E-cigarettes and other Nicotine Delivery Devices

Recent years have seen a rapid expansion in the market for non-tobacco products that deliver inhaled nicotine, most notably, electronic cigarettes. These do not involve burning processes, rather converting an “e-liquid”, containing nicotine and other excipients, into a vapour that is inhaled by the user. Thus, we provide critical e-cigarette safety evaluations, for regulatory compliance and more.

In general, in the EU, electronic cigarettes and other electronic nicotine delivery systems (ENDS) and non-tobacco nicotine delivery devices (NTNDD) require notification to the revised Tobacco Products Directive (TPD2; 2014/40/EU). Article 20 of TPD states the need for manufacturers and importers of e‑cigarettes to submit a ‘notification’ six months prior to the intended placing on the EU market (or, if the product was already on the market on 20 May 2016, the notification needed to be submitted within 6 months). The notification in question must include “toxicological data regarding the product’s ingredients and emissions, including when heated, thus referring in particular to their effects on the health of consumers when inhaled and taking into account, inter alia, any addictive effect”. Bibra has produced toxicity monographs on 100s of e-liquid ingredients and carried out numerous health risk assessments of ENDs products including assessment of the emissions (e.g. VOCs such as aldehydes, following analytical determination) and extractable and leachable assessment of the devices (and device components), helping companies meet their TPD-compliance obligations. Where Member States consider that the submitted information is incomplete, as a result they shall be entitled to request the completion of the information. In addition, and especially relevant, Member States shall ensure, among other requirements, that “except for nicotine, only ingredients are used in the nicotine-containing liquid that do not pose a risk to human health in heated or unheated form”.

We provide valuable advice on toxicological issues relating to e-cigarettes, and can support your regulatory submissions within the scope of MHRA, REACH and CLP

Whereas, according to the Medicines and Healthcare Products Regulatory Agency (MHRA), the relevant UK competent authority, any such product “which claims or implies that it can be used for cutting down, quitting and reducing harm is considered to be a medicinal product and must be licensed as a medicine”. Therefore, as part of the license application process, a supplier must assess the safety and efficacy of the product, including a detailed safety review of all chemical components in the liquid formulation and a comprehensive e-cigarette safety evaluation of the potential extractables and leachables originating from all parts of the e-cigarette. We have good experience of the MHRA approval process, having assisted a client with obtaining a medical license for the general sale of their breath-operated product (Voke®) from the MHRA.

In the US, and following clarification by the US Food and Drug Administration (FDA) in the final May 2016 deeming rule (81 FR 28973), the pathway for gaining regulatory approval for ENDS products is through the submission of a Premarket Tobacco Product Application (PMTA) to the FDA, under section 910 of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 387j). This covers e-cigarette devices and e-liquids (including those not containing nicotine). Although companies are still feeling-their way with the preparation of PMTAs for ENDS, the FDA has produced a guidance document for industry (FDA, 2019). Regarding the human health aspects, a full assessment of the toxicological effects of ENDS (e.g. ingredients, components, product use) is needed to allow the FDA to determine whether the product can be authorised for marketing. Ideally, this assessment will be based on “well-controlled investigations” although other “valid scientific evidence” may be considered sufficient by the Agency. The FDA does note that, in general, it “does not expect that applicants will need to conduct long-term studies [e.g. rodent carcinogenicity bioassays or long-term clinical trials] to support an application”. Rather applicants can consider long-term studies in the existing literature (with appropriate bridging information), extrapolating from shorter-term studies and supportive data (e.g. in vitro). Indeed a thorough literature review is recommended, and should cover ADME and toxicity data (e.g. cytotoxicity, respiratory and cardiac toxicity, genotoxicity, carcinogenicity, and reproductive and developmental toxicity) with a focus on physiological exposure routes (i.e. inhalation, oral, dermal and ocular) and a “conclusion as to whether there is a toxicological concern with respect to the ingredients, constituents, flavours, humectants, and mixtures of humectants (glycerin, propylene glycol, and other ingredients) that will be delivered in the aerosol”. Emissions analysis must include screening for over 30 harmful and potentially harmful constituents (HPHCs) which includes aldehydes, glycols, NNN, NNK and several heavy metals). A comparative quantitative health risk assessment is also important in the evaluation of the health effects of product switching, for comparing similar products (e.g. other e‑liquids) and, if the ENDS product is marketed as a replacement for combusted cigarettes, for comparing the ENDS product with the risks of cigarettes.

As in the UK, if an ENDS manufacturer in the US wishes to make a smoking cessation claim or market its product for therapeutic purposes, it must submit an application as a medical product (i.e. as a medical device or a drug).

 

Toxicological assessments – E-cigarettes and other NTNDDs

  • Preliminary hazard screening of e-liquid ingredients to outline critical toxicology and identify substances of high concern to human health. This screening allows companies to identify at an early stage possible substances of high human health concern in their formations and to act on this (e.g. consider reformulation of the e-liquid), prior to analytical testing of their products and submission of a regulatory notification/registration.
  • Toxicity monographs including expert searches to identify existing toxicology (and ADME) data on the product, individual components, ingredients, impurities, emissions, metabolites and/or read-across candidates. These include the key available data for a comprehensive range of toxicological endpoints (including cardiopulmonary and Carcinogenic, Mutagenic and Reproductive (CMR) properties) as well as addictiveness data. These monographs have proved to be a key part of companies TPD2 notifications, and could form the basis for a PMTA submission
  • Human health risk assessment
    • emissions, including carbonyls, VOCs, TSNAs and potentially hazardous metal impurities. This is routinely conducted by bibra toxicologists following the identification and quantification of the emissions profile of the product by a trusted analytical laboratory
    • extractables and leachables from the ENDS device and/or its components, as well as e-liquid container closure systems
  • Thorough toxicological reviews and e-cigarette safety evaluations on the product components, formulation ingredients, emissions, and extractables and leachables.
  • Application of read-across and (Q)SAR to fill data gaps, where identified, and the use of the TTC approach.

 

Electronic cigarettes and other ENDS may also fall within the scope of both REACH and CLP, due to being regarded as containers of chemical substances. Most noteworthy, for substances imported at one tonne or more per year per legal entity, it is required that they are registered under REACH and are notified to the Classification and Labelling Inventory. Our internationally renowned team of scientific experts can guide you through your REACH registration process and classification and labelling requirements.

Get in touch if you need help, for example, in the preparation of a ‘notification’ for submission under TPD2, in the preparation of a medicine license application (e.g. for the MHRA), a thorough toxicological evaluation for a PMTA in the US, or assistance with your REACH or CLP obligations.

 

Continue reading about our previous work in the e-cigarette industry:

Find out more about our work on “Extractables and Leachables in the ENDS (electronic nicotine delivery system) sector

Read our recent interview regarding e-cigarette safety evaluation with ECigIntelligence on “TPD test requirements criticised as vague: what can manufacturers do?

Read Charlie’s e-cigarette series of blogs, on our dedicated webpage.

Pete and Richard recently gave an interview to Smithers Rapra, about the e-cigarette safety evaluation and ongoing safety assessment obligations for e-liquids and e-cigarette hardware…click here to read more!

 

Recent work in this field

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