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

Ronald_Baynes@ncsu.edu

Conflict of Interest Statement

THERE IS NO CONFLICT OF INTEREST

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

Effect of Formulation Additives on Skin

● Hydration water, creams, lotions, occlusion

● Delipidization solvents, ionic surfactants

● Protein Denaturation solvents, ionic surfactants.

}

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

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

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 !!!!

Effect of Solvents (Acetone, DMSO, and Ethanol) on DEET Absorption in Three Species

Pigs

Mice

Rats

Effects of Solvent Concentration and Surfactants on Carbaryl Absorption

CA+40%Solvent

0

1

2

3

4

0 1 2 3 4 5 6 7 8Time (hr)

%D

ose/

hr

0

0.5

1

1.5

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

Influence of DEET On Carbaryl Absorption

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

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

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

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

Skin Absorption of Metal Working Fluids (MWFs) and Complexities Inherent in Additional Components

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)

Can These Additives Influence the Dermal Absorption of Other Additives ?

Minimal EffectLubricantsSurfactants

YES– Biocides– Corrosive Inhibitors

Influence of MWF Contaminants on Triazine: Effects of TCE, NDLEA, Ni

14C-triazine Flux in Mineral Oil

0.00

1.00

2.00

3.00

4.00

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)

Phenolic Biocide Permeability in MWF Formulations

0

1

2

3

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

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.

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.

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

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

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

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

Porcine Skin Permeability (Log Kp) of 25 Diverse Solutes Dosed in Methanol, Astrocut (e.g., SO MWF) or Tapfree (e.g., SYN MWF)

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)

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.

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

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

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.

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.