Regulatory testing for agrochemicals has traditionally included a 90-day toxicity study in a non-rodent species, usually the dog. With growing emphasis on the 3Rs—replacement, reduction, and refinement of animal use—and increased adoption of New Approach Methodologies (NAMs), there is interest in determining when such studies are truly necessary. This case study on florpyrauxifen-benzyl ester uses a weight-of-evidence (WoE) framework integrating short-term in vivo, in vitro, and in silico data to evaluate the need for a 90-day dog study in human health risk assessment. In 28-day studies, rats and dogs showed no adverse effects up to approximately 1000 mg/kg/day, so the assessment focused on toxicokinetic sensitivity. Rat and dog toxicokinetic data—from metabolism, dose-range-finding, and 28-day studies—were combined with in vitro plasma protein binding and microsomal clearance data in physiologically based pharmacokinetic (PBPK) models. These models predicted 90-day internal exposure and showed higher exposures in rats than dogs at comparable doses, with no evidence of accumulation. The model predictions aligned with observed data and supported waiving the 90-day dog study. The existing study also did not change human health risk conclusions. Overall, this WoE framework shows how integrated data can justify waiving subchronic dog studies while maintaining protection of human health and reducing animal use.