Amandine Gras is product development coordinator and CMC expert at Nestle Skin Health. 

Amandine Gras

The International Council for Harmonization 

 (ICH Q3D) establishes permissible daily exposures (PDE) in µg/day to evaluate elemental impurities (EI) in pharmaceutical drug products (DP) administered by oral, inhalation, or parenteral routes. The guidance document provides the option to re-evaluate PDEs for alternative administration routes when supported by data, taking into consideration specific toxic endpoints by other routes and differences in absorption. Differences in absorption between the dermal and oral routes are known for several compounds (1); thus, dermal absorption data may allow re-evaluations (increase or decrease) of some oral PDEs.

	On the other hand, as the skin is the primary organ in contact with DP, specific toxic endpoints may appear for some EIs and require a specific dermal PDE (dPDE). Among skin-specific toxic end points, sensitization has been identified for few EIs after dermal contact from occupational exposure or from cosmetic and house-hold product uses (2-4). Such exposure represents an additional safety issue to consider in the evaluation of EIs in dermal DP.

	The authors conducted an analysis of all EIs for which an oral PDE was assigned in ICH Q3D to identify differences between oral and dermal bioavailabilities, following the work previously published by Tesdale 

. (5). When possible, the oral PDE was corrected by the difference between the oral and dermal absorptions to propose a specific dPDE for topical DP. In addition, skin sensitization was investigated to propose minimal dermal concentration limits (µg/g) for few EIs in DP.

	Sufficient data to correct the oral PDE were available for a few EIs only but establishing a dPDE may increase the safety of dermatological products. Skin sensitization has been identified as a cause of potential safety issue for a few EIs. The consideration of concentration limits, in addition to PDEs, may increase the safety of EIs for their overall dermal safety evaluation.

. For each EI, a literature search for toxicity endpoints was performed covering the time period since the establishment of the oral PDE for the EI. New information related to carcinogenicity, genotoxicity, reproduction toxicity, and dermal toxicity-including sensitization-were particularly scrutinized.

Determination of oral and dermal absorptions

. The literature search explored the oral absorption value for each EI when administered under its specific ionic salt form corresponding to the no observable adverse effect level (NOAEL) in animal studies, or to the maximal residual limit (MLR) in humans; this information was used to calculate its oral PDE. When ranges of values were reported without a definitive conclusion, the lowest reported value--the most conservative approach--was used for the oral bioavailability.

	The literature search also explored the human dermal bioavailability for each EI. If no human data were available, 

human skin penetration studies were considered and, lastly, animal data. All ionic forms were generally considered and the most reasonable penetration value was retained excluding maximizing procedures (e.g., occlusion). For chromium (Cr), only Cr(III) was considered; Cr(VI) is highly unstable and reactive, and is unlikely to be present in DP.

	The percentage of dermal penetration was calculated as the sum of quantities recovered in the stratum corneum, epidermis, dermis, and in the liquid receptor. Skin washing procedures or tape stripping before measuring skin concentrations were considered on a case-by-case analysis. When 

 dermal applications were conducted for more than 24 hours, results were interpreted with caution.

. When oral bioavailability data to establish the oral PDE and human skin dermal penetration were both available with a certain level of robustness from literature, the ratio of the oral values versus the dermal values were calculated. The dPDE was then calculated by multiplying the oral PDE by this factor if dermal and oral absorptions differed by at least a two-fold factor.

. For each EI, a review of the dermal toxicity was undertaken, looking for specific dermal toxicity, dermal irritation, and skin sensitization. When a particular safety endpoint was identified by the dermal route (toxicity or sensitization), the minimal concentration at which such effect is not expected to occur in the normal population was proposed as the dermal concentration limit. For skin sensitization, the dermal concentration limits selected were from subjects not previously sensitized for the EI and were based on human studies conducted under normal conditions, excluding concomitant uses of irritants (e.g., sodium lauryl sulfate) and occlusive patch applications exceeding 24 hours.

	Due to missing data for oral or dermal absorption, it was not possible to determine dPDE for antimony, barium, gold, iridium, molybdenum, osmium, palladium, rhodium, ruthenium, selenium, thallium, tin, or vanadium. A summary of results for other elements can be found in 

: Summary table of oral permissible daily exposures (PDEs), dermal PDEs, and dermal concentration limits.

Articles

The authors offer recommendations for permissible daily exposures and concentration limits of elemental impurities for dermal drug products.