OR WAIT null SECS
Current guidance for absorption of elemental impurities does not address dermal exposure, resulting in a simplistic approach to limit setting.
Submitted: Feb. 11, 2015. Accepted: April 7, 2015.
Applications for a drug product that is administered dermally must define acceptable limits for elemental impurities in the product. Current guidelines for exposure limits, however, are based on oral, parenteral, or inhalation exposure and do not adequately address other routes, such as dermal exposure. This article reviews the information available about dermal exposure to metals and considers how it differs from oral or parenteral exposure.
The International Conference on Harmonization’s (ICH’s) Q3D Guideline For Elemental Impurities establishes acceptable exposure limits and defines these limits based on route of administration, but does not specifically address dermal limits (1). Thus, developers of dermally delivered drugs are challenged to establish and define those limits. Is it appropriate, for example, to transpose limits based on other routes of administration (i.e., to apply oral or even parenteral limits)? This article seeks to examine the available data relating to dermal exposure to metals and evaluate appropriate approaches to ensure that the limits established will adequately address actual risk.
The skin is made up of several layers including stratum corneum, viable epidermis, and dermis (2). The largest organ in the body, the skin provides a formidable barrier to exogenous materials. Within the skin, the outer layer (the stratum corneum) provides the most significant barrier and is rate limiting for any substance applied to the skin, whether intentional, in the form of a deliberately applied ointment, or a contaminant to which the skin is inadvertently exposed (e.g., a metal impurity present in a dermal product). The stratum corneum is highly lipophilic and contains very little water. As a result, penetration of hydrophilic or charged molecules is particularly difficult, and such species are effectively unable to partition into the lipid layer and hence pass through the skin at significant levels.
Absorption of dermal products
The skin provides a formidable barrier to any drug. Even when a formulation has been deliberately designed to facilitate transport across the dermal barrier, exposure levels are typically a fraction of those obtained when the drug is delivered by injection. Consider lidocane, for example. Using topical formulations containing lidocaine, the systemic levels that are reached are as follows (3):
Systemic levels of lidocaine of 0.1 µg/mL were observed following the application of 10 g dermally (to intact skin). For the same dose administered orally, the level is 6 times higher. Even when applied to burnt skin, the level (0.3 µg/mL) is still 50% lower than the level achieved through oral administration. When compared to endotracheal application, where there is no effective barrier, the level adjusted for dose is significantly below 5% of the systemic concentration level. These data clearly demonstrate the significant barrier the skin provides and indicate significant concerns for the simplistic approach of applying oral-based limits for elemental impurities.
Similar data have been generated for polydimethylsiloxane and linear and cyclic siloxanes.
Polydimethylsiloxane (PDMS). Dimethicone, a polysiloxane polymer, is widely used in a range of cosmetics. In-vitro human dermal absorption/penetration studies in which neat material was applied to abdominal skin showed that 0.2% and 0.1% of the applied dose of PDMS (10 cST fluid) or PDMS (350 cSt fluid), respectively, remained at the dosing site and could be considered absorbed. The percentage of applied dose that penetrated through the skin to the receptor fluid was ~0.0002% for the 10 cSt fluid and ~0.0003% for the 350 cSt fluid. Studies of its dermal absorption showed no evidence that it had penetrated the dermal barrier (4).
Oral-dosage absorption is also challenged. In studies where an oral dose of 350-cSt 14C-PDMS was administered to rats at 1000 mg/kg body weight, more than 99% of the recovered dose was excreted by the animals (4). PDMS by the dermal or oral route is minimally absorbed.
Cyclic siloxanes.In-vitro human dermal absorption data for cyclic siloxanes (octamethylcyclotetrasiloxane, D4; decamethylcyclopentasiloxane, D5; and dodecamethylcyclohexasiloxane, D6) again showed extremely low levels of absorption following dermal application (5,6). As the molecular weight and lipophilicity of the cyclic siloxane increased (from D4 through D5 and D6), the percutaneous absorption decreased. The percentages of applied dose absorbed following a neat application was 0.5%, 0.05%, and 0% for D4, D5, and D6, respectively. Penetration into the receptor fluid was 0.01%, 0.002%, and 0.003% for D4, D5, and D6, respectively.
Absorption data are available in rats following a single oral administration to rats of D4 (300 mg/kg), D5 (1000 mg/kg), and D6 (1000 mg/kg). These mass balance studies indicate that 52%, 20%, and 12% of the orally administered dose was absorbed (7-9). In the case of cyclic siloxanes, a greater percentage of the administered dose was absorbed orally than dermally.
Dermal absorption of metals
There are several comprehensive reviews covering exposure to metals. These reviews are predominantly focused on environmental exposure from sources such as soils. In 1993, Hostynek et al. (10) sought to summarize data relevant to the qualitative and, where possible, quantitative evaluation of metal permeation through skin. They looked at assessments for 31 elements, although coverage of ICH Q3D Class 1 metals (mercury, arsenic, cadmium, and lead) is incomplete, as there is no assessment of mercury or lead.
They concluded that dermal absorption of metals is a complex process affected by multiple factors including size, charge, and oxidation state. They did not, however, draw any definitive overall conclusions regarding generic estimates of absorption, nor does it seek to generically compare rates to other routes of administration.
A review by the National Environmental Policy Institute, Assessing the Bioavailability of Metals in Soil for Use in Human Health Risk Assessments (11), sought to specifically examine bioavailability. This review provides a thorough assessment of the available toxicological data for soil samples containing six metals: arsenic, cadmium, chromium, lead, mercury, and nickel. This review focuses on evaluations performed using soluble salt forms of the metals and assesses main routes of administration, including dermal limits. The overriding conclusions are that there are little data available to allow for the specific calculation of dermal exposure; however, the data that are presented support the view that even when present in an aqueous soluble form, metals are poorly absorbed through the skin.
The most comprehensive and most recent review of dermal exposure to metals is the HERAG 1 factsheet, Health Risk Assessment Guidance for Metals--Assessment of Occupational Dermal Exposure and Dermal Absorption for Metals and Inorganic Metal Compounds (12). This review, sponsored by the International Council on Mining and Metals and Eurometaux, critically examines existing models used to estimate levels of dermal exposure, and determines their value in assessing the absorption of inorganic metals. One of the most prevalent models used is the EASE (Estimation and Assessment of Substance Exposure) model, developed by the United Kingdom’s Health and Safety Executive. This model defines default dermal absorption rates of 100% or 10% depending on the properties of the substance in question.
Without relevant experimental data, 10% dermal absorption is used when the molecular weight (MW) of the substance is > 500 and the log Pow [partition coefficient for the compound in question between octanol (o) and water (w)] is smaller than -1 or higher than 4, otherwise 100% dermal absorption is used. The major issue with such an approach is that it was developed for organic chemical compounds; this is not considered relevant for metals, for the following reasons:
The review repeatedly makes the point that such general approaches are not only scientifically flawed, but also grossly overestimate the actual levels of exposure.
Crucially, the review cites recent studies that fundamentally challenge the EASE model, with data derived from studies performed on soluble and insoluble zinc compounds. These data show that penetration of the dermis by soluble zinc sulfate is low and that dermal penetration of insoluble zinc oxide is even lower. The review concludes that dissolution kinetics are the rate-limiting factor. The results from these and other studies are summarized in Table I.
The article concluded, based on these experimental data, that recent studies conducted to Organization for Economic Cooperation and Development (OECD) standards indicate dermal absorption rates to be at or below 0.3% (12). There is no clear correlation between absorption and such factors as speciation, valency, and/or water solubility. Crucially, the HERAG guidance document concluded that it should be feasible to establish default absorption factors, concluding that a default absorption rate of 1% was reasonable and adequately conservative when the skin is exposed to metals in wet or liquid media. For “dry” exposure to dusts, it proposes a default dermal absorption factor of 0.1% (12).
Absorption of ICH Class 1 metals
The following summarizes literature references with specific data relating to ICH Class 1 metals.
Arsenic. A white paper specifically focused on arsenic was developed by the New Jersey Department of Environmental Protection (13). The paper provides a useful summary of several studies pertaining to the dermal absorption of arsenic. The data presented show that significant levels of arsenic were found to penetrate the skin of mice; however, this contrasted markedly with the results obtained for human skin, for which levels were within the range of 2-6% of the dose applied. The differences were attributed to the significant intra-species variation in skin thickness, that of a human being substantively greater.
The National Research Council (1999) (14) evaluated the available information on this subject and stated that “these results indicate a low degree of systemic absorption of arsenic via the skin.” The Agency for Toxic Substances and Disease Registry (15) concluded that “it is usually considered that dermal uptake of Arsenates and Arsenites is sufficiently low that this route is unlikely to be of health concern …, but studies to test the validity of this assumption would be valuable.” Arsenic does not act as a sensitizer upon casual skin contact due to poor skin-penetrating ability of its naturally occurring compounds.
Further studies were reported by Wester et al. (16). These studies reported a low permeability coefficient of 2.71 x 10-6 following topical application of water containing radio-active arsenic.
Cadmium. Absorption of cadmium through the skin is reported to be extremely low (0.5%) (17). Specific in-vitro experiments reported by Hostynek et al. (10) were conducted using human skin; these involved exposure for 16 hours to 116 ppb cadmium chloride applied as 2.5 and 5 ul/cm2 solution. Only 0.1 to 0.6% was found in the receptor solution.
The HERAG factsheet (12) cites the relative absorption rate for cadmium metal and cadmium oxide, concluding that percutaneous absorption is likely to be significantly less than 1%.
Lead. The US Occupational Safety and Health Organization (OSHA) (18) concluded that lead can be absorbed by inhalation (breathing) and ingestion (eating) lead (except for certain organic lead compounds not covered by the standard, such as tetraethyl lead). It was also concluded, however, that lead is not readily absorbed through skin, concluding that cutaneous absorption of lead is limited. The amount absorbed through the skin depends on the physical characteristics of the lead (i.e., organic vs. inorganic) and the integrity of the skin.
The HERAG paper (12) presented data from a variety of studies concluding that dermal absorption rates greater than 0.01% were unfeasible.
Mercury. The Hostynek paper (10) concludes that mercury can penetrate the skin in all forms including its elemental form, outlining both intra and intercellular pathways. Data relating to studies performed using guinea-pig skin and limited data relating to human skin are described. The data are complex, showing an apparent non-linear dose response, which was thought to be related to significant skin retention caused by reaction with skin proteins. There are no specific conclusions as to the actual level (%) absorbed.
Absorption of ICH Class 2 metals
The following summarizes literature references with specific data relating to ICH Class 2 metals.
Vanadium. No specific studies were located regarding absorption in humans or animals after dermal exposure to vanadium, although absorption by this route is generally considered to be very low, according to the World Health Organization (19). Absorption through the skin is thought to be quite minimal due to its low lipid/water solubility.
Molybdenum. The dermal absorption of molybdenum (as the molybdate ion) is low to negligible at approximately 0.2% of the applied dose. These results were shown in an in-vitro percutaneous study by Roper of the absorption of sodium molybdate dehydrate, a highly soluble substance, in human skin (20).
Nickel. While the HERAG report (12) raises concerns over the methodology employed in the studies described, it reports that even in the highest example (one where data for level absorbed was combined with the level retained in the stratum corneum) the absorption of a soluble salt form was reported to be only 2%.
Cobalt. There is some evidence of absorption of cobalt metal through skin. Scansetti et al. (21) found that an experimental study with four volunteers, whose skin was exposed to freshly mixed or waste powder containing 5-15% cobalt, measured a ten-fold increase of cobalt in urine. Results confirmed that absorption through skin is a potential route of entry. Later studies by Filon et al. (22) concluded that cobalt can pass through the skin only when it is oxidized to ionic cobalt (Co2+) by synthetic sweat.
Regulatory policyEPA. The US Environmental Protection Agency (EPA) has not developed actual toxicity values for metals based on dermal administration. Instead, the EPA has devised a process for making route-to-route (oral-to-dermal) extrapolations for systemic effects. The EPA developed Risk Assessment Guidance for Superfund: Volume I Human Health Evaluation Manual (Part E, Supplemental Guidance for Dermal Risk Assessment) (23) to address human health risk related to dermal exposures. Part E uses a consistent methodology for assessing the exposures from the dermal pathway for Superfund human health risk assessments.
Primarily, Part E accounts for the fact that most oral reference doses (RfDs) and slope factors are expressed as the amount of substance administered per unit time and body weight, whereas exposure estimates for the dermal pathway are expressed as absorbed dose. The process uses the dose-response relationship obtained from oral administration studies and makes an adjustment for absorption efficiency to represent the toxicity factor in terms of absorbed dose. Crucially, this does not advocate direct correlation between oral and dermal exposures, which would be crude and simplistic, nor does it advocate the simple direct application of oral limits to dermal application.
European Union (EU) risk assessments, occupational dermal exposure. EU assessments have historically been based on the EASE model, which proposes a default absorption of 10%. This is now largely discredited (see HERAG review ).
Michigan Department of Environmental Quality (MDEQ). The review by the National Environmental Policy Institute (NEPI) (11) reports that MDEQ has had a 1% value in place as the default dermal absorption value for all inorganic compounds since 1995.
West Virginia Department of Environmental Protection (WVDEP). In addition, the NEPI report (11) indicates that WVDEP relies heavily on EPA in providing guidance for considering bioavailability in assessing dermal exposures. Default assumptions provided for dermal absorption of metals from soil are 3% for arsenic and 1% for cadmium and other metals.
Although fragmentary in nature, existing data do nevertheless show that dermal exposure to metals is limited, often well below 10% of that observed when the same materials are administered orally. This conclusion is entirely consistent with the fundamental nature of the dermis and the obvious barrier it presents to charged materials in particular, such as metal ions. Reflecting on the variable approaches taken by regulatory bodies, it is clear than even the most conservative and largely discredited (in the context of applicability to charged metal species) EASE model differs substantially from assumed parity with parenteral or even oral exposure. Certainly the assumptions prescribed by MDEQ and WVDEP of exposure levels equivalent to <5% absorption correlate well with data available, even though it is limited.
With respect to ICH Q3D and the establishment of dermal exposure limits, the available evidence and data challenge any attempt to correlate dermal limits directly with oral data. The available evidence and data strongly support the need for a case-by-case approach that takes into consideration such factors as metal form and relevant specific data to establish scientifically justifiable limits. Ultimately, the overriding evidence to date supports the view that dermal exposure to low-level elemental impurities is unlikely to represent a substantive toxicological concern.
About the authors
Andrew Teasdale, PhD* is principal scientist, chair of AstraZeneca‘s Impurities Advisory Group, Hurdsfield Road, Macclesfield, Cheshire, England, SK10 2NX, email@example.com; Katherine Ulman is global regulatory compliance healthcare manager, and Jean Domoradzki is an EHS specialist, both at Dow Corning Corporation, Auburn, MI; and Phyllis Walsh is associate director, compendial affairs at Merck, Rahway, NJ.
*To whom all correspondence should be addressed.
Vol. 39, No. 9
Citation: When referring to this article, please cite it as A. Teasdale et al., “Establishing Limits for Dermal Absorption of Elemental Impurities,” Pharmaceutical Technology39 (9) 2015.