The increasing demand for assessment of Nicotine pouches
Since the FDA initiated their pilot programme for faster review of nicotine pouch products, there has been an increased interest in the risk assessment of ingredients. In Europe where the market entry is via the somewhat unregulated route, the standard PAS8877:2022 is utilised to define the required deliverables. In the US, it is not so clear, we have narrative from recent MGOs, we have the PMTA guidelines for ENDs, and then we have industry opinion of what is needed. Whether you need E&L or in vitro studies remains unclear, whether many products have HPHCs at levels to cause concern by the oral route is also worthy of a conversation, but an assessment of the ingredients remains a key deliverable most can agree on, which makes the TRA supporting EU and the US, similar in structure, but with a different casting eye.
To achieve an assessment of ingredients you require complete disclosure from the flavour house which is only permitted with a trusted toxicology partner, and a well worded NDA. The ID of each ingredient is required to run hazard searches and the levels of these ingredients to conduct a quantitative risk assessment (QRA). A flavour house may imply ingredients are safe as they are typically GRAS, but the quantity is key for that assessment. Also, they will not be aware of the other flavour complexes that may also be used, or the expected exposure, and typically no flavour house will define a safe level. More likely they will provide a statement that all companies using their product must do appropriate assessments and testing to confirm safety.
Identifying the hazards
The primary investigation of any ingredient or chemical is to identify known or potential hazards. Here, a positive carcinogen classification will no doubt render the ingredient unwise to use, and these are unlikely to be found in commercial flavour complexes, but data suggesting potential mutagenicity or reproductive toxicity concerns, or even possible carcinogens, need investigating and often a subjective call from a registered toxicologist. Often data is lacking and the toxicologist is required to use (Q)SAR to predict the outcome from the structure. Even then, not all predictions or data is clean, so an expert opinion is needed within the context of the product, as well as commercial use, metabolism and wider toxicity findings.
Natural substances are the bane of every toxicologist
Natural substances are the bane of any toxicologist. Firstly, the flavour house may not have all the data or control over the constituents, the constituents can change over time, there may be multiple constituents to assess, and the natural substance may contain undesirables, ingredients with toxicology concerns which preclude their use if added directly. These undesirables may include substances like safrole, pulegone or methyleugenol, so here an assessment would need to be done to see if all possible sources of each undesirable, are below the maximum permitted level. A natural substance is also typically devoid of toxicology data. Here we may have to look at consumer use data but also look at the hazards of the major components. There are no rules on which percentage of a component constitutes consideration or how many components to consider, since any concerns identified will dictate their weight in such an assessment.
Stacking up?
Stacking or cumulative quantification of an ingredient is key. There may be more than one flavour complex using the same ingredients, there may be natural substances where that ingredient is a major component or even the ingredient appears additionally as a base ingredient. Importantly, the exposure from all sources needs to be calculated and compared against the acceptable daily intake.
Not the only consideration!
A toxicologist must also consider the effects of similar ingredients that have the same toxicological concerns or share toxicological pathways. An example of this is pinenes where individual sub types have their own acceptable daily intake, yet the toxicological concerns are very similar. These group effects are often overlooked.
Group effects and effects of stacking are typically considered as part of a holistic assessment of the formulation, rather than the QRA for individual ingredients.
The advantages of early screening
If a toxicological risk assessment occurs later in the process, when stability trials and even clinical work has initiated, it will be very expensive to change the formulation. It is therefore advisable to conduct a formulation screen as early as possible before product lock. This way the toxicological findings can be used to swap in or reduce certain ingredients to allow for a better profile. A clear example of this is the use of cooling agents. These agents are typically data-poor albeit with enough toxicity data to ring alarm bells. Careful selection of alternatives with more data, can achieve the same sensory effect while preventing the headaches of having to justify potentially unsafe levels.
The overall value of the TRA
A TRA or an ingredient assessment amount to the same thing, and they provide an expert opinion on the toxicological concerns of, in this case, a pouch product. This is required to demonstrate the product has no known safety issues beyond that which is defined and will provide a safer ‘nicotine’ option than combustible cigarettes or perhaps evens electronic cigarettes. It may be required to get approval from a regulator (U.S), or even acceptance by a big supermarket to sell a product. What is important is that it is a step that really cannot be avoided.