Molecular iodine is not responsible for cytotoxicity in iodophors

BACKGROUND: Ten percent povidone-iodine (PVP-I) was initially promoted as ‘tamed iodine’ as the chemical activity of the active biocide, uncomplexed or free molecular iodine (I(2)), is reduced 30- to 50-fold compared with Lugol's solution. The idea that I(2) is responsible for topical iodine staining and irritation remains widely held. However, there are no controlled studies that characterize the cytotoxicity and staining of the hydrophobic I(2) species compared with the other hydrophilic iodine species that comprise over 99.9% of the total iodine in topical iodine disinfectants. AIMS: To compare the staining properties of the I(2) species with other topical iodine disinfectants; to evaluate if the concentrations of I(2) in diluted PVP-I used to reduce severe acute respiratory syndrome coronavirus-2 in the nasal cavity are potentially cytotoxic; and to determine if high concentrations of I(2) can be delivered beyond the stratum corneum into the hypodermis, which could provide a mechanistic rationale for I(2) out-gassing. METHODS: Five liquid compositions that contained complexed and uncomplexed (free) I(2) in aqueous and non-aqueous carriers were used to evaluate the interaction of I(2) with mammalian cells in culture as well as human and pig skin. FINDINGS: Concentrations of I(2) (7800 ppm) that are 1500 times higher than that found in PVP-I can be applied to skin without irritation and staining. I(2) is not cytotoxic at concentrations >100 times higher than that found in PVP-I, and does not contribute materially to staining of skin at concentrations found in Lugol's solution (approximately 170 ppm). I(2) can partition into hypodermis tissue, remain there for hours and out-gas from skin. PVP-I and Lugol's solution are highly effective topical disinfectants, but do not facilitate diffusion of I(2) through the stratum corneum. CONCLUSION: The maximum concentration of I(2) found in diluted PVP, approximately 25 ppm, is not cytotoxic or irritating. The potential clinical utility of I(2) has been limited by incorporating this broad-spectrum biocide into acidic aqueous formulations that contain numerous chemical species that contribute toxicity but not biocidal activity. I(2) can be delivered topically into hypodermis tissue without irritation.