According to the common format cited above, submission of the following toxicological information for each ingredient may be mandatory depending on the submission type in the EU^[1]:

• Available toxicological data of the ingredient either isolated or as part of a mixture and in the heated and unheated form.
• Data on the chemistry and/or toxicity of emissions.
• Information on the substance's carcinogenicity, mutagenicity or toxicity to reproduction properties. 
• Available in vitro and in vivo data on cardiopulmonary effects.
• Information on the potential addictive properties. 
• Any other available toxicological information different from the stated above. 

The Medicines and Healthcare products Regulatory Agency (MHRA) provides the requested format to submit the TPD notification files for Great Britain (GB). Chapter 6 for the GB notifications follows the same format as the one published by the EU, with additional dispositions for submitting the toxicological data. These additional requirements were published in March 2022 and apply to the GB TPD notifications since then. The main changes are listed below^[2]:

• Submission of files for each toxicological aspect of the ingredients is mandatory.
• Each mandatory file requires an upload, even when there is no relevant data or no data available.
• When no data is available for at least one toxicological mandatory aspect of the ingredient:
• Information on the searches conducted (e.g., search terms and databases) can be uploaded.
• Vague statements indicating the absence of data or lack of assessment will not be acceptable.
• Notifiers should perform their own safety assessment.
• Notifiers could seek specialist advice.
• Notifiers could review and assess their ingredients using the Framework for risk assessment of flavouring compounds in electronic nicotine (and non-nicotine) delivery systems (E(N)NDS – e-cigarettes) published by the Committee on Toxicology (COT).

The COT framework provides guidance for an in-depth toxicological analysis of the substance. Therefore, the toxicological report should be performed considering the inclusion of the mandatory files, including the following data^[3]: 

• The inclusion of the self-notified classification and labelling (C+L) 
• The inclusion of the substance classification regarding the Candidate list of substances of very high concern (SVHCs) and The International Agency for Research on Cancer (IARC) monograph list.
• The provision of the Threshold of Toxicological Concern (TTC) of the ingredient.
• Information from QSAR models (ToxTree, VEGA, OECD ToolBox and the Danish QSAR database, among others). 
• The exposure to the ingredient via the ENDS use compared to the exposure via culinary use.
• The Margin Of Exposure (MOE) assessment if the ingredient intake via the product use exceeds the exposure levels from culinary use. 

At a practical level, which the implications of these changes in the toxicological reports for companies are:

• The requirement of a certain level of expertise from the toxicological/safety assessor.
• Time to adapt current toxicological reports to the additional requirements.
• Additional testing may be required if the toxicological data is insufficient to ensure the ingredient's safety at the quantity presented in the product. 

Formulation changes may be required if the ingredient level in the finished product is deemed unsafe upon the toxicological assessment.

In conclusion, toxicological ingredient reports for TPD notifications in Great Britain require an in-depth assessment to ensure the ingredient's safety. At Inter Scientific, our team perform toxicological reports for TPD notifications adapted for the EU and GB. Contact us today for more information on this and our other services.

[1]Official Journal of the European Union (2015). COMMISSION IMPLEMENTING DECISION (EU) 2015/2183 of 24 November 2015 establishing a common format for the notification of electronic cigarettes and refill containers. Retrieved from: https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32015D2183&from=EN

[2]Medicines and Healthcare products Regulatory Agency (2022). Guidance

Chapter 6 - Ingredient Guidance - Great Britain. Advice on ingredients in nicotine-containing liquids in electronic cigarettes and refill containers. Retrieved from: https://www.gov.uk/government/publications/chapter-6-ingredient-guidance-great-britain

[3]Committee on Toxicology (n.d.). Framework for risk assessment of flavouring compounds in electronic nicotine (and non-nicotine) delivery systems (E(N)NDS – e-cigarettes). Retrieved from: https://cot.food.gov.uk/sites/default/files/2020-08/frameworkforriskassessingflavourings_0_madeaccessibleinadobepro_to%20be%20uploaded_.pdf