Development and evaluation of two-parameter linear free energy models for the prediction of human skin permeability coefficient of neutral organic chemicals

AbstractThe experimental values of skin permeability coefficients, required for dermal exposure assessment, are not readily available for many chemicals. The existing estimation approaches are either less accurate or require many parameters that are not readily available. Furthermore, current estimation methods are not easy to apply to complex environmental mixtures. We present two models to estimate the skin permeability coefficients of neutral organic chemicals. The first model, referred to here as the 2-parameter partitioning model (PPM), exploits a linear free energy relationship (LFER) of skin permeability coefficient with a linear combination of partition coefficients for octanol–water and air–water systems. The second model is based on the retention time information of nonpolar analytes on comprehensive two-dimensional gas chromatography (GC × GC). The PPM successfully explained variability in the skin permeability data (n = 175) with R2 = 0.82 and root mean square error (RMSE) = 0.47 log unit. In comparison, the US-EPA’s model DERMWIN™ exhibited an RMSE of 0.78 log unit. The Zhang model—a 5-parameter LFER equation based on experimental Abraham solute descriptors (ASDs)—performed slightly better with an RMSE value of 0.44 log unit. However, the Zhang model is limited by the scarcity of experimental ASDs. The GC × GC model successfully explained the variance in skin permeability data of nonpolar chemicals (n = 79) with R2 = 0.90 and RMSE = 0.23 log unit. The PPM can easily be implemented in US-EPA’s Estimation Program Interface Suite (EPI Suite™). The GC × GC model can be applied to the complex mixtures of nonpolar chemicals.

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Development and Evaluation of Two-Parameter Linear Free Energy Models for the Prediction of Human Skin Permeability Coefficient of Neutral Organic Chemicals

10.21203/rs.3.rs-60132/v3 ◽

2020 ◽

Author(s):

Sana Naseem ◽

Yasuyuki Zushi ◽

Deedar Nabi

Keyword(s):

Free Energy ◽

Permeability Coefficient ◽

Estimation Methods ◽

Skin Permeability ◽

Linear Free Energy Relationship ◽

Organic Chemicals ◽

Permeability Coefficients ◽

Linear Free Energy ◽

Zhang Model ◽

Permeability Data

Abstract The experimental values of skin permeability coefficients, required for dermal exposure assessment, are not readily available for many chemicals. The existing estimation approaches are either less accurate or require many parameters that are not readily available. Furthermore, current estimation methods are not easy to apply to complex environmental mixtures. We present two models to estimate the skin permeability coefficients of neutral organic chemicals. The first model, referred to here as the 2-parameter partitioning model (PPM), exploits a linear free energy relationship (LFER) of skin permeability coefficient with a linear combination of partition coefficients for octanol-water and air-water systems. The second model is based on the retention time information of nonpolar analytes on comprehensive two-dimensional gas chromatography (GC×GC). The PPM successfully explained variability in the skin permeability data (n = 175) with R2 = 0.82 and root mean square error (RMSE) = 0.47 log unit. In comparison, the US-EPA’s model DERMWIN exhibited an RMSE of 0.78 log unit. The Zhang model a 5-parameter LFER equation based on experimental Abraham solute descriptors (ASDs) performed slightly better with an RMSE value of 0.44 log unit. However, the Zhang model is limited by the scarcity of experimental ASDs. The GC×GC model successfully explained the variance in skin permeability data of nonpolar chemicals (n = 79) with R2 = 0.90 and RMSE = 0.23 log unit. The PPM can easily be implemented in US-EPA’s Estimation Program Interface Suite (EPI Suite™). The GC×GC model can be applied to the complex mixtures of nonpolar chemicals.

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Development and Evaluation of Two-Parameter Linear Free Energy Models for the Prediction of Human Skin Permeability Coefficient of Neutral Organic Chemicals

10.21203/rs.3.rs-60132/v2 ◽

2020 ◽

Author(s):

Sana Naseem ◽

Yasuyuki Zushi ◽

Deedar Nabi

Keyword(s):

Free Energy ◽

Permeability Coefficient ◽

Estimation Methods ◽

Skin Permeability ◽

Linear Free Energy Relationship ◽

Organic Chemicals ◽

Permeability Coefficients ◽

Linear Free Energy ◽

Zhang Model ◽

Permeability Data

Abstract The experimental values of skin permeability coefficients, required for dermal exposure assessment, are not readily available for many chemicals. The existing estimation approaches are either less accurate or require many parameters that are not readily available. Furthermore, current estimation methods are not easy to apply to complex environmental mixtures. We present two models to estimate the skin permeability coefficients of neutral organic chemicals. The first model, referred to here as the 2-parameter partitioning model (PPM), exploits a linear free energy relationship (LFER) of skin permeability coefficient with a linear combination of partition coefficients for octanol-water and air-water systems. The second model is based on the retention time information of nonpolar analytes on comprehensive two-dimensional gas chromatography (GC×GC). The PPM successfully explained variability in the skin permeability data (n = 175) with R2 = 0.82 and root mean square error (RMSE) = 0.47 log unit. In comparison, the US-EPA’s model DERMWIN exhibited an RMSE of 0.78 log unit. The Zhang model T a 5-parameter LFER equation based on experimental Abraham solute descriptors (ASDs) h performed slightly better with an RMSE value of 0.44 log unit. However, the Zhang model is limited by the scarcity of experimental ASDs. The GC×GC model successfully explained the variance in skin permeability data of nonpolar chemicals (n = 79) with R2 = 0.90 and RMSE = 0.23 log unit. The PPM can easily be implemented in US-EPA’s Estimation Program Interface Suite (EPI Suite™). The GC×GC model can be applied to the complex mixtures of nonpolar chemicals.

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Development and Evaluation of Two-Parameter Linear Free Energy Models for the Prediction of Human Skin Permeability Coefficient of Neutral Organic Chemicals

10.21203/rs.3.rs-60132/v1 ◽

2020 ◽

Author(s):

Sana Naseem ◽

Yasuyuki Zushi ◽

Deedar Nabi

Keyword(s):

Free Energy ◽

Permeability Coefficient ◽

Estimation Methods ◽

Skin Permeability ◽

Linear Free Energy Relationship ◽

Organic Chemicals ◽

Permeability Coefficients ◽

Linear Free Energy ◽

Zhang Model ◽

Permeability Data

Abstract The experimental values of skin permeability coefficients, required for dermal exposure assessment, are not readily available for many chemicals. The existing estimation approaches are either less accurate or require many parameters that are not readily available. Furthermore, current estimation methods are not easy to apply to complex environmental mixtures. We present two models to estimate the skin permeability coefficients of neutral organic chemicals. The first model, referred to here as the 2-parameter partitioning model (PPM), exploits a linear free energy relationship (LFER) of skin permeability coefficient with a linear combination of partition coefficients for octanol-water and air-water systems. The second model is based on the retention time information of nonpolar analytes on comprehensive two-dimensional gas chromatography (GC × GC). The PPM successfully explained variability in the skin permeability data (n = 175) with R2 = 0.82 and root mean square error (RMSE) = 0.47 log unit. In comparison, the US-EPA’s model DERMWIN exhibited an RMSE of 0.78 log unit. The Zhang model \(-\) a 5-parameter LFER equation based on experimental Abraham solute descriptors (ASDs) \(-\) performed slightly better with an RMSE value of 0.44 log unit. However, the Zhang model is limited by the scarcity of experimental ASDs. The GC × GC model successfully explained the variance in skin permeability data of nonpolar chemicals (n = 79) with R2 = 0.90 and RMSE = 0.23 log unit. The PPM can easily be implemented in US-EPA’s Estimation Program Interface Suite (EPI Suite™). The GC × GC model can be applied to the complex mixtures of nonpolar chemicals.

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Linear Free Energy Relationship Analysis of Solvent Effects on Singlet Oxygen Reactions

Current Organic Chemistry ◽

10.2174/1385272033486657 ◽

2003 ◽

Vol 7 (9) ◽

pp. 799-819 ◽

Cited By ~ 15

Author(s):

Else Lemp ◽

Antonio Zanocco ◽

Eduardo Lissi

Keyword(s):

Free Energy ◽

Singlet Oxygen ◽

Solvent Effects ◽

Linear Free Energy Relationship ◽

Relationship Analysis ◽

Linear Free Energy

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Synthesis and characterization of a series of 1-methyl-4-[2-aryl-1-diazenyl]piperazines and a series of ethyl 4-[2-aryl-1-diazenyl]-1-piperazinecarboxylates

Canadian Journal of Chemistry ◽

10.1139/v04-081 ◽

2004 ◽

Vol 82 (8) ◽

pp. 1294-1303 ◽

Cited By ~ 19

Author(s):

Vanessa Renée Little ◽

Keith Vaughan

Keyword(s):

Free Energy ◽

Chemical Shifts ◽

Linear Free Energy Relationship ◽

Piperazine Ring ◽

Linear Free Energy ◽

In Series ◽

Methylene Groups ◽

Diazonium Coupling ◽

The Difference

1-Methylpiperazine was coupled with a series of diazonium salts to afford the 1-methyl-4-[2-aryl-1-diazenyl]piperazines (2), a new series of triazenes, which have been characterized by 1H and 13C NMR spectroscopy, IR spectroscopy, and elemental analysis. Assignment of the chemical shifts to specific protons and carbons in the piperazine ring was facilitated by comparison with the chemical shifts in the model compounds piperazine and 1-methylpiperazine and by a HETCOR experiment with the p-tolyl derivative (2i). A DEPT experiment with 1-methylpiperazine (6) was necessary to distinguish the methyl and methylene groups in 6, and a HETCOR spectrum of 6 enabled the correlation of proton and carbon chemical shifts. Line broadening of the signals from the ring methylene protons is attributed to restricted rotation around the N2-N3 bond of the triazene moiety in 2. The second series of triazenes, the ethyl 4-[2-phenyl-1-diazenyl]-1-piperazinecarboxylates (3), have been prepared by similar diazonium coupling to ethyl 1-piperazinecarboxylate and were similarly characterized. The chemical shifts of the piperazine ring protons are much closer together in series 3 than in series 2, resulting in distortion of the multiplets for these methylenes. It was noticed that the difference between these chemical shifts in 3 exhibited a linear free energy relationship with the Hammett substituent constants for the substituents in the aryl ring. Key words: triazene, piperazine, diazonium coupling, NMR, HETCOR, linear free energy relationship.

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Absorption Spectra of Substituted 2-Phenylindan-1,3-Dion-2-YL Radicals in Solution

Zeitschrift für Naturforschung A ◽

10.1515/zna-1983-1209 ◽

1983 ◽

Vol 38 (12) ◽

pp. 1337-1341

Author(s):

J. Zechner ◽

N. Getoff ◽

I. Timtcheva ◽

F. Fratev ◽

St. Minchef

Keyword(s):

Free Energy ◽

Absorption Spectra ◽

Flash Photolysis ◽

Bathochromic Shift ◽

Substitution Effects ◽

Linear Free Energy Relationship ◽

Linear Free Energy

Abstract Flash photolysis of a series of 2-phenylindandione-1,3 derivatives substituted in the 4′ position results in both the formation of stable benzylidenephthalides and of phenylindan-1,3-dion-2-yl radicals. The u. v. absorption maxima of these radicals are dependent on the solvent and show a bathochromic shift upon substitution. These substitution effects were correlated by means of a linear free energy relationship. Attempts were made to draw conclusions concerning the changes in the gap of the states involved and their curvature due to substitution.

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