For the non-clinical safety evaluation of pharmaceuticals for new drug applications (NDA), various toxicity studies must be conducted at each stage, from clinical trials to NDA. For topically applied drugs, the level of exposure at the administration site is high because the drug is administered directly to the administration site. However, because systemic exposure to ophthalmic drugs is generally lower than that of systemic drugs, systemic effects may not be adequately assessed. The bone marrow and liver are generally evaluated after systemic administration in in vivo genotoxicity tests, and local genotoxicity studies are conducted on a case-by-case basis. Therefore, we surveyed packages of genotoxicity and carcinogenicity tests for ophthalmic drugs approved in Japan from 2004 to 2021 to assist in the decision of test packages for the development of ophthalmic drugs. There were no major differences in genotoxicity test packages compared to systemic drugs; however, an unscheduled DNA synthesis test using the cornea after ocular instillation was conducted in some products as a test specific to ophthalmic drugs. In the development of ophthalmic drugs, if a positive result is found in an in vitro genotoxicity test, the safety margin between the positive concentration and the clinically applicable concentration (eye drop concentration) is required for safety assessment. If the safety margin cannot be ensured, additional tests may support safety assessment.