A Spreadsheet-Based Method for Estimating the Skin Disposition of Volatile Compounds: Application to N,N-Diethyl-m-Toluamide (DEET)

Abstract

The disposition of N,N-diethyl-3-methylbenzamide (DEET) applied to split-thickness human cadaver skin was measured in modified Franz cells maintained at 32°C and fitted with a vapor trap. Ethanolic solutions of DEET (1% w/w) spiked with ¹⁴ C radiolabel were applied to skin at a dose of 10 μL per cell, corresponding to a DEET dose of 127 μ g/cm ² . Room air was drawn over the skin at velocities ranging from 10–100 mL/min. Evaporation of radiolabel from the skin surface and absorption into the receptor solution were monitored for 24 hr post-dose. The percentage of radioactivity collected in the vapor trap after 24 hr increased with airflow, ranging from 16 ± 4% at 10 mL/min to 59 ± 7% at 70 mL/min. The percentage of radioactivity absorbed through the skin after 24 hours decreased with increasing airflow, ranging from 69 ± 7% at 10 mL/min to 20 ± 1% at 80 mL/min. Tissue retention after 24 hr was 6–14% of the radioactive dose with no clear correlation to airflow. This data as well as DEET absorption data from two previous in vitro studies in which dose and location (fume hood or bench top) was varied were analyzed in terms of a recently developed diffusion/evaporation model for skin implemented on an Excel spreadsheet. A priori model calculations based on independently estimated transport parameters (Model 1) were compared with calculations based on fitted parameters (Models 2 and 3). The analysis of the combined dataset (n = 272 observations) showed that the Model 1 estimates matched the cumulative disposition profiles to within a root mean square error of 12.4% of the applied dose (r ² = 0.65), whereas the Model 2 and Model 3 fits matched to within 9.4% (r ² = 0.80) and 6.5% (r ² = 0.91), respectively. The Model 3 fits were obtained using a concentration-dependent diffusivity of DEET in the stratum corneum, the value of which increased 3.4-fold between low concentrations and saturation. This result was consistent with the mild skin penetration enhancement effect for DEET reported elsewhere.

[Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: a word document containing tables and figures including more information on the spreadsheet skin absorption model.]

Keywords:

• dermal risk assessment
• mathematical model
• percutaneous absorption
• skin penetration

ACKNOWLEDGMENTS

DEET protein binding measurements were skillfully conducted by Rania Ibrahim. Financial support for this study was provided by NIOSH/CDC grant R01 OH007529. The conclusions reached represent the opinions of the authors and have not been endorsed by NIOSH.

The present affiliation for Varsha D. Bhatt is Dow Pharmaceutical Sciences, Inc., Petaluma, California.

Notes

^A Density

^B Calculated from reported value of 0.996 at 20°C using an estimated thermal expansivity of 0.0003 K^3/4l

^C Octanol/water partition coefficient

^D Vapor pressure

^E Extrapolated from 25°C value of 0.00167 torr by modified Grange method.⁽ 5 ⁾

^F Water solubility

^G Estimated to be equivalent to 25°C value reported in Qui et al.⁽ 21 ⁾

^H Fraction unbound in a 2% albumin solution

^I Fraction nonionized at pH 7.4

^A Ref. 12

^A Ethanol rinsing of evaporation trap, modified Franz cell top and connecting tubes (where applicable)

^B % dose recovered from skin and tape strip (where applicable) after 24 hr

^A Model 2 assumes a constant diffusivity in the stratum corneum (D _sc)

^B Model 3 assumes that D _sc varies with DEET concentration according to Eq. 9

^C Bolded parameter values were used to generate the solid curves plotted in Figure 2, Figure 3, Figure 4, Figure 5, Figure 6, Figure 7

^D Bracket denotes that parameter value was fixed at the value obtained for Model 2