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The authors offer recommendations for permissible daily exposures and concentration limits of elemental impurities for dermal drug products.
The International Council for Harmonization Guideline for Elemental Impurities (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 et al. (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.
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, in-vitro 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 in-vitro dermal applications were conducted for more than 24 hours, results were interpreted with caution.
Calculation of dermal PDE. 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.
Determination of concentration limits. 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 Table I.
Table I: Summary table of oral permissible daily exposures (PDEs), dermal PDEs, and dermal concentration limits.
Concentration limits µg/g (a)
* Dermal PDE values were calculated based on oral PDE values before rounding as reported in the appendix of Guideline for Elemental Impurities (ICH Q3D)
a) Concentration limit for dermatological product, expressed in µg per g of drug product (DP).
NA: Not applicable. As no specific limit related to skin toxicity was identified, the dermal PDE must be used.
Concentration limits. Ni is nickel. Hg is mercury. Co is cobalt. Cr is chromium.
Cadmium. The oral PDE for cadmium (Cd) has been derived from the chronic human MLR. In humans, oral Cd absorption was difficult to estimate accurately because Cd can be trapped in the intestine mucosa without being transferred into the systemic circulation (6). Cd excretion in feces should be investigated for more than five days for a mass-balance calculation. Human oral absorption values varied from 5–20% but with extremes between 1.5–47.2% (7). Some studies reporting high values (25–42%) were probably not following Cd excretion for a sufficient time to reflect accurately oral absorption (6). A study determined the dietary absorption of radiolabeled Cd in healthy women at 7.4% after seven days (7) and corresponds more or less to the median value of the published values for the oral bioavailability of Cd in humans (6, 8). A single human skin in-vitro study determined the dermal penetration of Cd at 13.3% after a 16-hour application time (9).
In conclusion, the dermal absorption value (13.3%) is within the overall range of reported human values (1.5–47.2%) and the selected oral absorption value of 7.4% is less than two-fold different; there is no rational to propose a specific dPDE for Cd.
Lead. The oral PDE for lead (Pb) has been derived from human data, and the oral human bioavailability is estimated to be up to 53% in children (10). In a study performed on eight male volunteers after application of Pb in cosmetic preparations (0.1–0.18 mg/application), the dermal absorption over 12 h represented no more than 0.3% of the applied dose (11). Another study, in which a single subject was treated for 24 h with an occluded patch containing Pb (4.4 mg), reported a possible absorption of 30% of the applied dose based on the fact that only 70% was recovered from the cover material and rinse (12). Finally, a study conducted in three subjects reported less than 1% of dermal penetration of Pb over a 24-hour skin contact based on measurements of radiolabeled Pb in blood, sweat, and urine (10).
Overall, the dermal absorption of Pb was then reported from 0.3%–30% in vivo and at 6.3% in vitro. To be conservative, the authors retained the value of 30% for the maximal possible dermal penetration of Pb, and based on the similar oral (53%) and dermal (30%) absorption rates, concluded there is no rational to propose a specific dPDE for Pb.
Arsenic. The PDE for arsenic (As) has been derived from human data and the oral bioavailability was reported to be at least 95% (13). In one in-vitro human skin penetration study, As-applied as arsenic acid-penetrated at up to 1.91% after a 24-h application period (14). In another study, the in-vitro dermal penetration of As was found not to exceed 15% after a 24-h application period (15). The dermal penetration of As was investigated in Rhesus monkeys under semi-occluded conditions on abdominal skin for 24 h. A recovery corresponding to 6.4% of the applied dose was found in excreta over a seven-day period (13), with similar results in a subsequent study (16). Another study in monkeys using similar experimental conditions showed absorption rates from 0.32–16% of the applied dose (17). The authors propose to select the in-vitro dermal penetration value on human skin reported at 15% as this value corresponds well to the in-vivo maximal dermal penetration value of 16% reported in monkeys.
Although the estimated dermal penetration in humans of As is 15% compared to an oral bioavailability of at least 95%, the oral PDE for dermal exposure will not be changed to take into account that the skin is a significant target organ for As. In humans, exposure to As inorganic or organic salts by any route (inhalation, oral, dermal) was associated with dermatitis, pigmentation of skin areas, and hyperkeratinization (13). Although these effects were already considered for the oral PDE, a lower dermal penetration does not justify modifying the oral PDE to allow higher exposure by the dermal route.
Mercury. The PDE for mercury (Hg) has been derived from rat toxicity data and the oral bioavailability in the species has been reported to be in the range of 30–40 % (18).
An in-vitro absorption study of mercuric chloride (HgCl2) dissolved in water on human skin showed Hg penetration into the liquid receptor at 0.07%, and a quantity retained on the skin representing up to 35% of the applied dose (19). Other reported skin-penetration values are 0.07% in the liquid receptor and 28.5% into the skin (3) and 0.8–3.7% for the total absorbed dose (skin and liquid receptor) depending of the concentration used (20). The dermal penetration factor in humans will be considered as a worst-case scenario at 35%, within the oral penetration in rats of 30–40%; a specific dPDE for Hg is not supported.
Cobalt. The PDE for cobalt (Co) has been derived from human data and the oral bioavailability was reported to vary between 18–97% (21). Consequently, the oral bioavailability of Co in humans is taken at 18% as a conservative approach.
The indirect dermal absorption of Co in humans has been reported from studies with exposed workers and volunteers, including from Co metal particles contacts (22, 23, 24). Measurements of Co56 absorption applied as cobalt(II) chloride (CoCl2) on the forearm of volunteers failed to demonstrate absorption after an eight-hour dermal contact (25); no other study was identified to quantify the absorption of dissolved Co. Co skin absorption data in guinea pigs were reported at 17.8% after 24 h (26) with the skin of a Guinea pig being two to three times more permeable than human skin (27). In the absence of robust human skin penetration data, the oral PDE for evaluation of dermal DP for Co will not be changed.
Nickel. The PDE for nickel (Ni) has been derived from toxicity data obtained after oral administration to rats treated with Ni sulfate hexahydrate, for which the absorption was determined to be 11.2% (28).
A study in human volunteers under occluded conditions reported penetrations between 55–77% using radioactive nickel sulfate (29); it was unclear if Ni penetrated into the blood stream or remained on the skin. An in-vitro study (30) reported penetration through the skin between 0.23–3.5% under non-occluded and occluded skin conditions, respectively, and total absorption (considering the dose remaining in the skin) at up to 18–63% for NiCl2 applied on leg and breast skin, respectively, but under occluded conditions only. The majority of the Ni was distributed in the stratum corneum (50.9%), the epidermis (10.6%), and to a lesser extent the dermis (1.6%) and the liquid receptor (0.4%) after in-vitro application of NiCl2 to human skin (31).
Another study (32) failed to detect Ni in the liquid receptor after in-vitro application of NiCl2 for up to 69 h on human abdominal skin. Results from Fullerton et al. (31) show a large penetration into the stratum corneum (approximately 50.9% of the applied dose), which was recovered in the three tape strips (44.3%); consequently this penetration in the upper layers of the stratum corneum was probably over estimated due to occlusion and to the absence of a reported skin cleaning procedure. The large excess in the first tape strip (37.3% of the applied dose) can probably be excluded because it represents a dose seven-times greater than what was recovered in the second tape strip. Such a large difference was not observed in tape strips performed in vivo (33) where the difference in Ni content between the first and third tape strip was less than two-fold.
In conclusion, a low penetration of Ni in the blood stream can be expected, but Ni can distribute into the skin. The data reported by Fullerton et al. (31)-but excluding the quantity recovered in the first tape strip (13.6% of the applied dose)-estimate the Ni skin penetration at 26.2% of the applied dose. This value looks reasonable and conservative when comparing previous in-vitro and in-vivo studies. Considering that the oral absorption in rats to determine the oral PDE was 11.2% for Ni sulfate, and that the dermal penetration in humans was estimated at 26.2% for Ni chloride of the applied dose, the authors propose lowering the oral PDE by a two-fold decrease factor to establish the dermal PDE for Ni at 110 µg/day (220 µg/day/2).
Silver. The oral PDE for silver (Ag) was based on a mouse toxicity study, and the oral absorption of Ag as nitrate in mice to establish the oral PDE was similar to the in-vitro dermal penetration of the same salt on human skin at approximately 1% (34). Consequently, the oral PDE will be used for dermal products.
Platinum. The oral PDE for platinum (Pt) was based on a rat toxicity study, and the oral bioavailability of platinum(II) chloride (PtCl2) in rats represents less than 1% (35). The only dermal penetration study in vitro using human skin reported a total penetration of 2.24% of the applied dose (36), with most of the compound retained into the skin. Thus, the authors propose applying a two-fold decrease factor to derive the dermal PDE at 50 µg/day (rounded value) from the oral PDE (108 µg/day/2).
Lithium. The oral PDE for lithium (Li) has been established based on human data, and the oral absorption of Li-carbonate in humans was reported at 85–100% (37). No dermal absorption of Li-as lithium chloride (LiCl) -was detected after repeated dermal contact (20 min/day for four days) in warm water containing 40 ppm Li under bathing conditions used in spas (38). Consequently, a conservative default value of human skin penetration of Li is taken as 1%.
Considering 85% absorption by the oral route compared with a 1% dermal absorption by the dermal route, the authors propose to apply an 85-fold increase factor to oral PDE to establish the dermal PDE at 47,600 µg/day (560 µg/day x 85).
Copper. The oral PDE for copper (Cu) has been established based on rat toxicity data, and the oral absorption of Cu ions in rats ranges from 11.4–25% (39). The in-vitro human skin penetration of Cu has been reported at 22% (40, 41). As the oral absorption values of Cu in rats overlap the value for the in-vitro dermal absorption in humans, no correction will be applied and the oral PDE will be used for dermal products.
Chromium (Cr). Cr(VI) is excluded from this evaluation and “Cr” refers to Cr(III).
The oral PDE for Cr was based on a rat study using administration of Cr(III) picolinate, (CrPic). Administration of radiolabeled 51Cr (0.15 µg/rat) given as CrPic resulted in an oral absorption representing 1.1% at 4 h and 0.5% at 24 h of the applied dose (42). In a second study (43), the total absorbed dose after seven days represented 1.16% after oral administration of 8 µg Cr. In another study (44), the oral administration of CrPic to rats (1– 100 µg/g) gave urinary excretion rates representing 1.47–1.36% of the CrPic; however, other routes of elimination were not investigated, so these values may have underestimated the absolute oral bioavailability of Cr. The whole-body-retention seven days after oral administration of 6 µg 51Cr-picolinate/rat corresponded to 0.044% and the two-day urinary excretion represented 0.91%, of the administered dose, respectively, representing up to 0.95% of the applied dose (45). Overall, the authors consider an oral bioavailability of Cr at 1% corresponding to the median of values reported for CrPic oral absorption (0.5%–1.47%).
An in-vitro human skin study reported a penetration of 1.7% for 51Cr (46), but Cr was measured only in the dermis and the liquid receptor, 67 h after application and the treated skin area was unclear. Using in-vitro frozen (dead) human skin (47), the recovery of Cr applied as chromium chloride (CrCl3) (0.034 M Cr) represented 0.4% after 168 h and 3% after 190 h of the applied dose. All Cr was recovered in the epidermis and dermis after 190 h without detection in the liquid receptor (limit of detection of 0.5 µg/L) and only values for the epidermis and dermis were reported after the 168-h exposure period.
When chromium nitrate (Cr(NO3)3) was used (0.034 M of Cr), 2.2% of the applied dose was recovered again in the epidermis and dermis but not in the liquid receptor after 190 h (47). These results, obtained with incubation times of 190 h using frozen human skin, should be taken with caution as frozen skin cannot give reliable results after 24-h incubation (48). This is illustrated by results generated in the same study (47) using Cr(VI) (0.034M) indicating a total penetration of 32.2% of the applied dose after 190-h incubation compared to 1.4% after 48 h, resulting in a 23-fold difference. Thus, the in-vitro human skin penetration values of 0.4% (168 h) and 3% (190 h) were probably over estimated. In another study (49), CrCl3 and Cr(NO3)3 applied at 0.034M Cr in vitro on human cadaver skin dermatomed to 600 µm for seven days, gave penetration values of 4.3% and 5.3% of the Cr applied dose, respectively. Again a 168-h, in-vitro incubation for frozen skin does not allow reliable results due to the loss of skin integrity after 1–2 days. In addition, the skin was dermatomed in this experiment, which may have altered the skin permeability. Finally, the prolonged contact of human volunteers with water contaminated with Cr(VI) at low level (22 ppm) resulted in no appreciable systemic uptake of Cr(III) or Cr(VI) (50).
In conclusion, Cr(III) penetration data are difficult to evaluate properly because most in-vitro skin incubations were performed for excessive time periods (67–190 h) and all compartments were not always analyzed. Values ranged from 0.4–5.3% of the applied dose and experiments with Cr(VI) have shown that Cr(VI)-penetration increases 23-fold when measured at 190 h compared with 48 h, indicating that values reported at 67–190 h are most probably over estimated. These results are supported by the only study in human volunteers, that show a minimal penetration of Cr(VI). Thus, the authors conclude that there is no robust human skin penetration data between 0.4–5.3% to modify the oral bioavailability of CrPic in rats, considered at 1%, to derive a dermal PDE.
After a thorough evaluation of the toxicological information available for EIs, and especially for skin sensitization (2), the authors established concentration limits by the dermal route, for mercury cobalt, nickel, and chromium. Concentration limits are summarized in Table I.
Mercury. The induction of contact dermatitis by mercury (Hg) has been extensively documented (2, 3, 51) and often associated with use of antiseptics, disinfecting agents, and with dental amalgams (52). Concentration limits were established by some authorities for cosmetic products ranging from 1–65 µg/g (3). Although no threshold value for skin sensitization with Hg was identified, other known strong human skin sensitizers as nickel (Ni), chromium (Cr), and cobalt (Co) were reported to be unlikely to elicit skin sensitization under normal conditions below 10 µg/g (53). Thus, the proposed concentration limit for Hg in DP is 10 µg/g.
Cobalt. Skin sensitization was reported with cobalt (Co) from occupational exposures, domestic exposures, cosmetics, and jewelry products (53, 54). The risk of skin sensitization for Co was limited below a concentration limit of 10 µg/g because Co-sensitive patients failed to react after repeated exposure to concentrations ranging for 10–200 µg/g Co (23). Confirming this, an analysis of patch-test dose-response studies established that the dose of cobalt that would elicit allergic contact dermatitis in 10% of allergic individuals was 30.8–259 ppm (55). Consequently, the value of 10 µg/g was set as the concentration limit for Co in topical DP.
Nickel. Nickel (Ni) is the most common metal associated with contact dermatitis in humans with up to 15% of the population developing dermal reaction to this metal (56). Ni and its salts were banned as intentional ingredients in cosmetics (3, 57), and Ni release for products that come into direct contact to the skin has been tightly regulated (58) leading to a significant decrease in the incidence of Ni sensitization in some countries (59). A review of studies in individuals sensitized to Ni showed rare reactions to Ni levels below 10 µg/g (53). Since then, a study evaluated the threshold for Ni sensitization in known Ni-sensitized subjects using the patch-test (60). One out of 20 subjects still reacted at a concentration of 1 ppm and 10% reacted at 5 ppm. Considering, that this study used 48-h application under occlusion and was performed in subjects already sensitized to Ni, the concentration of 5 ppm, lower than the 10-ppm concentration reported previously as rarely associated with Ni reactions (53), looks reasonable to ensure safety in patients treated with a pharmaceutical DP. Therefore, the authors propose a concentration limit of 5 µg/g Ni for topical DP.
Chromium. Skin sensitization is a significant risk for Cr(VI) ion, which is outside the scope of this document whereas it has been evaluated to be low for Cr(III) (61). One patch test in Cr(VI) sensitized subjects, reported that one out of 14 subjects reacted at a Cr(III) concentration of 89 ppm (62). Considering that all other reactions reported in the literature (61) occurred at much higher concentrations (>1000 ppm) and that these tests were performed in subjects already sensitized to Cr(VI) under occlusion patch application, the authors propose setting a concentration limit for Cr(III) in DP at 100 µg/g.
Among the 24 elements in the ICH Q3D guideline evaluated for dermal absorption, PDEs were unchanged for 21 elements, increased for one and decreased for two. The literature search found that absorption data was not available for at least one route of exposure for antimony, barium, gold, iridium, molybdenum, osmium, palladium, rhodium, ruthenium, tallium, tin, selenium, and vanadium. Oral and dermal absorption values were within the same range for cadmium, lead, mercury, silver, copper, and chromium. Conflicting dermal penetration values did not allow an estimate for cobalt.
An in-vivo human skin absorption data for lithium (Li) indicated no absorption; however, a high oral absorption value was reported in animal species (at least 85%). As in-vivo human skin absorption data for Li indicated no absorption, the authors set the dermal absorption at 1% as a default and conservative approach. This led to increasing the oral PDE by 85-fold to establish dermal PDE at 47,600 µg/day for Li. However, as this value is very high, the source of contamination and the justification for such high impurity concentration of an EI in a DP should be provided.
A lower absorption by the dermal route was also determined for arsenic (As) but this compound is known to be toxic for the skin, regardless of route of administration, and to have a specific tropism for it. As dermal toxicity was observed after oral and parental administrations, the specific toxicity of As to the skin is considered addressed. Nevertheless, the authors concluded that the lower dermal penetration of As does not justify a higher PDE.
Finally, a two-fold higher absorption by the dermal route for nickel and platinum (Pt) justified decreasing the dPDE for each element.
The authors considered skin sensitization as a specific potential concern for some EIs, justifying a concentration limit in addition to the PDE. The selection of each limit criteria is presented in Figure 1. When a dermal concentration limit is defined for an EI, it is necessary to compare this value to 30% of the PDE considering the daily posology of the dermal DP and to evaluate which of the two limits is the lowest. For example, the PDE for mercury (Hg) is 30 µg/day; thus, the daily exposure from a dermatological DP should not exceed 30% (e.g., 9 µg/day) and the concentration limit of 10 µg/g. Thus, up to a posology in DP of 0.9 g/day, the dermal concentration limit for Hg (10 µg/g) must be applied; whereas above 0.9 g/day the 30% PDE (9 µg/day) will be the applicable limit.
These dermal concentration limits will increase safety by limiting high concentrations of products on small skin areas, which could cause skin sensitization elicitation or reactions. The dermal concentration limits defined apply only for compounds applied on the skin without rinsing.
In case of restricted uses (e.g., shampoo), mitigation factors taking into account the time of contact may be applied as described in cosmetic regulations (63). For example, for a shampoo, a retention factor of 0.01 can be applied, increasing both the concentration limit and the PDE. Evaluation of such short-contact DP should be made on a case-by-case basis.
These concentration limits must not be applied for DP applied as occlusive patches as it is well recognized that occlusion increases significantly the risk of skin sensitization reaction or elicitation (64). In addition, uses of occlusive patches compromises the skin function barrier and often increase percutaneous absorption. Thus, for drugs applied with occlusive patches, the skin penetration should be measured. If the change in dermal absorption is greater than a two-fold factor, the concentration limit and the dermal PDE should be corrected, or a dPDE should be established from the oral PDE.
Finally, these dermal concentration limits and revised PDE are not applicable for topical DP applied on skin requiring preparations, like curettage, keratolytic pretreatment, or abrasion, for which a case-by-case evaluation should be performed, taking into account changes in dermal penetration.
In conclusion, the authors propose the establishment of dPDEs for some EIs to take into consideration differences between oral and dermal penetration levels and to set dermal concentration limits for some EIs due to their significant skin sensitization risk. These new values should ensure a higher safety profile of dermal DPs.
The views, thoughts, opinions, and recommendations expressed in this article belong solely to the authors, and do not necessarily reflect the opinion or position of Nestlé Skin Health.
G. Bouvier, Amandine Gras, Jean-Guy Boiteau, Anne-Pascale Luzy, Jean-Pierre Etchegaray are employees of Nestlé Skin Health.
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Guy Bouvier,* guybouvier06FR@gmail.com, is nonclinical coordination and evaluation manager; Amandine Gras is product development coordinator and CMC expert; Jean-Guy Boiteau is head of process research and development; Anne-Pascale Luzy is head of in vitro toxicology; and Jean-Pierre Etchegaray is pharmaceutical development expert, all at Nestle Skin Health.
*To whom all correspondence should be addressed.
The financial support for this work was provided by Nestlé Skin Health.
Vol. 42, No. 1
When referring to this article, please cite it as G. Bouvier, et al, "Determination of Dermal PDE for Pharmaceutical Products," Pharmaceutical Technology 42 (1) 2018.