A Mild Industry
Fortunately, the cosmetic industry uses very few corrosive compounds and those are neutralized and/or diluted in the finished formulations so such an effect is not anticipated. The main concern with the use of corrosive compounds in the cosmetic industry is their utilization as raw materials in shipping, handling, storage and production.
In contrast to corrosion, primary skin irritation is defined as the generation of reversible damage to skin following the applications of a test substance. The clinical manifestation is redness (erythema) and sometimes slight swelling (edema). Primary irritation should resolve in full barrier healing and restoration within hours.
Probably the best-known primary irritants in personal care and cosmetics are detergents with sodium lauryl sulfate (SLS) being the utmost recognized. In fact, SLS is sometimes used as a positive control in skin irritation studies.
Both corrosion and irritation reactions are local (at the site of affected skin), non-immunogenic in nature, appear shortly after exposure and correlate to the level of exposure. Biochemically, both reactions involve rapid tissue damage and accelerated cell death. The healing process of the skin barrier as a result from corrosion and irritation can fluctuate greatly between individuals and may be dependent on overall immunity, physical and emotional condition, as well as age and the affected location on the body.
The table below summarizes the key differences between skin irritation and corrosion:
A variety of decision logic schemes are available in numerous publications and regulatory documents for the assessment of skin corrosive/ irritant and those can be modified according to risk assessment, exposure and nature of the chemical. An example of such a scheme is shown on the next page.
Surveying the Damage
A common in vitro assay to assess corrosivity is termed Corrositex. In 1999, ICCVAM (The US Interagency Coordinating Committee on the Validation of Alternative Methods) issued a review recommending Corrositex as a stand-alone assay for evaluating acids, bases and acids derivatives for the US Department of Transportation and as well as part of a tier testing strategy. ESAC (which is the European ECVAM Scientific Advisory Committee) followed by issuing a statement of validity in 2000. In 2006 the method was acknowledged internationally as OECD 435.
In brief, the method is a standardized, quantitative in vitro test for skin corrosivity assessment, based upon determination of the time required for a test material to pass through a bio-barrier membrane. The bio-membrane is a reconstituted collagen matrix, constructed to exhibit physico-chemical properties that are claimed to have some similarities to rat skin. It produces a visibly detectable change. The time required for the compound to pass through the barrier is reported to be inversely proportional to the degree of corrosivity. The longer it takes to detect a change in the Chemical Detection System (CDS), the less corrosive is the substance.
The 3D reconstituted human epidermal tissue model produced from primary keratinocytes EpiDerm by MatTek is a model used routinely to assess skin irritation and corrosion potentials of test substances and formulations. The endpoints typically evaluated for skin irritation testing are cytotoxicity assessed by MTT assay (for details, see my column published in the July issue) and interleukin 1 alpha release (IL-1α) which is a pro-inflammatory marker.
EpiDerm has been formally validated by The European Centre for the Validation of Alternative Methods (ECVAM) and testing guidelines have been accepted by OECD for the testing of skin irritation (OECD 439) and skin corrosion (OECD 431). This model is also used in the overall preclinical assessment of topically applied formulations.
An In-Depth Report
The relevancy of the suggested in vitro methodology for prediction of primary skin irritation was published in 2011 and presented by Cosmital SA, The Research Company of Wella and The L’Oréal Life Science Research Center. This included an evaluation of 22 topical formulations from different chemical classes and with various established in vivo irritation methods. Scores have been tested by patch test with repeat occlusive applications on humans and compared to two epidermis equivalent kits: EpiDerm and EpiSkin.
The parameters measured in vivo were visual observation of erythema, dryness and fissure as well as instrumental measurements of redness and trans epidermal water loss (TEWL) representing skin barrier breach. The parameters assessed in vitro were percent of cell viability measured by MTT, the release of extracellular of IL-1α and of lactate dehydrogenase (LDH). The LDH assay is a mean of determining the number of cells via total cytoplasmic enzyme or the cellular membrane integrity as a function of the amount of cytoplasmic LDH released into the medium.
The correlation obtained from this study was R= 0.94 for EpiDerm and R=0.84 for EpiSkin. One of the most relevant parameters for such assessment in vitro has been the detection of MTT after 16 hours of exposure.
The team concluded that those in vitro models can discriminate between potential skin irritant and a non-irritant. It should be noted, however, that these models were not proven to evaluate the magnitude of irritation; meaning assessing the relative severity of the irritation reaction and therefore cannot be used to assess the irritation on a scale such as “mild,” “moderate” or “severe.”
The images here describe Epiderm FT tissue viability testing procedure.
The clinical assessment of primary irritation in humans is conducted as part of the repeat insult patch test (RIPT). Although it is a common practice in the cosmetic industry to conduct this study for the evaluation of raw ingredients and finished formulations, it certainly presents an ethical problem. In this study human subjects are repeatedly exposed to a variety of chemistries and combinations, sometimes with no prior knowledge or in vitro screening established. This exposure is not only a concern for potential topical local reaction. The main concern is associated with cases in which the chemicals penetrate through the skin to the blood circulation and may cause sensitization reaction that will be discussed in an upcoming column on skin sensitization. To maintain reasonable ethical practice in conductance of study tier for safety assessment; prior to human exposure a battery of in vitro, in silico and other means of evaluation should be utilized and the human exposure should be, pending necessity, the final sealing study in the tier after all other relevant endpoints were proven negative.
The RIPT study involves expert grader subjective evaluation of the skin after the exposure to the chemical and allows classifying it on a range of severities. In addition to the ethical issue it presents it also has been criticized for its questionable scientific validity being subjective and not objective and quantifiable. Such may potentially generate confusion in terms of the exact nature of the reaction. It was also criticized for its statistical correlation of reactivity between the size of the panel (the most popular number of panelists being 50) and the prevalence of the tested skin reactions in the general population.
In summary, corrosion and irritation to skin are key safety endpoints to establish in the tier approach for safety of raw ingredients and formulations. The various guidelines and testing methods offer means of evaluation both theoretically and practically. As with other parameters of assessment; here too, the assessor should take into consideration population of interest; site of skin exposed, duration of exposure and potential accumulation in the skin.
Faller C., Bracher M., Dami R., Roguet R. Predictive ability of reconstructed human epidermis equivalents for the assessment of skin irritation of cosmetics. Toxicology In Vitro 16 (2002) 557-572.
Basketter DA. The human repeated insult patch test in the 21st century: a commentary. Cutan Ocul Toxicol. 2009;28(2):49-53.
Owner, Dr. Nava Dayan LLC
Nava Dayan Ph.D. is the owner of Dr. Nava Dayan L.L.C, a skin science and research consultancy and serving the pharmaceutical, cosmetic, and personal care industries. She has 25 years of experience in the skin care segment, and more than 150 publication credits. Tel: 201-206-7341; E-mail: email@example.com