Electronic Cigarette Industry Trade Association

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The Toxicology Collaboration Project: FAQs

18, Mar, 2016

 

1.   How does the collaboration work exactly?

The collaboration works by pooling resources to fund the massive body of toxicological data required for most vaping sector businesses to notify their product ranges. Every e-liquid flavour is made up of a number of different ingredients, with flavourings which are likely to contain several different flavour compounds. Altogether, an average e-liquid is likely to contain around 10 individual chemical compounds. There are also individual chemical compounds which need to be identified and toxicologically assessed in the emissions from e-liquids and hardware. Each of these needs to be toxicologically assessed to provide the data required for the TPD notification.

Each collaborator agrees to invest £25,000 (inc VAT) as a starting point, and we hope that enough collaborators will join so that no further investment is needed. The initial list of compounds agreed by the collaborators contains about 300 compounds. The total cost of toxicological analysis for these compounds - which are widely found in most ranges of e-liquids, and include some of the compounds likely to be found in emissions - will be about £600,000 (+VAT).

Fundamentally, this project is about sharing the costs and sharing the data, so that every company can get the data required for the TPD notifications, but without everyone having to invest a small fortune for the same data.

2.   How many companies are already involved?

Four collaborators have invested upfront to get this project off the ground. A further 20 companies have already expressed an interest. However, it’s hard to say how many will be involved by the time you read this. The initial four collaborators have provided bibra with their own £25,000 each, so that the work of the toxicologists has already begun, working through the agreed list of compounds as a starting point. There is a legally-binding Agreement which the collaborators are expected to sign up to, to protect their individual investments, their intellectual property rights, and to ensure that the data is not misused by anyone.

The Project is being administered by VKC Regulatory and Scientific Ltd.

3.   How much is the minimum investment?

The minimum investment is £25,000 (inc VAT) to join the collaboration. It is important to put this in context: if an individual company  has a range of, say, only 4 flavoured e-liquids, the likely number of individual compounds requiring toxicological assessment for this company is going to be in the region of 40. A reasonable estimate for the cost of carrying out the toxicological assessments for these 40 compounds would be approximately £80,000 (+VAT). This illustrates just what a financial saving might be achievable if enough companies join the collaboration to share the costs and share the data.

4.   How much is the maximum investment?

It is impossible to know at this stage the full number of compounds which will need to be assessed.  The existing list is the result of a certain amount of research and product knowledge, but analysis of natural extracts used across different companies might add more compounds which form part of those extracts. There is a mechanism in the Agreement for more compounds to be added to the list (as well as to remove them), so that the list can be updated to reflect the needs of the collaborators. We hope that enough collaborators will want to take advantage of this opportunity to share the costs and share the data, so that more funds can be generated than are needed for the initial agreed list of compounds, so that there is already a preparatory fund ready for adding in the other compounds as they are identified by emissions testing, and further e-liquid analyses.

The original four collaborators have agreed that they will pay more if required, to ensure that the full list of compounds can be assessed. Future collaborators joining the project will be expected to make a similar commitment.

Ultimately, these four have recognised that their own businesses need these data, if they are going to be able to submit their notifications for TPD and be in a position to make informed decisions about their products moving forward. In reality, every business wanting to continue marketing products under their own brands post TPD requires these data.

5.   What is the expected final cost (guessing you have a rough idea of how many companies will want to be involved)?

The original list would need more than 25 collaborators, but that is just a starting point. Ideally, we would have over 30 collaborators, adding flexibility to undertake additional compound assessments which may arise. At this stage, we have no way of knowing how many collaborators there will be.

It is equally difficult to guesstimate the expected final cost. This is why we have started with an agreed list of compounds, and we have bibra's estimate of about £600,000 (+VAT) for completing those. As more toxicity monographs are completed, bibra will probably gain a better understanding of the time each one actually takes, and we may be able to get more accurate estimates for future work streams. The really difficult bit is already done, in terms of working out how to approach particularly complex compounds (like vanillin), where there is a lot of data, but not much that is relevant for our sector. This has enabled bibra to formulate a strategy for approaching each compound, which is enormously helpful and (of course) compliant with the TPD notification requirements.

6.   Is there a closing date to register as a participant (subject to finalising cost)?

There is no closing date, as such, but clearly, the sooner you get on board, the sooner you are in a position to influence the decision-making about which compounds need to be added to or removed from the list.

7.   Are these going to be ready by the May deadline?

No, but fortunately, May is not the most pressing deadline. It is disappointing that the work started on this project two years ago made only minor headway at that time, because the whole sector is now having to play catch up. Fortunately, bibra have made a frankly astonishing commitment to this project, and have added extra resources to their team of over 20 expert toxicologists, with the aim to provide a sufficiently broad database of toxicological data ready for TPD notifications before 20 November 2016.

20 November 2016 is the 'hard' deadline in TPD, because that is the date which is 6 months before the transition period ends on 20 May 2017. In the UK at least, products which are not compliant with TPD may continue to be sold through until 20 May 2017. The rest of Europe may be a different matter, and bibra are working hard to get as many toxicology reports ready by 20 May 2016 as is physically possible to do.

8.   Which substances are in your list as part of the collaboration agreement?

The agreed list of compounds has taken considerable investment of time and money, and is viewed by the Collaborators as confidential information. The list forms a Schedule to the Agreement which collaborators are expected to sign up to.

Therefore, as a potential collaborator if you are able to share your own list of compounds of interest with either bibra or with VKC, we can check them against the currently agreed list, and let you know whether or not your compounds are covered already. (We believe it is likely that they will be, since the majority of the compounds on the agreed list occur in a wide range of commonly-used flavourings for e-liquids.)

It is important to recognise the difference between a 'test' and a toxicological (desk-based) assessment. The testing bit is the e-liquid analysis and emissions testing, conducted at a testing laboratory. Most companies should have already had their e-liquids tested, to identify the compounds which are present, but don't worry if you haven't yet, we can help, if needed.

9.  What will the toxicology assessment contain? And why is a literature search not sufficient?

There has been much talk in the sector about doing a 'basic literature search' - a cheap and (relatively) easy undertaking. However, a basic literature search will simply provide you with a (often lengthy) list of bibliographic references  of published papers. For example, vanillin, a compound found in a huge number of e-liquids, returns over 2,000 references in PubMed, but these are of very little use to your businesses. Bibra do not believe that this will be sufficient for TPD2 compliance purposes, notably, as you will not be able to:

  • understand the toxicological profile (i.e. potential hazards) of your substances,
  • understand if you have any substances of concern (e.g. respiratory sensitisers) in your portfolios;
  • understand if the ingredient/emission impacts on the cardiopulmonary system;
  • understand potential addictiveness of the ingredient/emissions;
  • assess the EU CLP classification of each ingredient, and therefore will not be able to classify and label your products appropriately;
  • use these searches for a basis for determining tolerable doses/concentrations (and therefore analytical detection limits); or
  • conduct product-specific human health risk assessments in future.

Due to the above considerations, merely conducting a literature search will not provide any support for determining the safety of the product; therefore the businesses will not be able to carry out their general product stewardship obligations nor be able to sign the declaration of product safety[1] with any confidence.

The Toxicity Monographs provided to the Collaborators under this project offer much more than a simple literature search. Essentially, a toxicologist will run carefully-tailored searches, assess the output, decide which papers are potentially key, and collect these. Once obtained, the full publications will be assessed in more detail and either excluded from the review or summarised in the Toxicity Monograph. This, therefore, is far more than a literature search but rather a human health hazard assessment. For further information on what will be included; please see Appendix I and Appendix II.

These Toxicity Monographs will enable all of the issues bulleted above to be resolved, or at least provide a basis for resolving them.

There is a further issue, in that a mere literature search very clearly fails to address two key aspects of the TPD:

  • A requirement for manufacturers/importers (Article 20, para 2):

(b) toxicological data regarding the product's ingredients and emissions, including when heated, referring in particular to their effects on the health of consumers when inhaled and taking into account, inter alia, any addictive effect;

(A literature search returns a list of references on the compound, without analysis, not "referring in particular to their effects on the health of consumers when inhaled" nor "taking into account, inter alia, any addictive effect".)

  • A requirement for Member States (Article 20, para 3):

            (e) 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.

(Not only is a literature search unlikely to reassure MS that they have the data for this, in some cases, it may actively encourage them to take the opposite view, particularly when a compound has been 'assessed' as a tobacco ingredient, (e.g. vanillin) as the use in tobacco brings certain assumptions with it (which is why the alleged assessment has more general text on the perils of smoking than anything directly related to the compound itself). If all they have to weigh this against is a list of abstracts, too long to read and impenetrable to the unskilled (and in the not infrequent case of articles with missing or poor abstracts, to the skilled too), the chance of them asking for more data, or declining to allow a product to be sold is disturbingly high.)

10.   What format will reports be presented in?

Each report will be a pdf file containing the relevant data on each ingredient/emission. This pdf file can then be attached to each TPD notification, where this substance is used (as an ingredient) or released from (emission). It will be marked with the following disclaimer:

This Toxicity Monograph was prepared under the instruction of VKC Regulatory and Scientific Ltd, specifically for "The Toxicology Collaborators" who are parties to the "Toxicology Collaboration Agreement". This Toxicity Monograph must not be used by any company or group outside of "The Toxicology Collaborators", unless previously agreed by said Collaborators.

11.   Is there an option for smaller companies to just pick and choose specific Monographs, if they can't afford to buy-in fully? If so, what is the cost of that?

Essentially, no - this is due to the large investment by several other companies. We recognise that £25,000 is a significant investment for a smaller company. However, the reality is that, as indicated above (at FAQ 3), even with a very limited range of products, the costs for the toxicology can mount up very quickly. Crucially, any business wanting to continue to market products under their own brand will need to provide all the required toxicological data. We believe the Toxicology Collaboration Project is the most cost-effective way of achieving that, but the ultimate travesty of the TPD is that the burdensome requirements are going to put some companies out of business. We have already seen this happening in the sector.

We hope that you will manage to find a way to make the investment in your compliance requirements, so that you can continue to provide your customers with the products they want, and which are giving them such enormous benefits. This Collaboration project will help to keep per-company costs as low as possible.

12.   As the initial total cost is around £600,000, how will we share the costs as the number of collaborating companies and toxicology data may keep rising?

The beauty of this project is precisely that: the number of compounds requiring assessment will increase, although the vast majority will be expected to already be on the list. But as more collaborators join, there is more funding to provide those further toxicological assessments. Alternatively, if a lot more collaborators join than expected and there is a large amount of money left over, it is a possibility to refund equally amongst all contributors.

13.   If we join in the project, can we have access to all the toxicology data in the collaboration?

Yes. Every collaborator will contribute an equal share to the investment (i.e. the same as everyone else), and then each collaborator gets access to all the data to use for their notifications.

Although not everyone will need every single compound's data, this will allow flexibility for the development of new products in the future, and crucially, ensures that each company has everything they need for their notifications.

The data cannot be resold – its use is restricted either for notifications or supply with products to a manufacturers' clients, since it would devalue the whole collaboration if one party supplied the data on a consultancy basis.

14.   Who "owns" the toxicological reports?

The Agreement between the Collaborators sets out very clearly the licensing terms of the data. In essence, bibra grants the license to VKCR&S, and there are very clear limitations, providing that VKCR&S may only and exclusively use the data for the purpose of distributing it to the Collaborators. VKCR&S do not retain any rights in the data whatsoever. There are also defined restrictions on how the Collaborators may use the data, i.e. only for their notifications and to provide it to their downstream customers as required for their notifications, but certainly not for resale or any other inappropriate use, which could devalue the whole Project.

15.   We have hundreds of flavours; what if the ingredients and emissions from our e-liquids are beyond the list?

There is a mechanism built into the Agreement between the Collaborators to allow further compounds to be added as necessary. If it is not possible to add specific individual compounds to the Collaboration Project, individual companies would be able to work with bibra directly on such compounds.

16.   Our e-liquid contains natural plant extracts, in which some of the trace ingredients and emissions are too hard to detect; therefore, their toxicology assessments are consequently hard to make. How will we solve this problem?

We have already come across a number of natural extracts, and indeed, there are some such compounds on the agreed list already. Ultimately, it will come down to the accuracy and capabilities of the e-liquid and emissions analyses, to identify the compounds, which can then be toxicologically assessed.


Appendix I: Bibra approach for provision of TPD-2 compliant 'Toxicity Monographs'

Bibra will search the public domain using a range of datasources (including our own database, TRACE; see Appendix for details) and will assess and briefly summarise/tabulate the key data on a large number of ingredients/emissions, as listed and provided by the Toxicology Collaboration Project.

Each report would be a concise Toxicity Monograph on a specific ingredient/emission, focusing on the inhalation route of exposure, and on data identified in the publicly-available literature. These Toxicity Monographs will be prepared by bibra in a format that assists each Company meet certain of the requirements of Article 20 of Directive 2014/40/EU (the so-called TPD2). Notably, they will be produced in a format that is compatible with the notification of their products (see section 4 of the Annex of Commission Implementing Decision EU 2015/2183 for details).

More specifically, each monograph will contain sections on:

  • Substance ID - e.g. name, key synonyms, MWt, CAS RN.
  • REACH status - e.g. REACH registration number.
  • EU CLP classification (1272/2008) - tabulate any harmonised classification on the ingredient/emission. Also consider the classification(s) notified to ECHA and disseminated on the C&L inventory database (with a focus on the Joint REACH registrants classification). Also a preliminary bibra screening assessment based on the existing toxicity data summarised, aimed at highlighting any ingredients for which the current CLP classification might not be appropriate and health-precautionary.
  • ADME/TK data – as identified in the toxicity searches. This is not a specifically required endpoint for TPD2 compliance. Therefore, very brief description of critical data, notably inhalation absorption (%), and any data that may help with the extrapolation of oral or dermal data to human inhalation exposures. Also identification of major metabolites for further assessment etc. This will help in the future determination of tolerable levels and for risk assessment purposes.
  • Toxicological data - a brief bibra textual summary of the critical data covering the key toxicological endpoints (including irritation, sensitisation, acute and repeated dose toxicity, genotoxicity, carcinogenicity, and reproductive and developmental toxicity). Special attention will be paid to studies assessing effects on the heart, blood vessels and/or respiratory tract. This will be restricted specifically to the listed substance (e.g. not other isomers or associated salts, or structurally-related substances, unless easy and quick to address).
  • Expert Group Health Criteria Values (HCVs) – again, this section does not appear to be a requirement for TPD-2 compliance. However, bibra will tabulate key values (e.g. ADIs/TDIs/RfCs as developed by Expert Groups), with a focus on the inhalation route (systemic and local) and the more critical/recent values. This will help in the future determination of tolerable levels and for risk assessment purposes.
  • Substance of High Concern and ‘non vaporised status’ - this section will highlight any CMR properties of the substance, or other areas of concern (e.g. respiratory sensitisers, neurotoxins, endocrine disruptors), and characterisation of substances with a “known type of toxicity”.
  • Chemistry or toxicity of emissions – Such information will be gleaned from the data identified in the searches for the other sections. Bibra will very briefly summarise any studies that usefully "inform about the chemistry and/or toxicity of emissions".
  • Addictiveness data - e.g. a brief summary of any studies assessing the ability of the ingredient/emission to promote dependence. May include data that show that the substance enhances the uptake or metabolism of nicotine, or reinforces the addictive effect of nicotine in e‑cigs. Bibra will consider nicotine absorption, bronchodilation, anaesthetic effects and self-administration.
  • Attractiveness – if, for example, the ingredient has a characterising flavour.

 

Where available, and to expedite the process, Expert Group reports will be consulted initially to provide a quick and efficient route to the key data on each substance. Bibra will prepare a separate report on each ingredient/emission in the list. This Toxicity Monograph would form part of the submitted notification to the competent authorities of the appropriate EU Member States, assisting each Company meet their regulatory (Article 20; TPD2) obligations, in the first instance.

To maximise speed and efficiency, in this initial phase, the Toxicity Monographs will not include (for example) bibra ADME/TK predictions/insights, physical-chemical data, bibra proposed benchmark values for future inhalation health risk assessments, or an executive summary. Further, no (significant) attempt will be made, at this stage, to fill identified data gaps (e.g. through the use of read-across or (Q)SAR). It will also not be a health risk assessment, and therefore no bibra conclusion on the safety/risks posed by each ingredient/emission will be included (although the identification of certain substances of concern, e.g. CMRs and respiratory tract sensitisers, will be possible).

Bibra would, of course, be able to carry out more comprehensive hazard assessments/characterisations and also mixture-specific classification and labelling work and health risk assessments for specified products if needed, as a separate exercise at a later date. These would build on the Toxicity Monographs as a basis.


Appendix II: The TRACE database and databank

Bibra toxicology advice & consulting Ltd

TRACE includes information from peer-reviewed toxicology and nutrition journals as well as secondary sources and websites. In addition to primary literature on the health effects of chemicals, TRACE covers official publications and evaluations issued by authoritative groups including:

  • WHO/IPCS reports and evaluations (including CICADs and EHCs, and IARC, JECFA and JMPR monographs), and the WHO Air Quality and Drinking-Water Quality Guidelines
  • OECD SIDS dossiers/SIARS
  • IUCLID data sets
  • EU Risk Assessment Reports
  • EU expert committee opinions (including EU scientific committees, and EFSA scientific panels) and other reports from EU agencies and institutes etc (including ECHA, ECVAM, EMA and CPS&Q)
  • ECETOC, HERA, Council of Europe and other pan-European programmes
  • UK government agency (including Defra, EA, FSA, DoH, HSE, HPA, PSD and VMD) and advisory committee (e.g. COT, COM, COC, ACNFP, SACN, ACP, ACAF, VPC, VRC and ACRE) reports and evaluations
  • Opinions from other UK organisations such as the Royal Society
  • US agency reports and evaluations (EPA, ATSDR, FDA, NTP, OSHA, NCEA, CFSAN, CERHR, NIEHS, CDC, OEHHA and ACGIH)
  • Health Canada evaluations
  • BUA, DFG, BG Chemie and BfR reports and monographs
  • Gezondheidsraad opinions, including those from its various committees such as DECOS
  • RIVM reports
  • Danish EPA reviews
  • Reports and other information provided by Swedish governmental organisations, including the National Food Administration and the Swedish Chemicals Agency
  • Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals
  • Australian agency reviews including NICNAS Priority Existing Chemical Assessments, APMVA reports and (jointly with New Zealand) FSANZ assessments
  • Japanese Chemical Industry Ecology-Toxicology & Information Center reports
  • CIR, RIFM and other specialist industry groups
  • Bibra Toxicity Profiles

[1] A declaration that the producer bears full responsibility for the quality and safety of the product when supplied and used under normal or reasonably foreseeable conditions