Aqueous, contains collagen

and elastin (inaccessible to

solute), aq fraction accessible

to solute, aq fraction

accessible to albumin and

lipid fraction

Lipophilic; Various diffusion

routes through the Stratum

Corneum

A. Mostrag-Szlichtyng1 J. Rathman1,2 B. Hobocienski2 F. Steinmetz4 J. Madden4 M. Cronin4 C. Schwab2 D. Hristozov1 C. Yang1,2,3

Contact: aleksandra@altamira-llc.com Acknowledgement: www.cosmostox.eu

Classification of skin permeability potential following dermal exposure

to chemicals to support safety assessment

INTRODUCTION

1Altamira LLC

Columbus OH

Degree of the percutaneous absorption (the transport of chemicals from the outer surface of

the skin to the systemic circulation) has impact on their bioavailability and potential toxicity

after topical exposure

We present a set of rules allowing to classify a query molecule to a category (low/med/high)

based on its skin permeability potential

2Ohio State University

Columbus, OH, USA

2Molecular Networks

Erlangen, Germany

SKIN PERMEABILITY DATABASE

4Liverpool John Moores

University, Liverpool,

United Kingdom

Diffusion of the compounds across the

individual skin layers (Fick’s 1st law).

Fig. 1. Skin structure represented as individual pseudo-homogenous membranes in which

particular biochemical processes occur after diffusion of the chemical through the SC.

Biology / Chemistry Physical basics

Skin

pro

tein

bin

din

g

Skin sensitization

ToxPrint CHEMOTYPES PROFILING

JMAX(SS) Max flux of a solute through skin

D Diffusion coefficient

SSC Saturated concentration of a solute

in the Stratum Corneum

h Membrane thickness

The part of the COSMOS Database, Skin Permeability Database, was developed within

the EU COSMOS Project (http://cosmosdb.cosmostox.eu)

Content compiled from various sources: EDETOX database (University of Newcastle, UK, available at: http://edetox.ncl.ac.uk/)

EDETOX update from Kent University (Kent, UK, published in: Int J Pharm (2012), 434(1-2), 280-291)

Harvested regulatory documents (European Chemicals Agency, ECHA, database of registered

substances; Opinions of EU Scientific Committee on Consumer Safety, SCCS) and scientific literature

Systematic quality control used to minimize concerns about data accuracy and reliability

Assessed from in vitro experiments

Defines the highest exposure risk

for a chemical

Fig. 2A. Statistics of COSMOS SkinPermDB. 2B. Details of the 2527 in vitro studies.

131 compounds with low variability (across the studies) of in vitro JMAX values

Fig. 3. Distributions of log JMAX values in the low/med/high categories of analysed dataset.

skin

permeability

ToxPrint Chemotypes: Predefined library of 729

structural fragments with annotated atom/bond

properties (partial charges, polarizability,

electronegativity, etc.), developed by Altamira LLC for

FDA CFSAN’s CERES project and available at:

www.toxprint.org

131 compounds were analysed in ChemoTyper

(developed by Altamira LLC and Molecular Networks

GmbH for FDA CFSAN’s CERES project) software

tool available at: www.chemotyper.org.

On the basis of the chemotypes analysis, 69

compounds were identified as JMAX categories

(low/med/high) defining

Fig. 4. Chemotypes-based Principal Component Analysis (PCA) projection plot (131

compounds) and profiling of low/med/high JMAX categories (69 compounds).

PC 1

PC

2

Med

aliphatic ethers,

ethylene oxides,

etc.

ketones (alkane and

alkene, aliphatic, acyclic

and cyclic), cyclic alkanes

(>C4), linear alkanes

(C>8), alkenes (linear and

cyclic), fused rings, etc.

alkyl halides, aromatic alcohols, carboxylic

acids, cyclic alkanes (C3), etc.

Log JMAX binned low/med/high based on the 33% and 67% quantiles:

PHYSICAL/CHEMICAL PROPERTIES PROFILING

Low

High

10 physical/chemical properties used for further profiling of low/med/high JMAX categories were calculated with

Corina-Symphony (Altamira LLC; Molecular Networks GmbH)

The following properties were used: Molecular Weight (MW), # H-bond acceptors (H Acc), # H-bond donors (H

Don), XlogP, McGowan Volume, Topological Polar Surface Area (TPSA), Complexity, Polarizability,

Homo/Lumo Gap, Lumo

Fig. 5. Kohonnen Map of 10 phys/chem properties

defining low/med/high JMAX categories

(rectangular topology, dimensions: 10x6, white

spaces denote unoccupied neurons).

SkinPermDB

Fig. 6. Physical/chemical properties-based profiling of low/med/high JMAX

categories (example properties presented).

Mo

lecu

lar

Weig

ht

Mean: 356.6

R: 280.5-524.9

Mean: 125

R: 72.1-204.3

Mean: 160.3

R: 94.5-252.7

Mean: 598.3

R: 266.6-957.1 Mean: 55.1

R: 14.4-136.1

Mean: 75.5

R: 8-186.2

Mean: 283.6

R: 206.5-493.2 Mean: 106.1

R: 62.2-170.9

Mean: 88.8

R: 58.7-155.4

Mean: -0.07

R: -1.4-1.1

Mean: 2.3

R: 1.2-3.1

Mean: -0.6

R: -1.7-0.5

Low Med High

Co

mp

lexit

y

McG

ow

an

Vo

l L

UM

O

CONCLUSIONS

The profiles of low/med/high JMAX categories were developed on the

basis of chemotypes and physical/chemical properties

Classification of a query chemical into the category reflecting its skin

permeability potential can support further modeling of its dermal

absorption/permeation and skin sensitization potential

This research can support safety assessment of dermal exposure to

chemicals.

Log Mean: -1.17

Log Median: -0.8

Log Range: -6.1 to -0.24

N=43

Log Mean: -0.79

Log Median: 0.3

Log Range: -0.22 to 1.24

N=45

Log Mean: 2.58

Log Median: 2.46

Log Range: 1.54 to 4.15

N=43

Low JMAX < 0.6 micro-g/cm2/h

Log JMAX < -0.15

High JMAX > 17.2 micro-g/cm2/h

Log JMAX > 1.24

Med JMAX <0.6,17.2> micro-g/cm2/h

Log JMAX <-0.15, 1.24>

CLASSIFICATION WORKFLOW

HAcc 3.00

HDon 0.00

Weight 179.22

Complexity 159.00

McGowan 145.42

TPSA 39.19

Polariz 19.62

XlogP 2.03

HomoLumoG

ap-9.58

Lumo -0.73

ENTER QUERY

MOLECULE

CHEMOTYPES

CALCULATE

PROPERTIES ASSIGN JMAX

CATEGORY

High Med Low

Low Med High

2A 2B

The analysis was performed by the means

of self-organizing neural network method

(Kohonnen algorithm) in SONNIA (Self-

Organizing Neural Network for Information

Analysis) v. 4.2 (Molecular Networks GmbH)