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Problems with Skin Protectants Part I: A Discussion

September 17, 2014 | Contact Author | By: Giovanni Pantini, PhD, Studio 24, Milan, Italy
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Keywords: protectant | barrier | exposure | dermatitis | regulations | test methods

Abstract: Problems with skin protectants include unsatisfactory performance, poor prospects for improvement, and the lack of methods for evaluation. Such problems are introduced here, while insights in the area of perfluoropolyethers and concepts to push skin protectants to new efficacies will be discussed in follow-up articles.

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G Pantini, Problems with Skin Protectants Part I: A Discussion, Cosm & Toil 129(8) 16-24 (Oct 2014)

Editor’s note: This is the first of a three-part series that discusses skin protectants. Here, the practical challenges to skin protection efficacy are discussed. Part two, in the November 2014 C&T, will review theoretical aspects of skin protection and introduce insights in the area of perfluoropolyethers. Finally, part three, scheduled for May 2015, will explore a solution based on the concept of shielding skin.

Many have likely observed a similar demonstration of the following: At an exhibition, visitors are impressed by the performance of an individual who immerses one hand, pre-treated with a skin protectant, into a diluted hydrochloric acid solution—apparently without suffering any negative consequences. This sort of test was popular years ago when foam skin protectants were used in various service activities and industrial sectors, informally earning such products the classification of “invisible gloves.”

Such demonstrations raise several questions. What exactly does it mean to protect the skin? How should an effective skin protectant work? How can its effectiveness be measured? How is it regulated? What are the obstacles to innovation in this area? These and other issues concerning skin protectants will be reviewed in this article. Follow-up articles in November 2014 and May 2015 will introduce an idea to improve their efficacy and explore this new idea in greater depth.

Skin Exposure Complexities

In order to illustrate the complexity of skin protectants, it is necessary to consider three different exposure situations and their consequences: First, a single-incident contact of the skin with a strong irritant, which causes an almost immediate injury that may heal within a few days; next, limited contact of the skin, i.e., a few times, with a weak irritant, which usually is harmless (or appears to be); and, lastly, the combination of repeated skin contact over time with weak or substances deemed as potentially irritating, in addition to internal or external adverse conditions. This latter combination may have severe consequences. While some form of dermatitis generally results from each of these occurrences, this last situation is a chronic pathology, usually of the hands, that takes weeks, months or even years to develop and requires a comparable length of time to heal. Only in this latter case, i.e., to prevent pathology, are protective products used, typically in the form of creams or lotions.

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Editor’s note: This is the first of a three-part series that discusses skin protectants. Here, the practical challenges to skin protection efficacy are discussed. Part two, in the November 2014 C&T, reviewed theoretical aspects of skin protection and introduce insights in the area of perfluoropolyethers. Finally, part three will explore a solution based on the concept of shielding skin.

Many have likely observed a similar demonstration of the following: At an exhibition, visitors are impressed by the performance of an individual who immerses one hand, pre-treated with a skin protectant, into a diluted hydrochloric acid solution—apparently without suffering any negative consequences. This sort of test was popular years ago when foam skin protectants were used in various service activities and industrial sectors, informally earning such products the classification of “invisible gloves.”

Such demonstrations raise several questions. What exactly does it mean to protect the skin? How should an effective skin protectant work? How can its effectiveness be measured? How is it regulated? What are the obstacles to innovation in this area? These and other issues concerning skin protectants will be reviewed in this article. Follow-up articles in November 2014 and May 2015 will introduce an idea to improve their efficacy and explore this new idea in greater depth.

Skin Exposure Complexities

In order to illustrate the complexity of skin protectants, it is necessary to consider three different exposure situations and their consequences: First, a single-incident contact of the skin with a strong irritant, which causes an almost immediate injury that may heal within a few days; next, limited contact of the skin, i.e., a few times, with a weak irritant, which usually is harmless (or appears to be); and, lastly, the combination of repeated skin contact over time with weak or substances deemed as potentially irritating, in addition to internal or external adverse conditions. This latter combination may have severe consequences. While some form of dermatitis generally results from each of these occurrences, this last situation is a chronic pathology, usually of the hands, that takes weeks, months or even years to develop and requires a comparable length of time to heal. Only in this latter case, i.e., to prevent pathology, are protective products used, typically in the form of creams or lotions.

Maintaining good skin health clearly is important, since the primary function of skin is to protect the human body against physical, chemical and microbiological insults. A first skin defense, although weak, is represented by a hydrolipidic film composed of an emulsion of sweat and sebum. A more important defense is the stratum corneum (SC), which also prevents uncontrolled water loss. The moisture condition of the SC influences the skin’s defense as well. Therefore, moisturization is a means to improve it.

Subjective and environmental factors, often in combination with mechanical trauma, may facilitate the infiltration and action of noxious substances, and repeated skin exposure to these conditions produce dryness, cracking, fissuring, hyperkeratosis, premature aging and, ultimately, chronic irritant dermatitis. This diagnosis is clinical and based on an individual’s history of exposures to known substances, as well as on negative patch test results to exclude allergic dermatitis.

Dermatitis

Atopic dermatitis, often referred to as eczema, is a general term used to describe differentiated inflammatory skin conditions; a simplified classification is shown in Figure 1. The origins of these pathologies can be exogenous or endogenous. Exogenous dermatitis is generated by contact with a substance, hence contact dermatitis (CD) is its common denomination.

There are two main types of CD. Irritant contact dermatitis (ICD), localized in the area of contact, is caused by irritants such as acids, alkalis, solvents, surfactants, lubricants, powders, etc. Contact with the irritant is necessary to produce ICD, but the probability and the severity of the reaction depend on individual factors and environmental conditions (see Figure 2). Many lists of occupations at risk for ICD have been published, although they are not exhaustive. ICD of the hands occurs most often in those whose hands are frequently washed or are in contact with water/wet materials—including cooks, hair dressers, gardeners, construction workers, mechanics, dentists and medical professionals, to name a few.

The other type of CD, allergic contact dermatitis (ACD), is due to contact with allergens such as salts, metals, fragrances, preservatives, dyes, resins, drugs, pesticides, etc. ACD, diagnosed by patch testing, may occur on any part of the body regardless of the site of contact by the allergen.

Regulatory Implications of Treatments

Beyond the complexities of dermatitis itself, complications in its treatment arise due to U.S. and European regulations. In the United States, skin protectants, often referred to as anti-irritants, are considered drugs, similar to sunscreens, since they are intended for the prevention of disease, i.e., dermatitis. As defined by Section 201 of the U.S. Federal Food, Drug and Cosmetic Act, Monograph 21 C.F.R., Part 347, “Skin protectant drug products [are] for over-the-counter human use.” Therefore, these products must comply with the Monograph, and their manufacture should be in conformance with Current Good Manufacturing Practices (CGMP).

Also similar to drugs, active ingredients should be distinguished from inactive ingredients (i.e., excipients) on the product label; the most recent Monograph contains a list of 19 permitted actives and their concentrations (see Table 1). Products for the lips are included, which explains why some are permitted at such high levels. Note that the Monograph and this list do not imply that skin protectants should be registered and approved by the U.S. Food and Drug Administration (FDA) before marketing.

The positives list includes three groups of actives, and only combinations from within the same group are permitted. In particular, allantoin, cocoa butter, cod liver oil, dimethicone, glycerin, hard fat, lanolin, mineral oil, petrolatum and white petrolatum can be combined with one other. Besides these combinations, actives can be combined with actives from other positive lists, such as analgesics and sunscreens.

This author believes that classifying these active ingredients as drugs is incorrect and inappropriate. And while this positives list for permitted skin protectants exists, these ingredients alone do not provide skin protection; the formulation as a whole should provide the desired benefit. The overall scope of the FDA Monograph is that “an over-the-counter skin protectant drug product, in a form suitable for topical administration, [be] generally recognized as safe and effective.” While the scope for safety is certainly achieved, there are reasonable doubts concerning effectiveness.

First, the positives list appears to include no innovative chemistries; in particular polymer chemistries. There is only one synthetic polymer—dimethicone, also known as polydimethylsiloxane—and it represents the first generation of silicon-based polymers developed in the 1950s. Ironically, and not surprisingly, many companies prefer not to use the claim of “skin protectant” or even exploit the claim of “silicone-free” for products containing dimethicone. This may be due to consumers’ negative impression of silicone oils. Thus, companies are left to either develop an effective product using ingredients that are not included in the positives list, which will not support skin protection claims, or to use dimethicone for its known efficacy and face potential negative consumer perception. (As an aside, dimethicone is a rather common ingredient, appreciated for its safety and sensorial profile.)

It is also important to note that although the United States treats skin protectants as drugs, these actives are not necessarily superior to similar products in Europe and in other regions, where they are classified as cosmetics. Outside of the United States, the working mechanism of these products and conditions of the skin are the primary considerations when determining their regulation. Another point to notice, in both the United States and Europe, there appears to be no remarkable difference in performance between products distributed through special channels in professional and industrial sectors and products sold in stores as cosmetics. The fact that it is possible to have different claims without different performance demonstrates a shortcoming of the regulations. (Editor’s note: for more on the FDA and skin protectant claims, read the “FDA Sidebar” accompanying this article.)

This is further highlighted by “invisible glove” products, which had similar commercial success in the United States and in Europe. On the one hand, more stringent regulations make no guarantee for better performance (and it is difficult to believe the situation would be better in less severely regulated markets); on the other hand, without regulation, skin protectants are cosmetics historically, technically and by logical market identification, so why include effective, more expensive ingredients in products with potential efficacy claims that would be no better than poorly performing products? It is difficult to say which is better (or worse). It seems that changes are necessary, in both the United States and Europe, favoring greater uniformity and revising the definition of what constitutes an “active.”

Evaluation Protocols

Test methods to evaluate and compare skin protectants also are a serious and unresolved problem. In a laboratory, it is practically impossible to reproduce the real life conditions that cause ICD. This situation is different for other types of skin protectants, e.g., sunscreens, whose UV filters can be evaluated for efficacy via in vitro and in vivo methods. Simple methods to test the efficacy of skin protectants have been proposed since the 1950s1 and involve submitting the skin to different markers—i.e., indicator reagents, dyes or irritants with and without the pre-application of a protective product for 5-60 min, depending on the nature of the marker. In these cases, each experiment can be regarded as an acute exposure to a well-defined penetrating substance, often high in concentration. This type of investigation is generally demanding, as far as the performance of the skin protectant, and it has poor value since, as stated, it does not successfully reproduce real life conditions.

To compare skin protectants against a single water-soluble irritant such as sodium lauryl sulfate, the hand immersion test is often used. In it, volunteers immerse their hands for a few minutes in an aqueous solution containing the irritant. Before immersion, like the “invisible glove” test, one hand is treated with a product while the other hand serves as the control. The protective properties are evaluated by measurements of trans-epidermal water loss (TEWL), Laser Doppler Flowmetry (LDF) or other bioengineering techniques. These protocols involve various levels of complexity including repeated applications on volunteers, internal and external controls and statistical analyses, but usually are conceived to evaluate skin protectants against a single irritant, thus conclusions regarding broader protection cannot be reached.

In an effort to create a test that better simulates real life factors, Frosch developed a test method applied first to guinea pigs then to human volunteers.2-5 This method involved nine separate applications of four standard irritants: 1% sodium hydroxide, 10% sodium lauryl sulfate, 30% lactic acid and pure toluene. One application consisted of an occlusive patch test for 30 min, and these applications were carried out for two weeks. Quantification of the irritation was measured by TEWL; evaluation of erythema was determined by visual scoring, from 0 = none, to 5 = very severe. The protocol of Frosch was modified by Elsner, who used more diluted irritants, such as 0.5% sodium hydroxide, 5% sodium lauryl sulfate, 15% lactic acid, in addition to pure toluene. Elsner also used test sites on the mid-backs of the 20 volunteers, instead of their forearms.6

Again to emphasize, alternative to standard methods, tests that better simulate real conditions should be conducted. Consider that rather than treating healthy skin with irritants to evaluate protection, it is more convenient to treat dermatis-afflicted patients to evaluate regression of their condition. Further, these volunteers may continue their normal daily routines under the conditions that produced the dermatitis. In relation, investigations of chronic ICD regression of volunteers treated with skin protectants assume the prevention and treatment of dermatitis address the same issue. These test protocols, conceived for homogeneous groups, should be adapted to specific characteristics and conditions of the volunteers and their environment. A good moisturizer for a German woman is not the ideal for an African woman, for example.

At any rate, neither the test methods or investigations using volunteers can be adopted routinely for screening experimental products, development work or for comparing commercial products. On the whole, however, these methods and investigations have helped to elucidate some theoretical aspects of skin protection, which will be described in part two of this series.

References

  1. RR Suskind, The present status of silicone protective creams, Indust Med Surg 24 413-416 (1955)
  2. PJ Frosch et al, Efficacy of skin barrier creams: The repetitive irritation test (RIT) in guinea pig, Contact Dermatitis 28 94-100 (1993)
  3. PJ Frosch et al, Efficacy of skin barrier creams: Ineffectiveness of a popular skin protector against various irritants in guinea pig, Contact Dermatitis 29 74-77 (1993)
  4. PJ Frosch, A Kurte and B Pilz, Efficacy of skin barrier creams: The repetitive irritation test (RIT) in humans, Contact Dermatitis 29 113-118 (1994)
  5. PJ Frosch and A Kurte, Efficacy of skin barrier creams: The repetitive irritation test (RIT) with a set of four standard irritants, Contact Dermatitis 31 161-168 (1994)
  6. P Elsner, W Wigger-Alberti and G Pantini, Perfluoropolyethers in the prevention of irritant contact dermatitis, Dermatology 197(2) 141-145 (1998)
 

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Table 1. Permitted Skin Protectant Actives After the Revision of the “Skin Protectant Drug Products for OTC Human Use” Monograph (April 1, 2011)

Table 1. Permitted Skin Protectant Actives After the Revision of the “Skin Protectant Drug Products for OTC Human Use” Monograph (April 1, 2011)

Per the U.S. FDA, active ingredients should be distinguished from inactive ingredients (i.e., excipients) on the product label; the most recent Monograph contains this list of 19 permitted actives and their concentrations.

Figure 1. Simplified classification of dermatitis

Figure 1. Simplified classification of dermatitis

Atopic dermatitis, often referred to as eczema, is a general term used to describe differentiated inflammatory skin conditions; a simplified classification is shown here.

Figure 2. Exogenous and endogenous risk factors for irritant contact (chronic) dermatitis

Figure 2. Exogenous and endogenous risk factors for irritant contact (chronic) dermatitis

Contact with the irritant is necessary to produce ICD, but the probability and the severity of the reaction depend on individual factors and environmental conditions.

FDA Sidebar

Regarding the claims of two U.S. skin protectant manufacturers, the main differences are indeed formal, as shown here by an excerpt from a U.S. FDA letter to one skin protectant manufacturer, and promotional materials from another. Also included here are comments for each, and finally, two commercial research investigations for skin protectants.

Warning Letter to a Manufacturer of Skin Protectants (Foams)

An investigator from the U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facilities . . . Based on information and labeling obtained during our inspection, your products […] are skin protectant drugs subjected to the ‘Skin Protectant Drug Products For Over-The-Counter Human Use’ monograph, which is set forth in Title 21 of the Code of Federal Regulations, Part 347.

Based on the claims appearing on the immediate container labels for each of these products (e.g., “Helps prevent and temporarily protects chafed, chapped, cracked, or wind-burned skin”), these products are drugs as defined by Section 201 of the Federal Food, Drug and Cosmetic Act. Moreover, they are subject to the final monograph covering skin protectant drug products for OTC human use.

In addition to these claims, promotional brochures, which you provide to your customers, include statements claiming that, when applied to the skin, these products provide an effective barrier that is unaffected by repeated hand washing. Statements on this promotional labeling also claim that “these products remain effective for up to four hours to prevent the adverse consequences caused by contact with:
- chemicals of all kinds, including acids and alkalis, organic and inorganic substances, and
- all pathogenic micro-organisms.”

Such statements include “that the product:
- becomes an invisible protectant that actually binds to the skin and helps protect it;
- prevents harmful substances from penetrating the skin and entering the bloodstream;
- doesn’t wash off even with repeated washing;
- lasts between 4-8 hours;
- prevents harsh solvents and chemicals from coming in contact with the skin;
- prevents caustic burns and industrial dermatitis; and
- [is] an effective and reliable second line of defense (under gloves)."

The FDA previously advised you, in the warning letter of April 22, 1993, that the OTC skin barrier claims described above cause [your products] to be unapproved new drugs. […] The FDA has not changed its position regarding these violations and, if they persist, the agency will pursue further enforcement action.

Comments

Here, the criticisms of the FDA concerned only the claims of the company promotional material. According to the Agency, due to these claims, the products should be classified as drugs, or better, as unapproved new drugs. After this letter, the company preferred to replace these items of its own production with others, based on a distributorship agreement.

It is almost useless to say that the "new" products the company promoted had improved performance since they contained nothing more than a bit of dimethicone; in order to maintain a legal status, it would only have been necessary to adapt the label. In other words, whether to comply or not with the FDA Monograph was essentially a marketing decision.

Excerpts from the promotional material of a skin protectant of another company are provided next.

Promotional Material of a U.S. 'Invisible Glove' (Foam) Manufacturer

Exclusive non-steroid, non prescription skin protection system that forms an ‘invisible’ glove around your skin, protecting against bacterial contamination, rashes and allergies, while healing previously damaged skin.

The Product moisturizes and promotes cellular renewal and fights symptoms such as itchy, red, cracked and dry skin, associated with eczema, contact dermatitis and other skin problems.

The Product protects the skin against common irritants abundant in today’s world, like soaps, cosmetics, paper, jewelry, harsh cleaners, chemicals, protective gloves, incontinence, water, and even drugs, that can cause contact dermatitis and eczema.

The Product binds to the outermost layer of the skin and forms a non-greasy, water resistant, anti-itch protective layer, that keeps irritants away from the skin while creating a safe and healthy skin environment.

The Product keeps the skin’s natural moisture inside (reduces trans-epidermal water loss) even through multiple washings, without clogging pores. Therefore, one small application of the Product provides hours of hand and body skin protection.

The Product absorbs quickly for an enhanced healing effect, which enables users to quickly return to routine daily work, home or sport activities without delay.

The Product is compliant with FDA monograph 21 CFR 347 for skin protectants.

Active ingredient: Dimethicone
Other ingredients: Water, SD Alcohol 40, Stearic acid, Glyceryl stearate, Triethanolamine, Isopropyl palmitate, Aloe vera gel, Triclosan, Tocopheryl acetate, Corn oil, Disodium EDTA, Lonicifera japonica extract.

Comments

In the above case, the product complies with the FDA Monograph since dimethicone is correctly reported on the label as the active. Therefore, an aggressive promotion policy based on the "invisible glove concept" is permitted without the need to support the claims with reliable tests.

As shown below, even the results of two investigations conducted by the U.S. Army and the U.S. Air Force seem to confirm the inadequate performance of skin protectants and the lack of criteria to define their use.

Two Commercial Research Investigations

U.S. Army: On January 21, 2000, the U.S. FDA granted the U.S. Army approval for the use of a skin protectant, defined as a "barrier paste for protection against chemical warfare agents" such as sulfur mustard (HD), lewisite (L), pinacolyl methylphosphonofluoridate (soman), and similar substances. The approval document disclosed that the product, named SERPACWA for Skin Exposure Reduction Paste Against Chemical Warfare Agents, contained "50% of a particulate of polytetrafluoroethylene (PTFE) dispersed in 50% of a perfluoropolyether oil (Y-PFPE)."

The development of this protectant was carried out in various stages. First, the availability of skin protectants for civilian use was assessed. Commercial skin protectants were then evaluated in vitro and in vivo in a rabbit model. Results indicated the available protectants were unsatisfactory. Hence, the decision was to adapt, through formulation work, industrial greases produced by DuPont in the United States and Ausimont (now of Solvay) in Italy. The prototype contained roughly two-thirds of a PTFE powder and one-third of a PFPE oil. In this case, the stickiness was indeed the main drawback of the final formula. Apparently, this drawback was overcome by replacing the PTFE powder manufactured by DuPont and Ausimont with a PTFE powder manufactured by ICI.

Addressing the stickiness was an issue because the final skin protectant was intended only for complementary protection; it was to be combined with protective equipment. With the limited area of application, the stickiness issue of a 50% PTFE-containing paste was a minor problem. Ironically, one reason for the present use of PTFE and PFPE as cosmetic materials is their effectiveness at low concentrations for improving the sensorial properties of cosmetics.

This work showed how difficult it was, and still it is, to develop skin protectants, while also confirming that skin protectants cannot be used to protect against aggressive chemicals for the prevention of acute injures. Finally, there are unclarified points in the official documents regarding this research work since details on the tests and administration route were not disclosed, and reasonably so due to military use.

U.S. Air Force: More details were available from a report by the U.S. Air Force dated April 2009, regarding another investigation on skin protectants. In this case, the investigation was motivated by the problem of operators being exposed to kerosene fuel for aircraft turbine engines. The desired skin protectant was to be efficient either alone or in combination with personal protective equipment, such as disposable chemical-resistant gloves or heavy-duty chemical resistant gloves, in addition to cotton clothes and a face shield. It was also considered as undesirable to wear it in some environmental conditions.

The development process, similar to that adopted by the U.S. Army, involved first evaluating over-the-counter (OTC) products manufactured in the United States and Canada for their ability “to attenuate or completely prevent the penetration of irritating chemicals such as jet fuel.” To these OTC products were added the industrial grease of Ausimont, the skin protectant developed by the U.S. Army (Serpacwa) and two other products formulated specifically for the U.S. Air Force. An in vitro test using cell diffusion chambers was adopted for a preliminary ranking of the permeability of the products. Then, in vivo tests were conducted in animal models to evaluate the irritation potential.

The combination of Ausimont's product and Serpacwa proved able to inhibit penetration by 99-98% and 95-95%, in wet and dry conditions, respectively—referring here to the order of magnitude better than the other creams. However, the combination was unable to pass in vivo tests, probably due again to the stickiness. The relevance of this problem depends on personal protection equipment, which is obviously different when the irritant is a warfare agent vs. kerosene and influences the area to treat.

Therefore, the rather unsatisfying conclusion of the investigation was: “The best way to protect one’s self from JP-8 [Kerosene] dermal exposure is by properly using personal protection equipment. […]. Skin barrier creams were not shown to be consistently effective in deterring dermal irritation as shown in the animal model used in this study. This study was determined to not move forward to human testing due to the lack of sufficient protection provided by candidate barrier creams in animal model."

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