Cumulative irritation

In a third report (very similar to the second), Hanhijarvi, Nevalainen and Mannisto (1985) clearly demonstrated that the type of vehicle can greatly influence irritation, in that dithranol was clearly more irritating when applied in paraffin that when applied in a gel. They were also able to demonstrate that although dithranol was less acutely irritating than butantrone, the cumulative irritations (mean scores at the end of six months of six times per week applications) were quite similar (Mannisto et al., 1984). There was no evidence of systemic toxicity nor of test article in plasma with either species. 

These are conducted to gain information on the cumulative irritancy of a product. This type of test is designed to mirror the intended use of the product, but exposure may also be exaggerated, to provide a greater margin of safety in the risk assessment on the product and also to provide information on problems that may be encountered should the product be misused. Some methods are designed to simulate the normal use of products, with controlled exposure. The skin irritation is monitored and comparisons made between the test and control product in the same panellist. The controls are... 

These are animal assays that evaluate the ability of chemicals to produce cumulative irritation. Many such tests have been described in literature, but only a few have been studied extensively enough to mention. Even those used more often are not as well standardized as Draize-type tests, and many variables have been introduced by multiple investigators. 

PURPOSE AND RATIONALE Inflammation produced late in the induction phase of sensitization tests without positive responses at challenge is cumulative irritation. The HRIPT for skin allergy was modified to evaluate skin irritation. As with single-application patch tests, many investigators developed their own version of the repeat application patch test. 

Kligman and Wooding (1967) applied the Litchfield and Wilcoxon probit analysis to cumulative irritation testing with calculation of IT 50 and ID 50 values. Their early work forms the basis for the 21-day cumulative irritation assay, which is currently widely used. 

The cumulative irritation assay was developed to compare antiperspirants, deodorants, and bath oils to provide guidance for product development. 

Modifications of the cumulative irritation assay have been reported. Intensity of response has been evaluated using other evaluation schemes, the interval between application of fresh patches has been varied, and other methods of data evaluation have been proposed. 

Direct irritation may thus be dehned as an adverse effect of chemicals directly applied to the skin that does not involve prior sensitization and thus initiation by an immune mechanism. Irritation is usually assessed by a local inflammatory response characterized by erythema (redness) and/or edema (swelling). Other responses may be present that do not elicit inflammation such as an increase in skin thickness. Irritant reactions may be classified as acute, cumulative, traumatic, or pustular. However, two classifications are generally used by toxicologists. Acute irritation is a local response of the skin usually caused by a single agent that induces a reversible inflammatory response. Cumulative irritation occurs after repeated exposures to the same compound and is the most common type of irritant dermatitis. 

Safety testing for cosmetics includes usually cumulative irritation, RIPT, phototoxicity, photoallergy, and finally, exaggerated use or home use studies. 

Cumulative irritation The scope of this study is to determine long-term irritation potentials under exaggerated conditions or to assess and compare the mildness of formulations. It consists of a controlled patch test involving 15-30 subjects using 14-21 repetitive 24 h applications. The FDA recommends a 21 day patch test in a 30-subject panel. For more irritating cosmetics, a 14 day application would satisfy the objective of the study. 

Cumulative irritation a reversible dermal response, which results from repeated exposure to a substance (each individual exposure is not capable of causing acute primary irritation). 

The reader should also be aware that there are a variety of cumulative irritancy test designs available, such as the guinea pig immersion test and the 21-consecutive-day occluded patch test in rabbits. 

Skin irritation (inflammation) from cutaneous exposures that are acute (primary irritation) and repeated (cumulative irritation). 

Cumulative irritation test. This is another test that is commonly used to evaluate the absence of skin reactions to the formulation. It involves a minimum of 25 panelists. The solutions of test products as well as reference products with well-known skin tolerance are applied to the backs of panelists under occlusion for several consecutive days (generally 5 or 21 days) and the absence of skin reaction is then evaluated by trained professionals [22],... 

Individual daily observations should be provided, as well as a tabulation that presents the percentage of subjects with each grade of skin reaction and degree of patch adherence on each study day. The mean cumulative irritation score, the total cumulative irritation score, and the number of days until sufficient irritation occurred to preclude patch application for all the study subjects should be calculated for each test product, and a statistical analysis of the comparative results should be performed (see Appendix C). 

For a variable for which low scores are better, such as mean irritation score or total cumulative irritation score, the hypotheses would be... 

Ziel K, Yelverton CB, Balkrishnan R, Feldman SR (2(X)5) Cumulative irritation potential of metronidazole gel compared to azelaic add gel after repeated applications to healthy skin. J Drugs Dermatol 4 727—731... 

Beutner KR, Lemke S, Calvarese B (2(X)6) A look at the safety of metronidazole 1% gel cumulative irritation, con-tad sensitization, phototoxidty, and photoallergy potential. Cutis 77(Suppl 4) 12-17... 

Some chemicals do not produce acute irritation from a single exposure, but may produce inflammation following repeated application to the same area of skin (cumulative irritation) (Shelanski 1951). Studies of skin corrosion are conducted in animals using standardized protocols, as it is not appropriate to conduct screening studies in humans. However, acute irritation is sometimes evaluated in humans after animals studies have been completed. Tests for cumulative irritation in both animals and humans have been reported. 

The cumulative irritation assay as described by Lanman and coworkers (1968) was used to compare antiperspirants, deodorants, and bath oils to provide guidance for product development. A 1 inch of Webril was saturated with test compound and applied to the skin of the upper back. After 24 h, the patch was removed, the area evaluated, and a fresh patch applied. The procedure was repeated daily for up to 21 days. The time it took to produce an irritant response in 50% of the test subjects [IT50, as... 

TEWL measured under standardized conditions presents low day-to-day intra-individual variations and represents a stable personal characteristic (Pinnagoda et al. 1989a). Therefore, some authors suggest that individuals susceptible to ICD due to occupational exposure may be reliably characterized by utilizing their baseline TEWL values for prediction of risk in epidemiological field studies. After cumulative irritation induced by the application of a solution of SLS of... 

Widmer J, Eisner P, Burg G (1994) Skin irritant reactivity following experimental cumulative irritant contact dermatitis. Contact Dermatitis 30 35-39... 

This distribution occurs in caterers and, described as dyshidrotic eczema it has been reported in metal workers with an ICD from cooling lubricants (Cronin 1995). Frequently, this condition heals spontaneously, resulting in hardening of the skin sometimes it progresses to cumulative irritant dermatitis. 

Many bioassays have been proposed for the purpose of identifying sensitive skin. A 24-h patch test with sodium lauryl sulphate (SLS) and repetitive patch tests, such as the 21-day cumulative-irritation assay, the chamber scarification test, and the soap-chamber test, have been used (Lee and Maibach 1994). 

Lee CH, Maibach HI (1994) Study of cumulative irritant contact dermatitis in man utilizing open application on subclinically irritated skin. Contact Dermatitis 30 271-275 Malten KE (1981) Thoughts on irritant contact dermatitis. Contact Dermatitis 7 238-247... 

Schwarz T (1988) Die Bedeutung epidermaler Zytokine in der UV-induzierten Immunsuppression. Hautarzt 39 642-646 Tupker RA, Pinnagoda J, Coenraads PJ, Nater P (1990) Susceptibility to irritants role of barrier function, skin dryness and history of atopic dermatitis. Br J Dermatol 123 199-205 Widmer J, Eisner P, Burg G (1994) Skin irritant reactivity following experimental cumulative irritant contact dermatitis. Contact Dermatitis 30 35-39... 

Whilst the test described above is a common way in which an attempt is made at predictive identification of those substances or products with significant skin-irritation potential, other information can also be used. Consideration is given to structure-activity relationships, although it must be said that this subject is in its infancy for skin irritants (Whittle et al. 1996 Barratt 1996). Data may also come from non-standard animal tests, predictive human tests and from human experience. These may cover either acute and/or cumulative irritant responses in skin. It is also possible for manufacturers to use data from in vitro studies. Lastly, where the product is a mixture of two or more substances [a preparation in European Union (EU) terminology], the manufacturer may elect to calculate the likely irritancy on the basis of the knowledge of the skin irritancy of the component substances and the concentration at which they occur in the product. For certain types of product, this process has been formalised in the EU as the conventional method (European Community 1988). 

Most commonly, skin irritation to chemicals occurs clinically as cumulative irritant dermatitis. MSDS data is most often based on evidence of the acute skin-irritation potential of the product. Such data may not always be fully predictive of cumulative irritation potential (Hannuksela and Hannuksela 1995). Furthermore, if the product is a preparation rather than a single substance, MSDS information may be based on the conventional calculation method, in which labeling is only applied if the sum of classified irritants is at least 20% (European Community 1988). To put this in simple terms, it means that 20% aqueous sodium lauryl sulphate would be described as irritant, whilst 19.9% would not be so labeled. 

Alcohols can delipidize and dehydrate the upper part of the stratum corneum, thereby impairing the barrier function of the epidermis. Irritant contact dermatitis from alcohol is most often of the cumulative irritant contact type and, in rare cases, of the acute irritant type (Adams 1986 Tupker et al. 1997). Alcohol dermatitis may take the form of an eczematous eruption, or, more rarely, a contact urticarial at the exposed site (Martin Scott i960 Fregert et al. 1963). Allergic contact dermatitis to ethanol and isopropanol is considered rare (Pecquet and Pradalier 1992), but was reported as a constituent of a transdermal patchsystem (Okazawa et al. 1998). The patch test concentrations for these substances are either as is or in 10% aqua. 

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