Toxicological Assessment of Flavor Ingredients in E-Vapor Products

Abstract

Many flavor ingredients are often used in potentially reduced-risk tobacco products (such as e-vapor products). Although most are “generally recognized as safe (GRAS)” when used in food, there is limited information available on their long-term health effects when delivered by inhalation. While obtaining route-of-exposure-specific toxicological data on flavor ingredients is critical to product evaluation, the large number of individual flavor ingredients available and their potential combinations render classical toxicological assessment approaches impractical, as they may require years of preclinical investigations and thousands of laboratory animals. Therefore, we propose a pragmatic approach in which flavor ingredients are initially assigned to groups of structurally related compounds (Flavor Groups), from which flavor group representatives (FGR) are then selected and tested individually and as a mixture in vitro and in vivo. The premise is that structurally related compounds would have comparable metabolic and biological activity and that the data generated using FGRs could support the toxicological assessment of other structurally related flavor ingredients of their respective Flavor Groups. This approach is explained in a step-wise manner and exemplified by a case study, along with its strengths, limitations as well as recommendations for further confirmatory testing. Once completed, this FGR approach could significantly reduce the time and resources required for filling the data gap in understanding the health risks of many flavor ingredients while also minimizing the need for laboratory animals.

Fruit flavors in electronic cigarettes (ECIGs) are associated with nocturnal dry cough: A population longitudinal analysis

“…The toxicological profile for most of the flavors remains difficult to define [ 8 , 68 ]. Our study did not perform a direct comparison among the different broad flavor categories assessed in the PATH Study.…”

Assessment of inhalation toxicity of cigarette smoke and aerosols from flavor mixtures: 5‐week study in A/J mice

“…We have previously demonstrated the concept of using flavor representatives for assessing the toxicity of flavors in an inhalation study in a 90‐day OECD study (Ho et al, 2020). In the current study, we included a greater number of individual flavors (a total of 245 flavors), grouped them on the basis of structural similarity, and then selected a FGR (38 FGRs in total) with the most severe toxicological profile from each structural group (Sciuscio et al, 2020, 2022). The selected concentrations of individual flavor chemicals were similar to or higher than those typically used in commercial e‐liquids (Behar et al, 2018; Hua et al, 2019; Omaiye et al, 2019).…”

“…The 38 FGRs from different chemical structure categories were selected on the basis of known and in silico‐predicted toxicological data (Sciuscio et al, 2022). Of the 38 FGRs, 37 flavor ingredients were first prepared in the form of preblended flavors (a total of 6 preblends) from MANE (Jakarta, Indonesia).…”

“…While inhalation studies have been valuable in assessing the long‐term impact of specific flavors or flavored e‐cigarette products (Ha et al, 2015; Olfert et al, 2018; Werley, Kirkpatrick, et al, 2016; Wong et al, 2021), it is not always feasible to test the large number of individual flavor ingredients or combinations of formulations (Zhu et al, 2014) because of the great amount of time and number of laboratory animals required for such testing. To comprehensively test the large number of diverse flavor compounds used in e‐cigarettes, we previously performed a 90‐day sub‐chronic inhalation study in rats by employing the “read‐across” and “flavor toolbox” concepts (Ho et al, 2020; Sciuscio et al, 2022). Flavors were allocated into structurally related groups (read‐across) on the basis of the Commission Regulation No.…”

“…1565/2000 grouping approach (European Commission, 2000). Expanding on this approach, an additional 245 flavor ingredients were classified according to their structural, toxicological, and metabolic properties (Sciuscio et al, 2022). This method of compound grouping was used by the European Food and Safety Authority, among others, to evaluate the toxicity potential of various flavor ingredients (Date et al, 2020; European Commission, 2000).…”