A new technique to assess dermal absorption of chemical vapor in vitro by thermogravimetric analysis (TGA)
Sammanfattning: There is a huge lack of dermal uptake data for chemicals, and it is frequent with large variations in reported permeability coefficients for chemicals with more than one data set, showing the need for a new and standardized in vitro method. The overall aim of this thesis was to develop the new method of measuring dermal absorption of chemical vapor using the TGA method. Assessment of dermal absorption by TGA (Study I) Round pieces (ø8 mm) of pig epidermis were placed on a platinum pan and inserted into the TGA furnace, where a constant temperature (35 ± 0.01°C) and humidity (45% RH) were maintained. The weight change of the skin was readily recorded prior, during and after exposure to an airflow containing known concentrations of chemical vapor (from water, 2-propanol, methanol and toluene). When no chemical vapor was present the weight of the skin was constant and upon addition of chemical vapor the weight of the skin increased until an equilibrium with the surrounding air was reached. After removal of chemical vapor the skin weight decreased until the baseline weight was reached. The shape of the weight curves was unique for each studied chemical, were the slope and total weight increase reflect the diffusion and skin:air partition coefficients of the studied chemicals, respectively. Vapor generating system (Study II) A computer-controlled, fully automated vapor generating system was created. The chemical vapor was generated by means of bubbling clean, dry air through tailor-made stainless steel chemical containing gas wash bottles, placed in a thermo regulated water bath. Magnetic valves were placed before and after each gas wash bottle to direct the airflow and to prevent back flow, respectively. The performance of a gas wash bottle was tested and close to full saturation was measured using cyclohexanone as test substance. A dedicated computer program was created allowing automated execution of schedules, facilitating precise timing and long time dermal uptake studies using TGA. Development of TGA-specific diffusion model (Study III) A multi compartmental, parallel diffusion model was created using a derived TGA-specific solution to Fick s second law of diffusion. Diffusion and skin:air partition coefficients were obtained by fitting the model to TGA obtained skin weight curves from studies on n-butyl acetate, methanol, 2-propanol and toluene. Akaikes Information Criterion (AIC) was applied and it was found that a two compartment model was sufficient to describe the weight curves. The first compartment was fast and having a low capacity whereas the second compartment was slower with a higher capacity. Validate TGA method against Franz cells (Study IV) TGA and Franz diffusion cell studies were preformed on pig skin testing dermal penetration of the above mentioned chemicals and n-butanol, cyclohexanone, ethyl benzene, n-hexane, styrene and m-xylene. The Franz cell obtained diffusion coefficients showed good agreement with the faster of the two TGA compartments. In conclusion, skin weight changes were readily recorded when dermal exposure to chemical vapor was studied using the TGA method. Diffusion and partition coefficients were obtained by fitting a TGA-specific two compartment model to the recorded weight curves. A good agreement was found when comparing the TGA obtained diffusion coefficients with those from Franz cell experiments.
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