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Assessing Mixture and Formulation Influence on Skin Absorption
Ronald E. Baynes DVM, PhDProfessor of Pharmacology
Center for Chemical Toxicology Research and Pharmacokinetics (CCTRP)North Carolina State University, College of Veterinary Medicine
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Conflict of Interest Statement
THERE IS NO CONFLICT OF INTEREST
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Outline/Objectives
How do formulations additives alter skin permeability?
Formulation effects on pesticide absorption
Formulation effects on MWF absorption
– (e.g., biocides, amines)
Can QSPRs be predictive of mixture/formulation effects
Summary
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Effect of Formulation Additives on Skin
● Hydration water, creams, lotions, occlusion
● Delipidization solvents, ionic surfactants
● Protein Denaturation solvents, ionic surfactants.
}
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Experimental Approaches for Comparing Formulations: Diffusion Cell Systems (Ideally Human or Pig Skin)
Diffusion cells used to quickly assess permeability of drugs prior to live animal exposures
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Talk Outline
How do formulations additives alter skin permeability?
Formulation effects on pesticide absorption
Formulation effects on MWF absorption
– (e.g., biocides, amines).
Can QSPRs be predictive of mixture/formulation effects?
Summary
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Does the Label Suggests the Pesticide will be Absorbed Across the Skin?
● Pesticide Formulation– Active ingredients (a. i.); generally, OPs > Pyrethrins
Pesticides with Log P 1–3 will more likely have higher absorption– Inert or other ingredients; proprietary and not useful ??
● One product with malathion insect spray concentrate– 50% malathion, 50% inert ingredients– Will diluting this concentrate lead to less skin absorption???
● No two product labels are always the same !!!!
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Effect of Solvents (Acetone, DMSO, and Ethanol) on DEET Absorption in Three Species
Pigs
Mice
Rats
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Effects of Solvent Concentration and Surfactants on Carbaryl Absorption
CA+40%Solvent
0
1
2
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0 1 2 3 4 5 6 7 8Time (hr)
%D
ose/
hr
0
0.5
1
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0 1 2 3 4 5 6 7 8
%D
ose/h
r
Time (hr)
CA+80%Solvent CA+40%Solvent+5%SLS
01234
0 1 2 3 4 5 6 7 8Time (hr)
%D
ose
/hr
CA+80%Solvent+5%SLS
0
0.5
1
1.5
0 1 2 3 4 5 6 7 8Time (hr)
%D
ose
/hr
Add surfactant, SLS
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Influence of DEET On Carbaryl Absorption
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Formulation Effects on SC Penetration of Abamectin
Porcine Skin Stratum Corneum8 Hour Flow Through
1.89 1.39
5.12
0.00
1.00
2.00
3.00
4.00
5.00
6.00
Ivomec Eprinex 100% Isopropanol
Formulation
% D
ose
bb
a
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Beware of Extrapolations Across Species and Formulation: In Vitro Dermal Studies for Abamectin
Absorption
0.10 0.09
0.14 0.14
0.10
0.18
0.12 0.13
0.16
0.10
0.17
0.20
0.00
0.05
0.10
0.15
0.20
0.25
Ivomec Eprinex 100% Isopropanol
Formulations
% D
ose
Abs
orpt
ion
PorcineCaprineBovineOvine
cbc
a
ab
a
a
a
aab
b
ab
a
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Does Repeat Exposure Increase Skin Absorption?
Chemical 1-day 4-day
Naphthalene 1.73 1.65 Ethyl benzene 1.98 4.07 Trimethyl benzene 1.93 4.56 Cyclohexyl benzene 3.02 1.81 o-Xylene 1.88 4.21 Nonane 3.03 2.23 Dodecane 1.65 3.50 Tridecane 0.74 4.90
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Talk Outline
How do formulations additives alter skin permeability? Formulation effects on pesticide absorption Formulation effects on Metal Working Fluid absorption
(e.g., biocides, amines). Can QSPRs be predictive of mixture/formulation effects? Summary
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Skin Absorption of Metal Working Fluids (MWFs) and Complexities Inherent in Additional Components
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Additives in MWF Formulations
Soluble oil and synthetic fluids:– Mineral oil, PEG
Surfactants:– Linear alkylbenzene sulfonate (LAS)
Lubricants:– Ricinoleic acid
Biocides:– Triazine, Phenols
Corrosive inhibitors:– Triethanolamine; dicylcohexylamine (DCHA)
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Can These Additives Influence the Dermal Absorption of Other Additives ?
Minimal EffectLubricantsSurfactants
YES– Biocides– Corrosive Inhibitors
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Influence of MWF Contaminants on Triazine: Effects of TCE, NDLEA, Ni
14C-triazine Flux in Mineral Oil
0.00
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5.00
6.00
0 60 120 180 240 300 360 420 480Time, minutes
%D
ose/
Hou
r
CF+Cts CF+Cts+TCE(topical) CF+Cts+TCE(pre-treatment)
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Phenolic Biocide Permeability in MWF Formulations
0
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0 100 200 300 400 500
Time (minute)
Flux
(ug/
hr)
Water Astrocut Tapfree Methanol
Experimental vs. pooled predicted log Kp of 4 phenolic biocides in 4 mixtures
O-Phenylphenol
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Influence of MWFs on Two Classes of Amines
Hydrophilic ethanolamines
Lipophilic amines:
Hydrophilic Ethanolamines(LogP: -1.08 to -1.05)
MEA, DEA and TEA: SO>SS = SYN.
Lipophilic Amines had reverse pattern(Log P: (2.86 to 3.69)
DCHA: SYN>SS = SO DPA: SYN>SS ≥ SODBEA: SS ≥ SYN ≥ SO
Thermodynamic activity of these amines in the various formulations could explain the permeability differences between MWF formulations.
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Summary MWF Mixture Effects
Biocides and DCHA more readily absorbed (1 - 4% dose) than LAS (<0.3% dose) or RA (< 0.3% dose) during an 8-hr exposure.
Permeability differences were observed between soluble oil and synthetic fluid formulations.
Formulation and contaminant-induced changes in additive absorption associated with the presence of single or combinations of additives.
These observations may be associated with changes in partitioning and diffusion from the MWF formulation into skin.
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Talk Outline
How do formulations additives alter skin permeability?
Formulation effects on pesticide absorption
Formulation effects on MWF absorption
– (e.g., biocides, amines).
Can QSPRs be predictive of mixture/formulation effects?
Summary
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Can LSER Such as QSPRs Predict Skin Absorption of Complex Mixtures and Formulations?
MWF formulations consist of hundreds of performance additives which can potentially influence solute permeability via various mechanisms
Therefore several, if not all, of these effects on skin permeability can be predicted within the context of a LSER model
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Linear Solvation Energy Relationships (LSERs)(Abraham Solvatochromatic QSPR)
Log permeability (Log Kp) = c + r R + sπ + aα + bβ + vVx
The Five Molecular Descriptors are Fixed Solute Properties R = excess molar refractivity (represents molecular force of lone pair electrons), π = solute dipolarity/polarizability, α = solute overall or effective hydrogen bond acidity, β is solute overall or effective hydrogen bond basicity, Vx is McGowan characteristic volume.
– R and Vx are calculated values – π, α, and β are determined experimentally from water/solvent partition systems.
The Strength Coefficients: ‘r’ = the tendency of solvent or phase to interact with π- and n-electron pairs of the solutes, ‘s’ = the tendency of phase to interact with dipolar/polarizable solutes, ‘a’ = phase hydrogen bond basicity, ‘b’ = phase hydrogen bond acidity and ‘v’ = phase hydrophobicity or cavity formation term
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Influence of MWFs on Two Classes of Amines: QSPR
Amine permeability in water and MWFs using:
(a) A simple Abraham multiple linear regression model
(b) Adding a vehicle indicator to this model
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Porcine Skin Permeability (Log Kp) of 25 Diverse Solutes Dosed in Methanol, Astrocut (e.g., SO MWF) or Tapfree (e.g., SYN MWF)
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Predicted vs. Experimental Log Kp Values for (A) the 20 Training Set Solutes and (B) the Test Solutes (Phenols) Dosed in Astrocut or Tapfree MWFs
Log K(Skin/Astrocut) = 0.96 - 0.47 R + 0.34 π - 0.35 α + 1.95 β - 3.54 V Log K(Skin/Tapfree) = 1.27 - 0.19 R - 0.67 π - 1.5 α + 1.21 β - 3.14 V
(A)
(B)
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Summary of Biocide Skin Permeation in MWF Formulations
● Large and hydrophobic biocides tend to be retained in commercial MWFs.
● More basic biocides will tend to permeate skin.
● Some ingredients in MWFs can limit biocide skin permeation.
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Recap
Formulations additives can alter skin permeability
Formulations can increase or decrease pesticide absorption
Formulations can increase or decrease MWF absorption
– (e.g., biocides, amines).
QSPRs can be predictive of mixture/formulation effects
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Other Related Work
Instead of fitting one simple model for each experimental condition, we developed an expanded version of the Abraham LSER model to adjust for the heterogeneity introduced by various MWF formulations.
IVIVC for ortho-phenylphenol in progress
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References
● Hughes-Oliver, J., Xu, G., and Baynes R. E. (2018). Skin permeation of solutes from metalworking fluids to build prediction models and test a partition theory. Molecules 24;23(12). doi: 10.3390/molecules23123076.
● Roux L. N., Brooks, J. D., Yeatts, J. L., and Baynes, R. E. (2015). Skin absorption of six performance amines used in metalworking fluids. J. Appl. Toxicol. 35(5):520-528.
● Xu G, Hughes-Oliver J. M., Brooks J. D., Baynes R. E. (2013). Predicting Skin Permeability from Complex Chemical Mixtures: Incorporation of an Expanded QSAR Model. SAR QSAR Environ Res. 24(9):711-731.
● Muhammad F., Monteiro-Riviere N. A., Baynes R. E., Riviere J. E. (2005). Effect of in vivo jet fuel exposure on subsequent in vitro dermal absorption of individual aromatic and aliphatic hydrocarbon fuel constituents. J. Toxicol Environ Health 68: 719-737.
● Baynes, R. E., Barlow, B., and Riviere, J. E. (2003). Dermal disposition of triazine in cutting fluid mixtures. J. Toxicol. Cut. and Ocular Toxicol 22(4): 215-229.
● Vijay, V., Yeatts, J., Riviere, JE., Baynes, R. E. (2007). Predicting dermal permeability of biocides in commercial cutting fluids using a LSER approach. Toxicol. Lett 175: 134-143.
● Riviere, J.E., Baynes, R. E., and Xia, X.R. (2007). Membrane-coated fiber array approach for predicting skin permeability of chemical mixtures from different vehicles. Toxicol Sci. 99(1): 153-161
● Baynes, R. E. and Riviere, J. E. (1998). Influence of inert ingredients in pesticide formulations on dermal absorption of carbaryl. Am. J. Vet. Res. 59(2): 168-175.
● Baynes, R. E., Halling, K. B., and Riviere, J. E. (1997). The influence of diethyl-m-toluamide (DEET) on the percutaneous absorption of permethrin and carbaryl. Toxicol. Appl. Pharmacol. 144: 332-339.
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Acknowledgements
Center for Chemical Toxicology Research and Pharmacokinetics (CCTRP)– Dr. Vikrant Vijay, Dr. Guangning Xu– Dr. Xin Rui Xia– Dr. Jacqueline Hughes-Oliver– Dr. Nancy Monteiro– Dr. Jim E. Riviere– Mr. Jim Yeatts, Mr. Jim Brooks, Ms. Beth Barlow
NIEHS, NIOSH, and US DOD Milacron Corp.