984; 376.142; 377.126; 402.11; 439.307; 450.14; 451.076; 472.319; 486.173; 538.387; 583.295; and 839.555. In summary, chemicals sharing very similar log P values of 2.0, 3.0 and 4.0 display quite wide ranges of molecular weights indicative of the great diversity of chemical structures capable of having similar or the same log P or log Koc values.

Table 1.

A diverse set of chemicals with log p values at or very near 2.0, 3.0 or 4.0.

logP	P	logKoc	Koc	ClogP	MgVol	CMR	Name	Molecular Weight	Formula	Chemical Class
1.99	97.72372	1.5931	39.18321	2.09	1.6	5.79	N-(3-methylphenyl)-2-oxo-1,3-oxazolidine-3-carboxamide	220.085	C11H12N2O3	Aromatic amine
1.99	97.72372	1.5931	39.18321	1.82	2.94	10.25	(1 S,3 S,4 S,6 S,9 S,10 S,11 S,13 S)-6,11-dihydroxy-5,5,9-trimethyl-14-methylidene-15-oxotetracyclo[11.2.1.0¹,¹ ⁰.0⁴,⁹]hexadecan-3-yl acetate	376.225	C22H32O5	Oxotetracyclohexadecanyl acetate
1.99	97.72372	1.5931	39.18321	1.85	1.41	4.98	2-ethyl-3-methyl-5 H,6 H,7 H,8H-imidazo[1,2-a]pyridine	164.131	C10H16N2	Imidazopyridine
1.99	97.72372	1.5931	39.18321	1.9	2.4	8.87	2-(3,4-dihydroxyphenyl)-5-hydroxy-4-oxochromen-7-yl (2 R)-2-hydroxypropanoate	358.069	C18H14O8	Oxochromenyl-hydroxypropanoate
1.99	97.72372	1.5931	39.18321	2.07	1.34	4.79	UNPD31574	150.104	C10H14O	Cyclohexadiene
1.9902	97.76874	1.593238	39.19566	2.03	3.03	10.69	(2 S)-N-phenyl-2-{[(1 S,2 R,6 R,8 R,9 R)-4,4,11,11-tetramethyl-3,5,7,10,12-pentaoxatricyclo[7.3.0.0²,⁶]dodecan-8-yl]formamido}propanamide	420.19	C21H28N2O7	Amide
1.991	97.949	1.59379	39.24551	1.86	2.31	8.65	4-methyl-1-(2-oxo-2-phenylethyl)-3H-1,4-benzodiazepine-2,5-dione	308.116	C18H16N2O3	Benzodiazepinedione
1.991	97.949	1.59379	39.24551	1.86	1.92	6.92	(8 S)-8-hydroxy-6,6,8-trimethyl-5 H,7H-azuleno[5,6-c]furan-4,9-dione	260.105	C15H16O4	Azulenofurandione
1.9926	98.31052	1.594894	39.3454	1.92	2.42	9.49	(3aR,6aR)-5-(2,3-dimethylphenyl)-3-(thiophene-2-carbonyl)-3aH,6aH-pyrrolo[3,4-d][1,2]oxazole-4,6-dione	354.067	C18H14N2O4S	Pyrrolooxazoledione
2	100	1.6	39.81072	2.09	3.63	12.98	Methyl (2 S)-2-{[(2 R)-1-acetyl-4-(phenylcarbamoyl)piperazin-2-yl]formamido}-3-(4-methoxyphenyl)propanoate	482.217	C25H30N4O6	Piperazinylformamidomethoxyphenylpropanoate
2	100	1.6	39.81072	1.92	2.66	9.37	(3aS,4 R,6 R,7 R,7aS)-6-ethenyl-3a-hydroxy-6-methyl-3-methylidene-2-oxo-7-(prop-1-en-2-yl)-tetrahydro-1-benzofuran-4-yl 2-(hydroxymethyl)prop-2-enoate	348.157	C19H24O6	Benzofuran propenoate
2.0004	100.0921	1.600276	39.83603	1.97	1.39	5.08	(2 R)-1-methyl-2-(pyridin-3-yl)pyrrolidin-1-ium	163.124	C10H15N2	Pyridinylpyrrolidinium ion
2.001	100.2305	1.60069	39.87402	1.96	2.33	7.49	Methyl (3 S,4E,6 S)-3-hydroxy-6-isopropyl-3-methyl-9-oxodec-4-enoate	270.183	C15H26O4	Methyloxodecenoate
2.001	100.2305	1.60069	39.87402	1.96	3.58	12.81	(1 S,2 R,6 S,7 R,9 R,11 S,12 S,15 S,16 S)-15-[(1 R)-1-[(1 S,4 R,6 S)-1,6-dimethyl-2-oxo-3,7-dioxabicyclo[4.1.0]heptan-4-yl]-1-hydroxyethyl]-6-hydroxy-2,16-dimethyl-8-oxapentacyclo[9.7.0.0²,⁷.0⁷,⁹.0¹ ²,¹ ⁶]octadec-4-en-3-one	486.262	C28H38O7	Oxapentacyclooctadecenone
2.001	100.2305	1.60069	39.87402	1.95	2.12	6.96	(3 R,4 R,5 R,7 S)-4,5-dihydroxy-3,5,7,9-tetramethyl-1-oxacycloundec-9-en-2-one	256.167	C14H24O4	Oxacycloundecenone
2.0014	100.3229	1.600966	39.89937	2.16	3.56	12.49	(1 S,3aS,5 S,7aR)-5-hydroxy-3,3,5-trimethyl-N-[(1-methylpyrrol-2-yl)methyl]-7a-[3-(morpholin-4-yl)-3-oxopropyl]-hexahydroinden-1-aminium	432.323	C25H42N3O3	Morpholinyloxopropylhexahydroindenaminium ion
2.0014	100.3229	1.600966	39.89937	2.08	2.68	9.84	(2 R,4 S,5 S)-5-(morpholin-4-ylmethyl)-2-[(thiophen-2-ylformamido)methyl]-1-azabicyclo[2.2.2]octan-1-ium	350.19	C18H28N3O2S	Azabicyclooctanium ion
2.0016	100.3691	1.601104	39.91205	1.97	3.78	13.57	(2E)-N-[(2 R,3 S)-2,3-dihydroxy-8-[(2 S,3 R)-3-[(6 S)-6-hydroxyoct-7-en-2,4-diyn-1-yl]oxiran-2-yl]octyl]-3-(3,4-dihydroxyphenyl)prop-2-enamide	483.226	C27H33NO7	Dihydroxyphenylpropenamide
2.0017	100.3922	1.601173	39.91839	1.82	3.5	13.05	N-[(3 S,7 S,10 R,12 S)-4-(2,5-dimethylbenzoyl)-2,9-dioxo-1,4,8-triazatricyclo[8.3.0.0³,⁷]tridecan-12-yl]-2-(thiophen-2-yl)acetamide	480.183	C25H28N4O4S	Thiophenylacetamide
2.002	100.4616	1.60138	39.93742	1.8	2.07	7.94	(2 R,3 R)-2,5,7-trihydroxy-2H-9’,11’-dioxaspiro[1-benzopyran-3,4’-tricyclo[6.3.0.0³,⁶]undecane]-1’,3’(6’),7’-trien-4-one	328.058	C17H12O7	Benzopyran
2.002	100.4616	1.60138	39.93742	1.94	6.54	22.65	(1 R,2 R,5 S,10 S,11 R,14 S,15 S,16 R)-14-acetyl-10,11,14-trihydroxy-5-{[(2 R,4 S,5 S,6 R)-4-hydroxy-5-{[(2 S,4 S,5 S,6 R)-4-hydroxy-5-{[(2 S,4 R,5 R,6 R)-5-hydroxy-4-methoxy-6-methyloxan-2-yl]oxy}-6-methyloxan-2-yl]oxy}-6-methyloxan-2-yl]oxy}-2,15-dimethyltetracyclo[8.7.0.0]	888.451	C47H68O16	Pyranose
2.002	100.4616	1.60138	39.93742	2.1	4.66	15.83	(2 R)-2-[(1 S,2 R,5 S,9 R,10 S,11 S,13 S,14 R,15 S)-5,9-dihydroxy-2,15-dimethyl-13-{[(2 R,3 R,4 S,5 S,6 R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}tetracyclo[8.7.0.0²,⁷.0¹ ¹,¹ ⁵]heptadec-7-en-14-yl]-6-methylheptan-4-one	594.377	C33H54O9	Tetracycloheptadecenylmethylheptanone
2.0023	100.531	1.601587	39.95646	1.84	2.19	8.06	(2 R,4 S,5 R)-5-[5-(furan-2-yl)-2-methylpyrazol-3-yl]-2-(hydroxymethyl)-1-azabicyclo[2.2.2]octan-1-ium	288.171	C16H22N3O2	Azabicyclooctanium ion
2.0024	100.5542	1.601656	39.96281	2.11	2.19	8.15	(1 S,12 S,14 R)-14-hydroxy-9-methoxy-4-methyl-11-oxa-4-azatetracyclo[8.6.1.0¹,¹ ².0⁶,¹ ⁷]heptadeca-6,8,10(17),15-tetraen-4-ium	288.16	C17H22NO3	Azatetracycloheptadeca-tetraenium ion
2.0024	100.5542	1.601656	39.96281	1.89	3.16	11.31	1-{2-[(2 S,5 S,6 S)-6-(cyclopropylcarbamoyl)-5-hydroxyoxan-2-yl]ethyl}-4-(2-methoxyphenyl)piperazin-1-ium	404.255	C22H34N3O4	Methoxyphenylpiperazinium ion
2.99	977.2372	2.2831	191.9111	3.13	2.71	9.31	(2 R,3 R,4 R,4aS,8aS)-4-[2-(furan-3-yl)ethyl]-2,4-dihydroxy-3,4a,8,8-tetramethyl-hexahydronaphthalen-1-one	334.214	C20H30O4	Tetramethyl-hexahydronaphthalenone
2.9901	977.4623	2.283169	191.9416	3.2	1.47	4.79	(1 R,3 S)-1-isopropoxy-3-methylcyclohexane	156.151	C10H20O	Methylcyclohexane
2.9902	977.6874	2.283238	191.972	3.08	2.65	10.09	N’-[(1E)-(4-hydroxy-3-methoxyphenyl)methylidene]-3-(2-methyl-1,3-benzodiazol-1-yl)propanehydrazide	352.154	C19H20N4O3	Benzodiazolylpropane hydrazide
2.9903	977.9125	2.283307	192.0026	2.81	2.97	10.83	(3 R,6’R,7’S,8’aS)-7’-(1,3-dimethoxy-3-oxoprop-1-en-2-yl)-6’-ethyl-2-oxo-2’,3’,4’,5’,6’,7’,8’,8’a-octahydro-1H-spiro[indole-3,1’-indolizin]-4’-ium	385.213	C22H29N2O4	Spiro[indole indolizinium ion
2.9908	979.039	2.283652	192.1551	2.82	3.19	11.08	(2 S)-1-(4-hydroxypiperidin-1-yl)-2-[(2 R)-7-(2-methoxyethoxy)-5,8-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl]propan-1-one	389.257	C23H35NO4	Tetrahydronaphthalenyl propanone
2.991	979.49	2.28379	192.2162	3.16	2.49	9.08	(1 S,8 R,12 R,13 R,14 R)-8,15,15-trimethyl-6,19-dioxapentacyclo[10.6.1.0¹,¹ ⁴.0³,¹ ¹.0⁵,⁹]nonadeca-3(11),4,9-triene-4,13-diol	330.183	C20H26O4	Dioxapentacyclononadeca-trienediol
2.991	979.49	2.28379	192.2162	3.16	2.1	7.17	(3 R,3aS,8 S,8aS)-8-hydroxy-3-isopropyl-8a-methyl-2,3,3a,6,7,8-hexahydro-1H-azulene-5-carboxylic Acid	252.173	C15H24O3	Azulene carboxylic acid
2.991	979.49	2.28379	192.2162	3.09	2.84	10.32	3-{[(2 S,4 R,5 S,6 R)-4,5-dihydroxy-6-methyloxan-2-yl]oxy}-1-ethyl-8-hydroxyanthracene-9,10-dione	398.137	C22H22O7	Hydroxyanthracenedione
2.9918	981.2959	2.284342	192.4607	2.95	3.74	13.9	(2 S,5aS,8aR)-2-(2-{[(4-fluorophenyl)methyl]carbamoyl}ethyl)-1-methyl-6-[(1-methyl-1,3-benzodiazol-2-yl)methyl]-5-oxo-octahydropyrrolo[3,2-e][1,4]diazepin-1-ium	493.273	C27H34FN6O2	Oxo-octahydropyrrolodiazepinium ion
2.992	981.7479	2.28448	192.5218	2.86	3.53	12.1	Methyl (1 S,2 S,4 R,7 R,8 S,11 R,12 R,17 S,19 R)-19-(acetyloxy)-1,8,12,16,16-pentamethyl-5,15-dioxo-3,6-dioxapentacyclo[9.8.0.0²,⁴.0²,⁸.0¹ ²,¹ ⁷]nonadecane-7-carboxylate	476.241	C26H36O8	Dioxapentacyclononadecane carboxylate
2.992	981.7479	2.28448	192.5218	2.94	2.16	7.77	(1 S,3 R,10 S,12 S)-12-bromo-1,11,11-trimethyl-2,5-dioxatricyclo[8.4.0.0³,⁷]tetradec-7-en-6-one	328.067	C15H21BrO3	Dioxatricyclotetradecenone
2.992	981.7479	2.28448	192.5218	2.83	1.25	3.9	Octanonitrile	125.12	C8H15N	Nitrile
2.992	981.7479	2.28448	192.5218	3.09	2.54	9.36	(3 S)-4’,5,5’,7-tetramethoxy-2H-spiro[1-benzopyran-3,7’-bicyclo[4.2.0]octane]-1’(6’),2’,4’-trien-4-one	356.126	C20H20O6	Spiro benzopyranbicyclo octane trienone
2.992	981.7479	2.28448	192.5218	3.05	1.54	5.85	4-hydroxybenzophenone	198.068	C13H10O2	Hydroxybenzophenone
2.9923	982.4263	2.284687	192.6136	2.93	2.65	9.61	(1 S,9 R,10 R,17 R)-N, N-diethyl-16-oxo-2-oxa-15-azatetracyclo[7.5.3.0¹,¹ ⁰.0³,⁸]heptadeca-3,5,7-triene-17-carboxamide	342.194	C20H26N2O3	Azatetracycloheptadecatriene carboxamide
3	1000	2.29	194.9845	2.99	4.89	17.67	2-[(2 R,4 R,5 R,6 R)-4-{[(2 R,5 R,6 S)-5-{[(2 S,4 R,5 S,6 R)-4,5-dihydroxy-6-methyloxan-2-yl]oxy}-6-methyloxan-2-yl]oxy}-5-hydroxy-6-methyloxan-2-yl]-1,6,10-trihydroxy-8-methyltetracene-5,12-dione	694.263	C37H42O13	Methyltetracenedione
3	1000	2.29	194.9845	2.98	2.05	7.15	2-[(2 R,4aR)-8-(hydroxymethyl)-4a-methyl-2,3,4,5,6,7-hexahydro-1H-naphthalen-2-yl]prop-2-enoic Acid	250.157	C15H22O3	Hexahydronaphthalenyl propenoic acid
3	1000	2.29	194.9845	3.01	4.24	14.27	Methyl (2 R,6 R)-6-[(2 S,5 S,7 R,11 R,12 S,14 R,15 R)-5,12-dihydroxy-2,6,6,11,15-pentamethyl-9,17-dioxotetracyclo[8.7.0.0²,⁷.0¹ ¹,¹ ⁵]heptadec-1(10)-en-14-yl]-2-methyl-4-oxoheptanoate	530.324	C31H46O7	Dioxotetracycloheptadecenyl]-2-methyl-4-oxoheptanoate
3.0005	1001.152	2.290345	195.1394	2.9	1.58	5.83	5,5-dimethyl-4-methylidene-3-phenyl-1,3-oxazolidin-2-one	203.095	C12H13NO2	Oxazolidinone
3.0014	1003.229	2.290966	195.4186	3.04	3.39	12.3	(2 R,4 S,5 R)-5-{6-[4-(dimethylamino)phenyl]-2-methylpyrimidin-4-yl}-2-[(2-methoxyacetamido)methyl]-1-azabicyclo[2.2.2]octan-1-ium	424.271	C24H34N5O2	Azabicyclooctanium ion
3.0017	1003.922	2.291173	195.5118	3.06	2.96	10.84	(11 R)-13-(3,3-dimethylbutanoyl)-5-(furan-2-yl)-1,9,13-triazatricyclo[9.4.0.0³,⁸]pentadeca-3,5,7-triene-2,10-dione	395.185	C22H25N3O4	Triazatricyclopentadecatrienedione
3.0017	1003.922	2.291173	195.5118	3.14	2.34	9.24	1-methyl-2-[(4-methylquinazolin-2-yl)amino]quinazolin-4-one	317.128	C18H15N5O	Methylquinazolinyl)amino]quinazolinone
3.0019	1004.384	2.291311	195.5739	3.18	3.18	11.79	2-[(5-hydroxy-4-oxo-2-phenylchromen-7-yl)oxy]-N-[3-(2-oxopyrrolidin-1-yl)propyl]acetamide	436.163	C24H24N2O6	Oxopyrrolidinyl)propyl acetamide
3.002	1004.616	2.29138	195.605	3.13	1.77	6.22	(2 S)-5-(2H-1,3-benzodioxol-5-yl)-2-methylpentan-1-ol	222.126	C13H18O3	Benzodioxolyl)-2-methylpentanol
3.0021	1004.847	2.291449	195.6361	3.19	3.36	12.7	2-(furan-2-ylmethyl)-N-{4-methoxy-6-methyl-2 H,5 H,7 H,8H-[1,3]dioxolo[4,5-g]isoquinolin-9-yl}-1,3-dioxoisoindole-5-carboxamide	489.154	C26H23N3O7	Dioxoloisoquinolinyl dioxoisoindole carboxamide
3.99	9772.372	2.9731	939.9397	3.85	2.34	8.3	(2 S,4E,6E)-12-(pyridin-3-yl)dodeca-4,6-dien-2-ol	259.194	C17H25NO	Pyridinyl)dodecadienol
3.99	9772.372	2.9731	939.9397	4.17	4.41	14.89	(1 S)-4-[(2 R,4aR,6 R,8aS)-6-[(2 S,5 R)-5-isopropyl-5-methoxy-2-methyloxolan-2-yl]-8a-methyl-hexahydro-2H-pyrano[3,2-b]pyran-2-yl]-1-[(2 R,5 R)-5-(2-hydroxypropan-2-yl)-2-methyloxolan-2-yl]pent-4-en-1-ol	538.387	C31H54O7	Hydroxypropanyl)- methyloxolanyl pentenol
3.99	9772.372	2.9731	939.9397	3.98	2.74	10.43	UNPD81982	377.126	C22H19NO5	Benzoxazole
3.9902	9776.874	2.973238	940.2384	4.04	3.62	12.96	(3 R,4 S)-3-{[5-(4-tert-butylphenyl)-1,2-oxazol-3-yl]methyl}-4-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]piperidin-1-ium	439.307	C26H39N4O2	Methylpiperazinyl oxoethylpiperidinium ion
3.9906	9785.883	2.973514	940.8362	3.88	2.2	8.77	2-[(2-bromophenyl)methylidene]-3-oxo-1-benzofuran-6-yl Acetate	357.984	C17H11BrO4	Oxobenzofuranyl acetate
3.991	9794.9	2.97379	941.4343	4.03	2.98	10.8	(3 R,3aS,6 S,6aR)-6-(4-methylbenzamido)-hexahydrofuro[3,2-b]furan-3-yl N-[3-(trifluoromethyl)phenyl]carbamate	450.14	C22H21F3N2O5	Hexahydrofurofuranyl N-(trifluoromethyl)phenyl carbamate
3.991	9794.9	2.97379	941.4343	4.05	1.96	6.94	(7 R)-4,10-dimethylidene-7-(prop-1-en-2-yl)cyclodec-5-en-1-one	216.151	C15H20O	Propenyl cyclodecenone
3.991	9794.9	2.97379	941.4343	3.9	1.93	6.84	2-[(2 R)-5,6-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl]propan-2-ol	218.167	C15H22O	Tetrahydronaphthalenyl propanol
3.9911	9797.155	2.973859	941.5838	3.85	2.55	9.43	(4aR,10aS)-6,6-dimethyl-2-phenyl-3 H,4aH,5 H,7 H,8 H,9 H,10 H,10aH-cyclohexa[g]phthalazine-1,4-dione	324.184	C20H24N2O2	Cyclohexaphthalazinedione
3.992	9817.479	2.97448	942.9312	3.97	2.78	10.67	2-[(3,4-dimethyl-2-oxochromen-7-yl)oxy]-N-(1-methylindol-4-yl)acetamide	376.142	C22H20N2O4	Methylindolyl acetamide
3.992	9817.479	2.97448	942.9312	3.86	2.72	10.14	Dimethyl[2-(2,3,4-trimethoxyphenanthren-1-yl)ethyl]amine	339.183	C21H25NO3	Trimethoxyphenanthrenyl ethylamine
3.992	9817.479	2.97448	942.9312	4.17	2.83	10.82	(7 S,13 R)-9-hydroxy-13-(4-hydroxyphenyl)-7-phenyl-4,14-dioxatricyclo[8.4.0.0³,⁸]tetradeca-1,3(8),9-triene-5,11-dione	402.11	C24H18O6	Dioxatricyclotetradecatrienedione
3.992	9817.479	2.97448	942.9312	3.81	3.88	13.47	(2 S,5 S,6 S,7 R,11 S,15 R)-5-hydroxy-6-(hydroxymethyl)-14-[(2 R,5 R)-5-methoxy-4-oxoheptan-2-yl]-2,11,15-trimethyltetracyclo[8.7.0.0²,⁷.0¹ ¹,¹ ⁵]heptadeca-1(10),13-dien-12-one	472.319	C29H44O5	Trimethyltetracycloheptadeca-dienone
4	10000	2.98	954.9926	4.04	3.59	13.8	(4 R,7 S,8aS)-4-[2-(benzylcarbamoyl)ethyl]-7-{[(4-chlorophenyl)carbamothioyl]amino}-1-oxo-octahydropyrrolo[1,2-a]piperazin-5-ium	486.173	C24H29ClN5O2S	Oxo-octahydropyrrolopiperazinium ion
4.0008	10018.44	2.980552	956.2072	3.86	1.76	7.22	15-methyl-9,13-dioxatetracyclo[8.7.0.0²,⁷.0¹ ²,¹ ⁶]heptadeca-1(10),2,4,6,11,14,16-heptaen-8-one	250.063	C16H10O3	Methyl-dioxatetracycloheptadeca--heptaen-8-one
4.001	10023.05	2.98069	956.5111	3.83	2.38	8.27	(4 S,4aR,5 S,8aR)-4a,5-dimethyl-9-oxo-4 H,5 H,6 H,7 H,8 H,8aH-naphtho[2,3-b]furan-4-yl 2-methylpropanoate	304.167	C18H24O4	Naphthofuranyl 2-methylpropanoate
4.0012	10027.67	2.980828	956.8151	3.91	3.09	12.12	(11 R)-5-(4-chlorophenyl)-13-(thiophene-2-carbonyl)-1,9,13-triazatricyclo[9.4.0.0³,⁸]pentadeca-3,5,7-triene-2,10-dione	451.076	C23H18ClN3O3S	Triazatricyclopentadecatriene-dione
4.0012	10027.67	2.980828	956.8151	3.98	2.22	8.23	1-(adamantan-1-yl)-3-butylthiourea	266.182	C15H26N2S	Adamantanyl butylthiourea
4.0014	10032.29	2.980966	957.1191	3.97	1.61	4.68	Tert-butyl 3,3,3-trifluoro-2,2-bis(trifluoromethyl)propanoate	320.046	C9H9F9O2	Bis(trifluoromethyl)propanoate
4.0016	10036.91	2.981104	957.4233	3.97	4.4	15.54	2-[(1 S,2 R,10 S,11 S,14 R,15 S,17 S)-14,17-dihydroxy-2,15-dimethyl-5-oxotetracyclo[8.7.0.0²,⁷.0¹ ¹,¹ ⁵]heptadec-6-en-14-yl]-2-oxoethyl 3-{[2-(4-fluorophenyl)ethyl]carbamoyl}propanoate	583.295	C33H42FNO7	Oxoethyl fluorophenyl ethyl carbamoyl propanoate
4.0019	10043.84	2.981311	957.8798	3.85	2.69	10.01	N-(2-methylpropyl)-2-[(2-oxo-4-phenylchromen-7-yl)oxy]acetamide	351.147	C21H21NO4	Oxophenylchromenyl oxyacetamide
4.0019	10043.84	2.981311	957.8798	4.12	6.72	23.32	(2 S,4aS,6 S,6aS,6bR,8aS,9 R,10 S,11 R,12aR,12bR,14bS)-2,9-bis(hydroxymethyl)-2,6a,6b,9,12a-pentamethyl-11-({4-[(methylammonio)methyl]phenyl}methoxy)-6-pentyl-10-{[(2 S,3 R,4 S,5 R)-3,4,5-trihydroxyoxan-2-yl]oxy}-1,3,4,5,6,7,8,8a,10,11,12,12b,13,14b-tetradecahydro	839.555	C49H77NO10	Pyranose
4.002	10046.16	2.98138	958.032	3.84	1.86	6.9	4-[2-(3-methoxyphenyl)ethyl]phenol	228.115	C15H16O2	Methoxyphenylethyl phenol
4.0028	10064.68	2.981932	959.2504	3.84	1.91	7.36	Chalepensin	254.094	C16H14O3	Furanocoumarin
4.0028	10064.68	2.981932	959.2504	3.87	1.94	7.93	1-{indolo[3,2-b]quinolin-10-yl}ethanone	260.095	C17H12N2O	Indoloquinolinyl ethanone

log Koc = 0.69 log P + 0.22

For the chemicals with log P values at or near 2.0 (for log P of 2, concomitant log Koc value is 1.6), the volumes of 1 mole of each compound at Standard Temperature and Standard Pressure (MgVols) display a wide range from a low value of 1.34 to a high of 6.54 (Table 1). In ascending order, the MgVols of the chemicals with log P values at or near 2.0 are as follows: 1.34; 1.39; 1.41; 1.6; 1.92; 2.07; 2.12; 2.19; 2.19; 2.31; 2.33; 2.4; 2.42; 2.66; 2.68; 2.94; 3.03; 3.16; 3.5; 3.56; 3.58; 3.63; 3.78; 4.66; and 6.54. For the chemicals with log P values at or near 3.0 (for log P of 3, concomitant log Koc value is 2.29), the MgVols display a wide range from a low value of 1.25 to a high of 4.89 (Table 1). In ascending order, the MgVols of the chemicals with log P values at or near 3.0 are as follows: 1.25; 1.47; 1.54; 1.58; 1.77; 2.05; 2.1; 2.16; 2.34; 2.49; 2.54; 2.65; 2.65; 2.71; 2.84; 2.96; 2.97; 3.18; 3.19; 3.36; 3.39; 3.53; 3.74; 4.24; and 4.89. For the chemicals with log P values at or near 4.0 (for log P of 4, concomitant log Koc value is 2.98), the MgVols fall over a wide range from a low value of 1.61 to a high value of 6.72 (Table 1). In ascending order, the MgVols of the chemicals with log P values at or near 4.0 are as follows: 1.61; 1.76; 1.86; 1.91; 1.93; 1.94; 1.96; 2.2; 2.22; 2.34; 2.38; 2.55; 2.69; 2.72; 2.74; 2.78; 2.83; 2.98; 3.09; 3.59; 3.62; 3.88; 4.4; 4.41; and 6.72. In summary, chemicals sharing very similar log P values of 2.0, 3.0 and 4.0 display quite wide ranges of molar volumes indicative of the great diversity of chemical structures capable of having similar or the same log P or log Koc values.

For the chemicals with log P values at or near 2.0 (for log P of 2, concomitant log Koc value is 1.6), the CMRs of each compound display a wide range from a low value of 4.79 to a high of 22.65 (Table 1). In ascending order, the CMRs of the chemicals with log P values at or near 2.0 are as follows: 4.79; 4.98; 5.08; 5.79; 6.92; 6.96; 7.49; 7.94; 8.06; 8.15; 8.65; 8.87; 9.37; 9.49; 9.84; 10.25; 10.69; 11.31; 12.49; 12.81; 12.98; 13.05; 13.57; 15.83; and 22.65. For the chemicals with log P values at or near 3.0 (for log P of 3, concomitant log Koc value is 2.29), the CMRs display a wide range from a low value of 3.9 to a high of 17.67 (Table 1). In ascending order, the CMRs of the chemicals with log P values at or near 3.0 are as follows: 3.9; 4.79; 5.83; 5.85; 6.22; 7.15; 7.17; 7.77; 9.08; 9.24; 9.31; 9.36; 9.61; 10.09; 10.32; 10.83; 10.84; 11.08; 11.79; 12.1; 12.3; 12.7; 13.9; 14.27; and 17.67. For the chemicals with log P values at or near 4.0 (for log P of 4, concomitant log Koc value is 2.98), the CMRs fall over a wide range from a low value of 4.68 to a high value of 23.32 (Table 1). In ascending order, the CMRs of the chemicals with log P values at or near 4.0 are as follows: 4.68; 6.84; 6.9; 6.94; 7.22; 7.36; 7.93; 8.23; 8.27; 8.3; 8.77; 9.43; 10.01; 10.14; 10.43; 10.67; 10.8; 10.82; 12.12; 12.96; 13.47; 13.8; 14.89; 15.54; and 23.32. In summary, chemicals sharing very similar log P values of 2.0, 3.0 and 4.0 display quite wide ranges of CMRs indicative of the great diversity of chemical structures capable of having similar or the same log P or log Koc values.

Table 2 shows the results from an analysis of variance (ANOVA) for one factor in which the means of the molecular parameters MgVol, CMR, and molecular weight were shown to not be related to the log Koc values derived from log Ps at or very near to 2, 3 or 4. The p value for the comparison of the means of MgVol values at the three different log Koc values was 0.896065. The p value for the comparison of the means of CMR values at the three different log Koc values was 0.759057. The p value for the comparison of the means of molecular weights at the three different log Koc values was 0.889793. Therefore, MgVol, CMR and molecular weight are not related to log Koc.

Table 2.

ANOVA of log koc (from log Ps at or near 2, 3 or 4) with MgVol, CMR, and molecular weight.

A	ANOVA: Single Factor–MgVol
	Summary
	Groups	Count	Sum	Average	Variance
	logKoc_1	25	69.41	2.7764	1.323574
	logKoc_2	25	67.59	2.7036	0.784957
	logKoc_3	25	71.11	2.8444	1.274767
	ANOVA
	Source of Variation	SS	df	MS	F	P-value	F crit
	Between Groups	0.247904	2	0.123952	0.109909	0.896065	3.123907
	Within Groups	81.19917	72	1.127766

	Total	81.44707	74
B	ANOVA: Single Factor—CMR
	Summary
	Groups	Count	Sum	Average	Variance
	logKoc_1	25	259.84	10.3936	14.87308
	logKoc_2	25	243.17	9.7268	10.42047
	logKoc_3	25	259.84	10.3936	14.87308
	ANOVA
	Source of Variation	SS	df	MS	F	P-value	F crit
	Between Groups	7.410371	2	3.705185	0.276736	0.759057	3.123907
	Within Groups	963.9993	72	13.38888

	Total	971.4097	74
C	ANOVA: Single Factor—Molecular Weight
	Summary
	Groups	Count	Sum	Average	Variance
	logKoc_1	25	9154.596	366.1838	24529.7
	logKoc_2	25	8878.437	355.1375	16553.83
	logKoc_3	25	9364.402	374.5761	19869.91
	ANOVA
	Source of Variation	SS	df	MS	F	P-value	F crit
	Between Groups	4752.591	2	2376.296	0.116956	0.889793	3.123907
	Within Groups	1462883	72	20317.81

	Total	1467635	74

Discussion

There are additional examples that illustrate the utility of employing Hansch molecular parameters toward better understanding of complex toxicological issues impacting the environment. Previously, Garg and Smith³² conducted a QSAR study to address an important problem encountered in the prediction of the bioconcentration factor (BCF) of highly hydrophobic chemicals. They noted that the linear relationship between the BCF and hydrophobic parameter, i.e. calculated octanol-water partition coefficient (ClogP), breaks down for highly hydrophobic chemicals. Their results suggested that a non-linear relationship between BCF and the hydrophobic parameter, along with inclusion of additional molecular size, weight and/or volume parameters, should be considered while developing a QSAR model for more reliable prediction of the BCF of highly hydrophobic chemicals.

In the current study, 75 randomly selected compounds with log P values at or very near 2.0, 3.0 or 4.0 were selected searching the Super Natural II database with a web scraper. Many more chemicals could have been selected via the same method, but 25 chemicals in each log P/log Koc category well illustrated the high degree of structural diversity that can occur at the same log P/log Koc value. The width of the molecular weight ranges found within a given log P/log Koc value were notable, i.e. 150.104-888.451 at log P = 2/log Koc = 1.6; 125.12-694.263 at log P = 3/log Koc = 2.29; 216.151-839.555 at log P = 4/log Koc = 2.98. There are similarly large ranges within a given log P/log Koc value for molar volumes and for CMRs, which are related to polarizability. The German Environment Agency (UBA) is considering the use of the Log Koc value as a proxy for mobility (M). The large degree of potential diversity in chemical structure and molecular parameters related to chemical behavior at a particular log P or log Koc value suggests that log Koc might not contain enough information to function as a standalone surrogate for the mobility (M) of a chemical as related to its ability to move from a drinking water resource through the water plant purification process.

Industrial chemicals and pesticides do not share similar use and release patterns into the environment. Development of regulatory schema based on persistent, mobile, toxic (PMT) and very persistent, very mobile (vPvM) criteria should account for the differences between these chemical classes.¹ Application of synthetic pesticides and herbicides to agricultural fields is a precise, highly technical, expensive and time-consuming process.³³ The number of applications required is specific to the soil type and fertility, rainfall, erosion and weathering, field slope and runoff pathways, potency toward the intended pests, and crop type.^34

–40 US EPA and the European Union (EU) promulgate regulations toward minimization of pesticide use via programs of Integrated Pest Management (IPM).^41,42 Several factors influence the environmental fate of pesticides including rates of abiotic or biotic degradation and dissipation, bioconcentration and sorption (mobility). In turn, these factors vary with sunlight intensity, pH of the water or soil, hydroxyl radical concentration, number and type of microbial organisms in contact with the pesticide, soil composition, and qualitative characteristics of the organic carbons present.^7,43

In summary, the German Environment Agency (UBA) is considering additional steps to protect the integrity of the drinking water supply. The chemicals of particular concern to the UBA as potential drinking water contaminants represent a subset of chemicals classified under REACH as PMT or vPvM substances.^2

–5 During routine water sampling, detection and quantitation of polar substances with high mobility can be problematic.^5,44,45 The UBA is considering the use of the Log Koc value as a proxy for mobility (M). Log Koc is related to Log P by the equation Log Koc = 0.69 Log P + 0.22. In this study, we demonstrate that chemicals with log P values at or very close to 2.0, 3.0 or 4.0 (and their concomitant log Koc values) can vary significantly in their chemical structures, molecular weights, molar volumes, and calculated molar refractivity (CMR), which is related to the mean polarizability of a molecule. The large degree of potential diversity in chemical structure and molecular parameters related to chemical behavior at a particular log P or log Koc value suggests that log Koc might not contain enough information to function as a standalone surrogate for the mobility (M) of a chemical, i.e. as related to its ability to move from a drinking water resource through the water plant purification process.⁴⁶

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Carr J Smith

Gene M Ko

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High structural and molecular parameter diversity among chemicals with similar log P and log Koc values

Abstract

Keywords

Introduction

Methods

Calculation of Clog P, CMR and MgVol

Statistical methods

Analysis of variance (ANOVA) for one factor 30

Results

Discussion

Footnotes

Declaration of conflicting interests

Funding

ORCID iD

References

Analysis of variance (ANOVA) for one factor³⁰