The 21-day cumulative irritation assay in man: a half-century summary and re-evaluation.

The 21-day cumulative irritation test (21-day CIT) has been widely used in dermatopharmacology and dermatotoxicology to assess the irritation potential of topical products. Since described by Lanman in 1968, it has been modified, shortened, re-evaluated, and statistically analysed by multiple groups of authors. As the assay has been recommended in FDA draft guidance, we bring subsequent experience to date. The shorter 14-day version is commonly used and may be as adequate as the 21-day application when used to discriminate between moderate to strong irritants. While previous authors stopped the test when subjects experienced an irritation score of 3 or more, the FDA suggested moving the test to another anatomical site to complete in 21 days. This approach avoids assumptions, thus may be more accurate to quantify skin irritation. As the scoring is based on visual grading, the 21-day CIT also does not account for sensory irritation. Therefore, future studies need to propose a way to evaluate the sensation objectively in dermatological product development.