For the U.S. Food and Drug Administration (FDA) to determine that a tobacco product is substantially equivalent, a New Product must have either the same characteristics as a Predicate Product, or if it has different characteristics, it must be demonstrated that the New Product does not raise different questions of public health. This presentation provides a toxicological risk assessment approach for combustible tobacco products that can be applied in the substantial equivalence pathway to demonstrate that differences between a New Product and Predicate Product do not raise different questions of public health. More specifically, the presentation focuses on the applicability of health-based occupational exposure limits (OELs) and a threshold of toxicological concern (TTC) approach to evaluate added or increased ingredients as well as their potential pyrolysis products. Occupational exposure levels that are based on health effects are derived through well-established risk assessment practices that rely on integrated analysis of critical health effects, dose-response relationships, and extrapolation methods. The resulting OEL is an inhalation-specific level that an adult can experience without adverse health effects over a working lifetime (i.e. 8 hours of continuous exposure per day, 5 days a week, 40 years). Thresholds of toxicological concern (TTC) have been extensively applied in various industries, including food and beverage, cosmetics, personal and household products, pharmaceutical impurities and medical devices. A TTC of 1.5 μg/person/day is used across regulated industries as an acceptable level for lifetime exposure (i.e. 70 years) to chemicals, including mutagenic compounds, and is applicable to all routes of exposure, including inhalation. In the absence of tobacco-specific guidance documents on toxicological risk assessment, two scientifically-valid approaches to evaluating ingredients for potential risk are presented while taking into consideration the inherent toxicity of tobacco products.