To investigate the safety of the topical application of glutaraldehyde to the ankle and heel of man, the in vitro penetration of glutaraldehyde in a 10% aqueous solution through isolated human thin stratum corneum (chest and abdomen), isolated human epidermis (abdominal), and human thick stratum corneum (blister tops from the sole) was determined 1 h after application. Under these conditions, glutaraldehyde did not penetrate thick stratum corneum, while 2.8%-4.4% of the applied dose penetrated the isolated epidermis, and 3.3%-13.8% of the applied dose penetrated thin stratum corneum. An 8-week irritancy test was conducted by applying a 10% aqueous solution of glutaraldehyde to the ankle and heel area of 12 volunteers. Irritation and one case of sensitization resulted from glutaraldehyde application to areas of thin stratum corneum (anterior ankle) but not from applications to thick stratum corneum (medial, posterior, and lateral heel and posterior ankle), which may be a privileged site with respect to glutaraldehyde sensitivity.