Phyllis Walsh is a senior compendial manager at Schering-Plough Corporation in Kenilworth, New Jersey.

Phyllis Walsh

) General Notices combined, it could be interpreted that API requirements apply to excipients. In 

 General Notices, an API equals the labeled entity plus impurities. Applying this logic to excipients, anything NOT the labeled entity would be an “impurity.” Most excipients are more complex and less well defined than APIs. The excipient name may not reflect its complete composition. The named entity may be a minor component. The other components may be essential for functionality. This article seeks to promote dialogue among stakeholders to facilitate consensus regarding this topic. 

Due to excipient diversity, including highly complex mixtures from animal, botanical, mineral, and/or synthetic sources, differing approaches to characterizing excipient properties may be required. More complex excipients, including excipients produced by biotechnological methods, may require extensive physico-chemical characterization to fully understand their composition.

Additives and Processing Aids in Pharmaceutical Excipients

Understanding Concomitant Components in Pharmaceutical Excipients

Excipients are a diverse group of materials, which are used for a vast range of available drug products. Excipients intended for use by different routes of administration may require different understanding of the composition profile. Excipient manufacturers should seek to establish how their ingredients will be used. However, in commerce, this information is not always available from or shared by the user.

IPEC-Americas and IPEC Europe have published an 

, which describes the complex nature of excipients (1).  There are many excipient types, which have different compositional profiles. These include standard excipients, sometimes referred to as conventional or traditional excipients, mixed excipients, and co-processed excipients.

The excipient composition profile may be defined as a description of the components present in a typical excipient lot produced by a given manufacturing process. The main components of an excipient are those, which in most cases; contribute to the excipient being able to perform its intended function within the drug product(s) in which it is used (also known as “nominal” components). Other necessary components also may be present (i.e., concomitant components, additives, and processing aids). Unreacted starting materials, by-products, degradants, and residual solvents also may be present as a direct result of the excipient’s manufacturing process. These components may arise at different stages in excipient processing (

) and are considered part of the excipient composition profile. 

Finally, contaminants may be present (i.e., substances not directly resulting from the excipient manufacturing process [synthesis and/or purification], but as a consequence of extraneous factors such as personnel, equipment, packaging, other products, etc.). Contaminants would not be regarded as part of the composition profile; however, they should be controlled through good manufacturing practices (GMPs). 

As excipients are used typically without further purification, excipient manufacturers should identify and set appropriate limits for components as appropriate. These limits should be based on appropriate safety data, limits described in official compendia, or other requirements and sound GMP considerations. Manufacturing processes should be adequately controlled to ensure that undesirable components do not exceed established limits. 

For many excipients, classifying and quantifying all components may not be possible. Composition-related methods and specifications should be justified. There are many traditional, well-established (qualified by use) excipients for which it is neither feasible, nor necessary, for safety purposes to identify all components. Evaluating (re-evaluating) their safety, unless scientific evidence becomes available that suggests otherwise, is generally unnecessary. Where feasible, generating composition profiles should involve each component’s identification, classification, and quantification (expressed as a range). If unidentified, an appropriate qualitative description such as a chromatographic peak retention time should be made available. A reasonable reporting threshold is available from the International Council for Harmonization (ICH) Q3A (R2) guideline (2).

In addition to the “nominal” component, excipient components may comprise the following:

Unreacted starting materials such as monomers in polymerization

Reaction by-products (e.g., isomers and side reactions)

Raw material components (especially for naturally sourced materials).

Establishing an excipient composition profile 

Where possible, excipient manufacturers should establish composition profiles where the main excipient components are identified and their normal concentration variability determined. Acceptable limits, where required, should be based on a risk assessment using sound science. It is typically not necessary to have limits for all components in the composition profile, but the profile should be understood. Limits should only be established when justified by risk assessment to address safety and/or customer-specific concerns. 

An excipient composition profile evaluation should be performed by the excipient manufacturer using their manufacturing process knowledge and understanding, which may lead to identifying associated potentially undesirable components. Excipient components (i.e., main/concomitant components, additives, processing aids, and undesirable components) should be identified and quantified using suitable analytical techniques, wherever possible. Appropriate analytical methods may be compendial or suitably qualified manufacturer-specific methods. The materials used for composition profile development should be representative of the excipient, and sampled in a manner consistent with that used for lot release by the quality control unit (i.e., same sampling technique and sampling point(s) in the manufacturing process). 

The United States Pharmacopeial Convention (USP) merged the General Notices for both the 


) in early 2000. In effect, this means that the same General Notices restrictions apply to both APIs and excipients. It could, therefore, be argued that API requirements also apply to excipients. In the General Notices, an API equals the labeled entity plus impurities. If the same logic is applied to excipients, anything other than the labeled entity could be considered an “impurity.”
	
The current 

“impurity” or “concomitant component” definitions only apply to drug substances and drug products but not excipients. Similarly, ICH addresses impurities in new drug substances and drug products as follows: 

Any component of the new drug substance that is not the chemical entity defined as the new drug substance (2)

Any component of the new drug product that is not the drug substance or an excipient in the drug product (3)

Any component present in the intermediate or API that is not the desired entity (4). 

	These definitions do not specifically apply to excipients and cause confusion when inappropriately applied to them. Excipient-specific definitions are therefore required and should be included in future issues of the 

The situation regarding excipients is put forth in an excerpt from the International Pharmaceutical Excipients Council (IPEC) Composition Guide:
	“For excipients, the situation is more complex as they are frequently multicomponent, and their composition may be less well defined. Their functionality may be dependent on the presence of components other than the labeled entity. The definition of the term ‘impurity’ as used above for drug product and/or drug substance is thus misleading when applied to excipients. To distinguish these components from true impurities, the appropriate term for describing excipients should be ‘minor component’ or ‘concomitant component’ (e.g., the water of crystallization in magnesium stearate required for optimum lubricant effectiveness)” (1). 

Advances in analytical technologies can give excipient manufacturers, users, and regulators more quantitative excipient composition detail, but not necessarily increased understanding of excipient functionality. Increased analytical capabilities are to be encouraged, but, taken out of context, can cause confusion and inappropriate or counterproductive actions by users and regulators.

Significant differences between APIs and excipients

FDA defines an “Active Ingredient” (here used interchangeably with the term API) as “any component that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or animals” (5). FDA does not have an official definition for “excipient,” but rather uses the term “Inactive Ingredient,” which they define as “any component of a drug product other than the active ingredient” (6).

 General Chapter <1078> Good Manufacturing Practices For Bulk Pharmaceutical Excipients defines an excipient as “Any substance, other than the active pharmaceutical ingredient or drug product, that has been appropriately evaluated for safety and is included in a drug delivery system to aid the processing of the drug delivery system during manufacture; to protect, support, or enhance stability, bioavailability, or patient acceptability; to assist in product identification; or to enhance any other attribute of the overall safety and effectiveness of the drug delivery system during storage or use” (7). 

Some of the general differences between APIs and excipients are summarized (

). Exceptions exist (e.g., in the case of small-molecule synthetic API-like excipients and naturally derived APIs such as digitalis and fish oil). 

In the case of APIs, the labeled entity is generally well-defined and quantified by assay to ensure purity. Other components are considered impurities, that is, the balance of 100% minus the assay. For excipients, the labeled entity can be nominal, and there is not always a specific assay (e.g., microcrystalline cellulose). The labeled entity itself may not even be the predominant component. For example, stearic acid 50 NF can contain as little as 40 wt. % stearic (octadecanoic) acid and as much as 50 wt. % palmitic (hexadecanoic) acid.  The latter major component is a concomitant component, not an impurity. There may also be up to 10 wt. % other components. The labeled entity may also be nominal for polymeric excipients, usually reflecting an average molecular weight.

, “The presence of any unlabeled other impurity in an official substance is a variance from the standard if the content is 0.1% or greater. The sum of all other impurities combined with the monograph-detected impurities may not exceed 2.0% unless otherwise stated in the monograph” (8). 

This statement is not appropriate for excipients. If a distinction is not made between concomitant components, additives, residual processing aids, and impurities, there is likely to be confusion regarding excipient applicability of specific impurity identification and quantification requirements typical for APIs. This could encourage attempts to set inappropriate specifications by users and result in excipient shortages, if the specifications are outside the process capability of excipient manufacturers.  

The authors propose that the following excipient-specific definitions be adopted by 

Concomitant component-A substance found in an excipient that is not the intended chemical entity, may be necessary for assuring the proper performance of the excipient in its intended use, and is not an impurity or a foreign substance. (Formerly referred to as minor component) (9) 

Additives-A substance added to the excipient to improve or maintain a characteristic such as a preservative, flow agent, antimicrobial, etc. (9)

Processing aids-A material added to a manufacturing step for the purpose of facilitating the completion of that step or subsequent step (9) 

Impurity-An undesirable material found in an excipient as a consequence of the raw materials, excipient manufacturing process, or excipient degradation (9).

Excipient composition example-Polyethylene Glycol 600

Excipients can be complex mixtures of substances, some or all of which may affect functionality.

Polyethylene glycol 600 NF (PEG 600), which is a complex mixture of the tridecamer (mol. wt. 590), other oligomers (concomitant components), and impurities, is a good example. It is by no means the only example. Other examples include polymeric excipients, some excipients derived from natural fats and oils, and mineral ores. 

Polyethylene glycols are polymers of ethylene oxide and water. In the NF, the number after polyethylene glycol or PEG indicates the mean molecular weight of the polymer. PEG 600, which has been safely used as an excipient for many years, is used (among other applications) in hard and soft gelatin capsule formulations to enhance active substance solubility (10). 

While the “600” nomenclature indicates mean molecular weight, other higher and lower molecular weight oligomers present impact performance. In addition, the specified impurities ethylene glycol and diethylene glycol must not jointly exceed 0.25 wt. %. A suitable antioxidant (additive) may also be present. The antioxidant would be a stabilizer and thus an additive, not an impurity.

Historically, polyethylene glycol grades were specified by viscosity, but their multicomponent nature is now revealed by modern chromatographic techniques. The Cleaver chromatogram (11) shows multiple oligomers present, most of which are present at levels well in excess of 0.1 wt. %, and the sum of which exceed 2 wt. %. Given the current impurity limits and “definition” put forth in the 

 General Notices, these oligomers could be construed as “impurities.”

However, since finished pharmaceutical formulations using PEG 600 have been based on PEG 600 functionality, which is predicated on the presence of the oligomers shown in the chromatogram, the effect of removing all oligomers except the tridecamer is unknown, even if it were possible to do so. The presence of these oligomers may provide essential contribution to PEG 600 drug delivery properties.  In addition, their presence does not pose a health or safety risk. 

In the case of ethylene glycol and diethylene glycol, both of which could be present in PEGs, there is a clear need to set limits for the “undesirable substances” (impurities) because they are toxic to humans and animals. 

Communication disclosure methods needed for additives and processing aids 

IPEC-Americas recognizes the need to provide appropriate details regarding excipient composition. There are excipients in approved medicines, which contain undeclared additives or residual processing aids and yet have a long history of use. Given the large number of excipients involved, and the much greater number of pharmaceutical products potentially affected, there is a need for IPEC-Americas, FDA, and USP to collaborate in developing a path forward and avoiding potential drug product shortages. There has not been a consistent approach to excipient additives and residual processing aids disclosure, even though these ingredients have been used safely for many years. However, it must also be recognized that the presence of certain other components in excipients may present intellectual property issues (trade secrets and know-how).  A mechanism is required, and should be developed, for sharing confidential information with FDA and without direct disclosure of the identity and level of additive or residual processing aids to users.

For an excipient having a monograph in the 

, there are issues with such additives and residual processing aids. USP General Notices 5.20 Added Substances (12) states as follows:

“5.20. Added Substances  “Added substances are presumed to be unsuitable for inclusion in an official article and therefore prohibited, if: (1) they exceed the minimum quantity required for providing their intended effect; (2) their presence impairs the bioavailability, therapeutic efficacy, or safety of the official article; or (3) they interfere with the assays and tests prescribed for determining compliance with the compendial standards.
	
“The air in a container of an official article may, where appropriate, be evacuated or be replaced by carbon dioxide, helium, argon, or nitrogen, or by a mixture of these gases. The use of such gas need not be declared in the labeling.

“5.20.10. Added Substances in Official Substances 

“Official substances may contain only the specific added substances that are permitted by the individual monograph. Such added substances shall not exceed the quantity required for providing their intended effect. Where such addition is permitted, the label shall indicate the name(s) and amount(s) of any added substance(s).”

The presence of undeclared additives and processing aids conflicts with General Notices requirements. A mechanism is needed for confidential disclosure of the presence of additives and residual processing aids without required labeling as specified currently by 

IPEC-Americas has submitted a background document on this issue to FDA and has requested a meeting to discuss possible disclosure mechanisms for these ingredients and potential changes needed in the 

Many excipients are multi-component with well-established safety profiles. Components other than the labeled entity may also impact excipient performance. For excipients, concomitant components, additives, and residual processing aids should be distinguished from impurities in terms of undesirable substances, which should be absent or controlled for safety reasons. 

The current API-specific requirements put forth in the USP 40-NF 35 General Notices are not appropriate for excipients. It is therefore recommended that USP and FDA take the following actions:

Revise General Notices 5.60.10 and 5.20.10 to address excipient requirements by incorporating the aforementioned proposed definitions. 

Include excipients in the list of exceptions in the Other Impurities requirements in 5.60.10.

Provide excipient manufacturers with a means to confidentially communicate additives and residual processing aids presence to regulators without public disclosure.

Q3A(R2) Impurities in New Drug Substances

, Current Step 4 Version (ICH, 2006).
3. ICH, 

, Current Step 4 Version (ICH, 2006).
4. ICH, Q7 

Good Manufacturing Practice Guide for Active Pharmaceuticals Ingredients

, Current Step 4 Version (ICH, 2000).
5. FDA, 

, May 14, 2015.
7. USP, “General Chapter <1078> Good Manufacturing Practices For Bulk Pharmaceutical Excipients,” 

 [Official May 1, 2017] (USP, Rockville, MD, 2015) 
8. USP, 

 [Official May1, 2017], p. 5.60.10 (USP, Rockville, MD, 2015).9. IPEC, “General Glossary of Terms and Acronyms,” Arlington, 2014.
10. Dow Corporation, “

,” year unspecified [online].
11. G. Cleaver, “Sensitive Analysis of Oligo Polyethylene Glycol by Reversed Phase HPLC with ELSD Application Note,” Agilent Technologies, Inc., UK, 2011.
12. USP, 

 [Official May 1, 2017], p. 5.20.10 (USP, Rockville, MD, 2015).

When referring to this article, please cite it as B. Carlin et al., "The Real Complexity of Excipient Composition," 

Articles

This article seeks to promote dialogue among stakeholders to facilitate consensus regarding requirements for excipients. 


The Real Complexity of Excipient Composition

	
	Peer reviewed:
	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) 

 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 

, 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 

) 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 

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.


	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):

		5 µg/mL, after the application of 2 g ointment to the endotracheal tube

		1.3 µg/mL, after the application of 10 g ointment to the oral mucosa for 30 minutes

		0.6 µg/mL, after an oral (ingested) dose of 10 g ointment (bioavailability 35%)

		2.5 µg/mL, after a rectal dose of 10 g ointment (bioavailability 60-70%)

		0.3 µg/mL, after the application of 10 g ointment to a partial thickness burn

		0.1 µg/mL after the application of 10 g ointment to intact skin.

	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.

 Dimethicone, a polysiloxane polymer, is widely used in a range of cosmetics. 

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.

 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.


	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 P

 [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:

 is a parameter that has no bearing whatsoever in the prediction of the properties of a metal or of an inorganic salt of a metal. Inorganic metal species do not permeate the skin by passive diffusion. Instead, the uptake of metals largely depends on the presence of specific transport systems that provide biological gateways for the metal to cross the membrane.

		The dissolution of an inorganic metal compound or the metal itself on the skin surface will intrinsically require dissociation and ultimately liberation of free metal cations. Thus, molecular weight, the second criterion for assigning a dermal absorption rate, is irrelevant for metals. Under no circumstances could any metal cation exceed the cut-off value of 500.

	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 

	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).


	The following summarizes literature references with specific data relating to ICH Class 1 metals.

 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

 following topical application of water containing radio-active arsenic.

 Absorption of cadmium through the skin is reported to be extremely low (0.5%) (17). Specific 

 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/cm

 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%.

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.

 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.


	The following summarizes literature references with specific data relating to ICH Class 2 metals.

 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.

 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).

 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 

) the absorption of a soluble salt form was reported to be only 2%.

 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 (Co

 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 [12]).

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.

		R. Mehta, “Topical and Transdermal Drug Delivery: What a Pharmacist Needs to Know,” 

		Astra Zeneca internal report, “Clinical Documentation on Xylocaine Ointment 5% (50mg/mL),” 2003.	

Technical Report No. 55. Linear Polydimethylsiloxanes 

		Hostynek et al., Critical Reviews in Toxicology  23 (2) 171-235 (1993).	

		National Environmental Policy Institute, 

Assessing the Bioavailability of Metals in Soil for Use in Human Health Risk Assessments. Bioavailability Policy Project Phase II Metals Task Force Report

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	Andrew Teasdale, PhD* is principal scientist, chair of AstraZeneca‘s Impurities Advisory Group, Hurdsfield Road, Macclesfield, Cheshire, England, SK10 2NX, andrew.teasdale@astrazeneca.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.

 When referring to this article, please cite it as A. Teasdale et al., “Establishing Limits for Dermal Absorption of Elemental Impurities,” 

Current guidance for absorption of elemental impurities does not address dermal exposure, resulting in a simplistic approach to limit setting.