Sodium lauryl sulfate (SLS) is known to penetrate skin and cause cutaneous irritation. Some of these effects have been well-defined using bioengineering techniques. In this study, the ability of SLS to penetrate skin was quantified in a hairless rat model. In addition, local deep tissue penetration and systemic exposure to SLS were also evaluated to assess the toxic potential of topically applied SLS. SLS was observed to penetrate directly to a depth of about 5-6 mm below the applied site. Systemic redistribution was predominantly responsible in determining concentrations of SLS in tissues deeper than 5-6 mm. Epidermal concentrations of SLS after application of 1% (34 mM) aqueous SLS solution for 24 h were above the threshold levels which are known to evoke typical skin irritation responses. Deeper underlying tissues including dermis, subcutaneous, and muscle may also be exposed to high levels of SLS. Topically applied SLS was also observed in blood and contralateral tissues but the observed levels were not likely to elicit any systemic side effects at these doses. Traces of SLS were observed in tissues 7 days after single 24 h application of SLS, which supports the prolonged barrier disruption data generated using conventional bioengineering techniques. Cumulative treatment of SLS significantly increased the concentration of this compound in the underlying epidermis. The known preferential affinity of SLS for skin lipids and proteins was further confirmed by both in vitro and in vivo results. However, in vitro studies failed to predict the underlying tissue toxicity of SLS under the patch site when compared to the in vivo results. Such quantitative pharmacokinetic-pharmacodynamic correlations may be useful predictors for effective use of surfactants as penetration enhancers in cosmetic, pharmaceutical, and industrial applications.