Dermal permeation of representative small molecule nitrosamines: Implications for risk assessment

Small-molecule nitrosamines (SMNs) are potent carcinogenic impurities that have been detected in pharmaceuticals, cosmetics, drinking water, and other environmental sources. Although regulatory risk assessments are primarily based on systemic exposure following oral intake, quantitative information regarding dermal absorption of these compounds remains limited. The dermal permeation of five representative SMNs (NDMA, NMBA, NPYR, NDEA, and NDIPA) was investigated across intact and tape-stripped human cadaver skin using Franz diffusion cells under occluded infinite-dose conditions. Steady-state permeability coefficients were determined and correlated with log P_Oct/water. An experimentally derived permeability relationship was externally validated using N-nitroso-desethyl lidocaine (NDL), a representative nitrosamine drug substance-related impurity. All nitrosamines permeated intact human skin with experimentally determined permeability coefficients ranging from 1.90 × 10⁻⁷ to 3.02 × 10⁻⁶ cm/s. Excluding NDMA, permeability demonstrated a stronger positive linear relationship with lipophilicity (R² = 0.766). Despite its extreme hydrophilicity, NDMA exhibited substantially greater permeability than expected. The experimentally derived correlation successfully predicted the permeability of N-nitroso-desethyl lidocaine within approximately 1.5-fold of the experimentally observed value. Barrier disruption significantly increased cumulative permeation of all compounds, with enhancement decreasing progressively as lipophilicity increased. Finally, we incorporated experimentally determined permeability coefficients into a steady-state screening framework to estimate the theoretical skin exposure area required to reach FDA's lifetime acceptable intake (AI) values. This study establishes experimentally determined dermal permeability coefficients for representative regulatory small nitrosamines, validates a predictive relationship applicable to structurally related compounds, demonstrates the influence of barrier integrity on dermal transport, and introduces a permeability-based steady-state screening framework for dermal risk assessment of nitrosamine impurities in topical products.