Risk assessment of reproductive and developmental toxicity in eye-drop drugs: a consideration based on threshold of toxicological concern

The systemic dose levels of eye-drop drugs are relatively low in comparison with that of systemic routes such as oral administration. We undertook overall risk assessment of eye-drop drugs for developmental and reproductive toxicity (DART) by comparing the estimated systemic dose level of eyedrop drugs with the known threshold of toxicological concern (TTC) for DART. The systemic dose level of eye-drop drugs in human were estimated to be 0.0005 to 0.05 mg/kg/day on the assumption of 0.01% to 1% of eye drop formulation, 0.04 mL/eye/time of instillation volume, and 60 kg body weight. The TTCs for DART ranged from 0.003 mg/day (0.00005 mg/kg/day; for anticacer drugs) to 7.860 mg/day (0.131 mg/kg/day). Therefore, the range of estimated systemic dose level of eye-drop drugs was almost overlapped with known TTC values for DART, excepting for that applied to the anticacer drugs. These knowledge simply indicates the safety of eye-drop drugs for DART from a view pont of absolute dosage levels, implying allowance of case by case basis planning non-clinical DART study.