Reported adverse side effects after using N,N-diethyl-m-toluamide (DEET)-containing mosquito repellent products appear to be the result of significant absorption of DEET through human skin. The overall objective was to develop formulations of DEET with significantly reduced permeation using the basic principles and model of skin permeation based on Fick's laws of diffusion at steady state. Ternary phase diagrams of DEET with water and semipolar solvents, ethanol, PG and PEG 400, showed an increase in the aqueous solubility of DEET. This resulted in a linear decline in octanol/water PC with an increase in the concentration of the solvent. Permeation of DEET across human skin was studied from vehicles containing various amounts of PG and PEG 400 using an infinite dose technique and Franz diffusion cell. DEET's flux reduced with increasing PG concentration and the flux from 90% PG was 9.9+/-2.1 microg/cm(2) h, 6-fold lower than flux of pure DEET control, 63.2+/-24.5 microg/cm(2) h. Flux was reduced 6-fold from 60% PEG 400 solution, and permeation of DEET was totally prevented from 90% PEG 400 which was very viscous. However, a combination of 60% PEG 400 with 30% PG not only reduced permeation 9-fold but was suitable as a vehicle for formulation. The decrease in flux and permeability of DEET with increasing concentration of solvent appeared to be a direct result of decrease in skin/vehicle PC and octanol/water PC. This study clearly demonstrates that alternative formulations can be developed for DEET aimed at reduced permeation and toxicity unlike the current formulations some of which contain ethanol which has been shown to enhance permeation of DEET. A similar approach can be used for developing formulations of other industrial and occupational agents to prevent their skin permeation when a user may be exposed to them.
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