A global manufacturer of electronic nicotine delivery systems (ENDS) and e-liquid products.
The client is required to provide regulatory authorities with up-to-date toxicological information related to the ingredients used in their products. Bibra were provided with a list of several substances and asked to produce a hazard review (considering the requirements of the European Tobacco Products Directive, TPD2) for each.
The aim was to produce a comprehensive hazard review on each ingredient, relying on existing Expert Group reports (where available) but also considering the primary literature for any more recent toxicological developments. The reviews would cover human health effects (including target organs and critical effect levels), mode of action (MoA) insights, existing expert group health-based guidance values (HBGVs) and information on classification and labelling (C&L). Key absorption, distribution, metabolism and excretion (ADME) data as well as information relevant to an understanding of each ingredients potential addictive properties would also be included. The reviews would have a particular focus on the inhalation route of exposure (the most relevant route for ENDS ingredients) and the existing high-quality studies, notably those conducted to Organisation for Economic Co-operation and Development (OECD) Test Guidelines (TGs) and to Good Laboratory Practice (GLP).
Approach and outcome
The bibra toxicologists have many years of experience in the preparation of hazard reviews on a diverse range of substances. Our first port of call was our own in-house database (TRACE) and databank, which we have been running for over 50 years. This provided a quick and efficient route to expert group evaluations, which were used (where available) as the initial basis for each hazard review.
A subsequent search of the primary literature was conducted for each ingredient in TRACE, PubMed (which includes Toxline) and PubChem, the European Chemicals Agency (ECHA) Information on Chemicals database, the OECD eChemPortal, the Lhasa Carcinogenicity Database, and the Registry of Toxic Effects of Chemical Substances (RTECS). These searches were date restricted (where appropriate) in an attempt to identify more recent critical data that would not as yet have been considered by the expert groups.
TRACE and the International Toxicity Estimates for Risk Assessment (ITER) databanks were the key sources for existing HBGVs, the focus being the identification of expert group-derived limits for the long-term inhalation exposure of the general population, covering cancer/non-cancer and local/systemic effects where available/appropriate. When such values were not identified, alternative levels were sought, for example industry established values (like REACH-registrant proposed Derived No-Effect Levels, DNELs), values covering shorter durations (e.g. acute or sub-chronic), occupational exposure limits (OELs), and/or health-based limits proposed for other routes of exposure (e.g. oral).
The data (human, laboratory animal, and in vitro) were selected based on a variety of factors (such as reliability, expert group acceptance, extent of documentation, and appropriateness for the sector) in a weight-of-evidence (WoE) approach. The critical details of each study were summarised and (where appropriate) effect levels (NOAEL/LOAEL/BMDL values) were identified. Expert judgement was used to prioritise the key studies for each endpoint and the critical Points of Departure (PoD) were highlighted for future risk assessment. The client was also made aware of any data gaps.
An executive summary was included in each review to highlight the critical information. The reviews provided the client with up-to-date evaluations of the critical mammalian toxicity data and summarised the available HBGVs for each ingredient. The project was successfully completed, according to a strict timetable.