2005 ANNUAL SCIENTIFIC MEETING 189 ABSORPTION AND EVAPORATION OF VOLATILE AND POTENTIALLY HAZARDOUS CHEMICALS FROM HUMAN SKIN Varsha D. Bhatt College of Pharmacy, University of Cincinnati, Cincinnati, OH Objective: To test an existing kinetic model for disposition of volatile compounds applied to human skin and to develop a predictive mathematical model based on diffusion theory that improves significantly on current predictions and extends the range of validity to pesticides and non-corrosive industrial solvents. Introduction: Estimation of penetration rates and systemic absorption of compounds following accidental or intentiooal application to the skin is an important aspect of risk assessment for cosmetic and personal care products, occupational exposures, environmental exposures, and chemical warfare agents. Previous work in our laboratory has shown that disposition of DEET and benzyl alcohol from human skin ex vivo is adequately described by first-order one and two comparbnent models. A simple diffusion model with a headspace compartment has also been developed. r.2 Presented below is an analysis of absorption and evaporation rates of the mosquito repellent DEET based on this model. Theory: A one-dimensional diffusion model is depicted in Figure 1. 1•2 Figure 1: Diffusion model for absorption and evaporation of DEET from human skin Diffusivity D SC 0 h/10 h J[ V h = headspace volume, M,.t = saturation dose (Cw•h/10) kevap = Evaporation mass transfer coefficient h2/D = diffusive time constant in SC, C = concentration in the SC, SC = stratum comeum Methods: Split thickness human cadaver skin was mounted on modified Franz diffusion cells connected to a customized volatiles trap using Tenaxill cartridges. Diffusion cells, filled with phosphate buffered saline (pH 7.4 with 0.02% sodium azide) were maintained at 37 ± 2 °C. Tissue integrity was ascertained using tritiated water. A 1 o/ow/w solution of 1 4 C-N, N-diethyl-3-methylbenzamide ( 14 C-DEET) was applied to the skin. An air pump attached to the system allowed air to be passed over the skin at a predetermined rate. Vapor was collected by means of a Tenax®absorbentcartridgeattached to the evaporation chamber. Samples were collected at 0.25, 0.75, 2, 4, 8, 12 and 24 hours post-dose. Evaporation and absorption of 14 C- DEET were measured at varying airflows (v =1 0-100 mllmin, n = 2-6 per airflow). Receptor solutions were analyzed by liquid scintillation counting (LSC). Tenax• cartridges were thermally desorbed and analyzed similarly. At the end of24 hours, the tissue was dissolved in Soluene-350R* and analyzed by LSC.

190 JOURNAL OF COSMETIC SCIENCE Results: The experimental data are shown in Table 1. Evaporation rate increased in direct proportion to airflow. The percent of dose evaporated after 24 h ranged from 16 ± 4 % at v = 10 mL/rnin to 53 ± 7% at v = 80 mL/rnin. Absorption and evaporation rates of DEET at selected airflows are depicted in Figure 2. Table 1: Mass balance of 1 ¾w/w solution of 14 C-DEET from human skin in vitro as a percent of dose rd1e app % Dose evaporated % Dose absorbed Total Airflow Para film Recovery mL/rnin Cartridge • Et-OH bTissue Receptor Rinsing Fluid IO 15.8±3.8 1.2±0.3 8.0±2.9 68.8±6.6 0.7±0.5 94.5±1.1 20 29.1±5.5 1.4±0.3 7.4±0.6 51.8±6.0 0.0±0.0 89.7±5.1 30 41.3±10.5 1.9±0.4 11.9±4.0 36.7±9.7 0.4±0.2 92.2±4.0 40 42.4±3.6 0.6±0.l 5.9±1.0 32.0±1.4 0.0±0.0 81.0±3.9 50 51.1± 14.8 1.4±0.3 13.5±8.3 24.7±6.1 0.0±0.0 90.8±7.0 60 44.9±3.0 0.9±0.2 5.8±1.l 26.5±3.1 0.0±0.0 78.1±1.2 70 58.8±6.7 0.8±0.3 11.3±8.2 20.0±2.6 0.4±0.3 92.0±1.0 80 52.4±7.3 0.7±0.l 13.4±6.l 19.7±1.3 0.8±0.5 87.0±3.6 100 37.6±10.6 0.5±0.2 13.6±9.2 21.6±6.6 1.9±1.8 89.2±3.7 a - (II) - Ethanol rmsmg of evaporation trap, modified Franz cell top and connecting tubes (where applicable), b =%dose recovered from skin and Para film (where applicable) at end of experiment, i.e, 24/25 hrs. Figure 2: 14C-DEET evaporation and absorption rates from human skin in vitro as a function of airflow over the diffusion cell. (E) = Experimental values, (T) = Theoretical Prediction x 12 10 6 6 4 2 0 -2 ◊ ◊ ■ • I 0 ABSORPTION EVAPORATION • 20 ml/min (E) 'iJ 40 ml/min (E) ◊ ■ 70 ml/min (E) 60 ml/min (E) 20 ml/min (T) 40 ml/min (T) 70 ml/min (T) 60 ml/min (T) 5 10 15 20 0 5 10 15 Hours, post dose Hours, post dose 20 Conclusion: Evaporation and absorption of solvent deposited volatile compounds from skin can be satisfactorily described by a diffusion model employing accessible physical properties and a simple representation of the skin barrier. References: 1. Arjun Santhanam, Matthew A. Miller and Gerald B. Kasting, Toxicology and Applied Pharmacology, 204, 81-90 (2005). 2. Matthew A. Miller, Varsha Bhatt and Gerald B. Kasting, J. Pharm. Sci, in press.