An international manufacturer of electronic nicotine delivery systems (ENDS) and e-liquids.
In order to market their latest product in the United States, the client was intending to submit a Premarket Tobacco Product Application (PMTA) for a pod-based ENDS device.
According to guidance published by the US Food and Drug Administration (USFDA), one important aspect to consider in assessing the potential impact of vaping on consumer health is the possibility of leaching of chemical substances from the device (and its subcomponents, e.g., the mouthpiece or cartomizer) into the e-liquid.
The client had therefore conducted a robust programme of extractables and leachables (E&L) evaluations on the ENDS device at a well-established analytical laboratory, specifically the pods and other subcomponents that directly contact either the e-liquid or the aerosol.
To demonstrate that the pod materials and manufacturing processes were not introducing substances posing health concerns to consumers, a toxicological risk assessment (TRA) of extracted or leached chemicals was conducted by bibra toxicologists. The results of this TRA were used in a submission to the USFDA, to support the client’s claim that the ENDS device could be regarded as “appropriate for the protection of the public health” (APPH).
Approach and outcome
In order to ultimately detect any potential leachables that the pod materials may introduce to the e‑liquid, the component materials were initially subjected to analytical extractables studies involving a range of extraction conditions. Based on the results of these analyses, bibra was asked to subject the identified extractables to a toxicological screening assessment with the purpose of advising on compound prioritisation (from a health risk perspective) for monitoring in subsequent leachables studies. This extractables screening assessment considered key toxicological hazards, including genotoxicity, carcinogenicity and sensitisation, based on a combination of (Quantitative) Structure-Activity Relationship ((Q)SAR) analysis, human health classifications (e.g., EU CLP) and expert judgement of each chemical structure. Following this initial hazard-based exercise, suitable health-precautionary benchmarks (e.g., the Threshold of Toxicological Concern (TTC)) were assigned to each extractable which were then compared to worst-case consumer exposures in order to inform on potential consumer health risks and prioritise the extractables for further investigation.
Those extractables considered of high priority were then subsequently targeted in leachables studies conducted with the e-liquid-containing pods themselves. Subsequently, for each detected and identified leachable, comprehensive literature searches were conducted to identify relevant and reliable absorption, distribution, metabolism and excretion (ADME) and toxicity data. Where substance-specific data were lacking, a “read-across” approach was considered and applied, where appropriate. Following this hazard identification phase, the critical toxicological endpoint of each substance was evaluated, and an appropriate Point of Departure (PoD) was identified from the key studies. Health-precautionary Uncertainty Factors (UFs) were applied to derive conservative Tolerable Intake (TI) values for each leachable. The TIs were then compared with the worst-case consumer exposure estimates, and Margins of Safety (MoS) generated. Overall, no significant toxicological concerns were identified for any of the leachable compounds. As such, bibra toxicologists were able to conclude that no significant health risks would be introduced to consumers.