The data were compiled from the literature and began with 50 cosmetic chemicals from one source that were measured for penetration in the skin under a standardized protocol in aqueous buffers10. The database was further expanded to include non-volatile chemicals11 and hydrocortisones12 for a total of 73 distinct chemicals that are identifiable by name, CAS (Chemical Abstracts Service) number, DSSTox (Distributed Structure-Searchable Toxicity) Substance ID, and SMILES (Simplified Molecular Input Line Entry System).Source identificationIdentification of a potential data source from the open literature was a key step for the development of this database. PubMed and GoogleScholar were used as primary search engines. Query phrases used included “human dermal absorption”, “aqueous vehicles”, “in vitro measurements”, and “epidermis, SC, and dermis”.The search was limited to publication between the years 1970 and 2022; details for the experimentation leading to data collection was required to be provided within the publication itself. Once a manuscript was identified, a researcher read the paper and decided if the data reported met the selection criteria. The criteria specified were: human skin, in vitro experiments, aqueous vehicle, and known dose. The researcher determined if the data published could be used for the database. The publications included in this database evaluated drug permeation utilizing Franz diffusion cells with human skin plugs that were removed during surgery. This, however, is a criteria that was not determined a priori.Recent publications typically include a table or electronic dataset reporting the values. Older manuscripts had their data entered by hand and curated by two separate individuals followed by a verification by a third. In all cases, the data were regarded as valid as reported. Only unit conversions were performed by the researcher to ensure that all data in this database had consistent units.Data contentThe following criteria were considered prior to including data from a publication:
The publication was publicly accessible
The primary source of data were the publication or the associated excel file
The units were included or able to be determined from the publication’s text
The permeability coefficient (kp) and/or diffusion coefficient was included with specifications of the layer(s) or could be calculated from other data
Any chemical vehicle(s), in addition to the aqueous buffer, were identified.
As as result of this criteria, the three sources of permeability and diffusion coefficients used in this database are Ellison et al.10, Krestos et al.11, and Anderson et al.12. Experimentation is detailed in the corresponding publications and was reviewed by all researchers to ensure all necessary criteria was met.In order to provide a consistent set of chemical descriptors, features not included with the experimental data were pulled from the EPA’s CompTox Chemicals Dashboard13 as well as the PaDEL-Descriptor15 and PubMed14 to allow for a more robust set of features, including structural information as well as the highlighted features below:
Molecular Weight (MW)
Vapor Pressure
Index of Refraction
Molar Refractivity
Henry’s Constant
Polarizability
Surface Tension
Molar Volume
Boiling Point
Melting Point
Water Saturation (Sw)
Octanol-Water Partition Coefficient (\(\log P\))
Bioconcentration Factor
Biodegradation Half Life
Michaelis constant (Km)
Atmospheric Hydroxylation Rate
Water Solubility
Density
Flash Point
Soil Adsorption Coefficient
Some features were reported more than once in the event of a unit conversion such as kp, which is reported in both centimeters/hour and centimeters/second. In the event that the data were unavailable for a specific chemical, the entry was left blank and that chemical was not included in any analysis of that feature. A list of features and the corresponding units, excluding some features that are dimensionless, can be found in Tables 1–4.Table 1 Units and approximate ranges of various features.Table 2 Units and approximate ranges of various features in the epidermis.Table 3 Units and approximate ranges of various features in the stratum corneum.Table 4 Units and approximate ranges of various features in the dermis.Data usage and calculationsFigure 1 shows the distributions for molecular weight (Fig. 1a) and \(\log P\) (Fig. 1b). The values for molecular weights for the chemicals fall between 18 g/mol and 519 g/mol whereas the values for \(\log P\) fall between -3 and 5. In Fig. 2, molecular weight is plotted against the values for \(\log {k}_{p}\) in the dermis (Fig. 2a) and all layers of the skin (Fig. 2b). While certain subsets of the data may show a trend, the data overall do not indicate a correlation between \(\log {k}_{p}\) and molecular weight. Similarly in Fig. 3, the diffusion coefficients are plotted against the molecular weights.Fig. 1(a) Distribution of molecular weight of all chemicals, (b) distribution of \(\log P\) values for all chemicals.Fig. 2Molecular weight versus the value of \(\log {k}_{p}\) of all chemicals in (a) the dermis and (b) all layers.Fig. 3Molecular weight versus the diffusion coefficients for (a) all chemicals in the dermis (b) non-volatile chemicals in the dermis, (c) all chemicals in all layers.The relationship between the diffusion coefficients (cm2/s) in the dermis and molecular weight (g/mol) for non-volatile chemicals shown in Fig. 3b indicates a negative correlation between the two. It is important to note, however, that the figure only includes a small subset of the chemicals in a single layer of skin. The other plots in Fig. 3, and the data in this compiled database, show no significant correlation between the molecular weights and diffusion coefficients despite the common assumption that larger chemicals would have lower diffusion coefficients. This lack of correlation further supports the need for a robust database with various features that may contribute to QSAR models in varying degrees.Dermal permeability (kp) is probably the most common parameter used to estimate dermal penetration and net absorption. Using ideal membrane theory, the diffusion constant is directly proportional to permeability, although modified by partitioning and membrane depth. The Potts-Guy correlation equation16 describe a direct relationship between \(\log {k}_{p}\) and \(\log P\), particularly for the epidermis (consisting of the stratum corneum and viable epidermis) skin barrier. Figure 4 summarizes individual correlations between \(\log {k}_{p}\), MW, and \(\log P\) for different layers.Fig. 4Scatter plot matrices for molecular weight, \(\log P\), and \(\log {k}_{p}\) values in all layers.The main aim of this dermal database was to aid in the development of mathematical models and computer simulations such that more information can be learned and extrapolated regarding how chemicals diffuse and permeate within the skin’s layers. The example chosen for this paper is the mechanistic modeling of dermis diffusion coefficient since the diffusion constant is rarely included in QSAR models.Example applications for dermis layerSince the dermis contains plasma proteins, an additional descriptor included was fraction unbound in the plasma (fu). The dermis diffusion constant was calculated using the diffusion equation presented by Chen et al.17. Predictions were compared to experimental values obtained from Hewitt et al. and Kretsos et al.10,11 Fig. 5 presents the results for the Kretsos dataset containing the 13 chemicals.Fig. 5Predicted diffusion coefficient vs experimental values collected in dermis. Chemical descriptors used: MW, \(\log P\), and fu (fraction unbound).