Many therapeutic agents are prepared in prodrug forms, which are classified into Type I, II and subtypes A, B based on their sites of conversion. Recently, an increasing number of INDs have appeared as Type II prodrugs that often contain dual tracks of toxicity profile exploration, one on the prodrug and another on the active drug. A comparative toxicology analysis is introduced here to assist reviewers to evaluate the dual toxicity profiles effectively. The analysis helps determine which toxicity is contributed by the prodrug itself, its intermediates, or the active drug itself. As prodrug INDs, or any other new molecular entity (NME) INDs progress into advanced phases of toxicology development, analysis of time-dependent component of toxicity expression, regarding the emergence of new target organs over time, becomes more significant. A strategy is developed to address Pharm/Tox issues such as what duration is required for a toxicity to emerge at the exposure level achieved or dose studied, how many animals in the group are affected, whether the toxicity is a cross-species phenomenon, and whether it is reversible, etc. In conclusion, dual-track comparative toxicology can be useful in the understanding of Type II prodrug's mechanism of toxicity, and that time-dependent toxicology analysis offers means to detecting new toxicity emergence over time. Both approaches could significantly facilitate secondary and tertiary review processes during IND development of a prodrug or NME.