L'Oreal, Laboratory of Mathematical Chemistry
DEVELOPMENT OF A MECHANISTIC SAR MODEL FOR THE DETECTION OF PHOTOTOXIC CHEMICALS & USE IN AN INTEGRATED TESTING STRATEGY
Phototoxicity is of increasing concern in dermatology, since modern lifestyle is often associated with exposure to sunlight. The most commonly reported process is via oxidative reactions.Therefore characterizing the photo-pro-oxidant potential of a compound early in its industrial development is of utmost interest, especially for compounds likely to undergo sunlight exposure in skin.Today there is a need for filtering compounds to be tested in the 3T3 Neutral Red Uptake in vitro test for phototoxicity since testing requires resources. A computational model aiming at predictingthe mechanisms that imply the generation of reactive oxygen species was developed using a diverse set of 56 chemicals having 3T3 NRU data. An historical mechanistic SAR model developedfor polycyclic aromatic hydrocarbons (PAH) was used to derive the new mechanistic model: descriptors were selected upfront to describe the modeled phenomenon. The historical parabolicrelationships between phototoxicity and the energy gap (EGAP) between energies of the Highest Occupied Molecular Orbital and the Lowest Unoccupied Molecular Orbital was confirmed.The model predicts chemicals to be •phototoxic or photodegradable•, or •non phototoxic and non photodegradable•. A four-step testing strategy is proposed to enable the reduction ofexperimental testing with the in silico model implemented as a first screen.