Introduction to the UK Framework Guidelines for Toxicological Assessment of E-cigarette Flavoring Substances
Flavoring substances are common ingredients in e-liquids, and although many flavorings have passed oral toxicity safety assessments and are approved for use in food, few substances have been assessed for acute or chronic toxicity risk by inhalation. In December 2019, the UK Committee on Chemical Toxicity in Food, Consumer Products and the Environment (COT) published the Framework for Risk Assessment of Flavoring Compounds in Electronic Nicotine (and Nicotine-Free) Delivery Systems (EN(N)DS Electronic Cigarettes), which is now available Adopted by the United Kingdom as a reference document for the risk self-assessment of substances listed in the MHRA notice of e-cigarettes.
This issue introduces the assessment steps and requirements of the framework for stakeholders to identify and assess the risks of substances in product ingredient lists.
Evaluation Framework Principles
The framework provides a series of principled steps to guide the risk assessment process for flavourings in e-cigarettes, as shown in the following figure:
Step 1: Assess whether flavoring compounds will thermally degrade or react with other components in the e-liquid.
Step 1a: Assess for complete decomposition of the flavoring compounds. Different flavoring compounds are expected to thermally degrade or react to varying degrees with other components of e-liquids. If 100% decomposition does not occur, the toxicity of the parent flavoring compound and the decomposition products also need to be assessed.
Step 1b: Assess whether the reaction product on smoking is different from the product on cooking. It has been reported that under acidic or alkaline conditions, PG can react with food flavorings to form new compounds. Therefore, if flavoring compounds are used in e-cigarettes to generate degradation products (thermal or other), information on whether they are formed during flavor assessment should be searched for, and where possible, systematic exposure estimates for each pathway should be obtained.
Step 1c: Determine the TTC structural class of flavoring compounds and degradation/reaction products and determine whether the intake when using e-cigarettes exceeds the TTC value. Threshold of Toxicological Concern (TTC) methods use general exposure levels to chemicals below which they have a low probability of causing adverse health effects.
Step 2: Evaluate whether the flavoring compound is classified as carcinogenic/mutagenic/reproductive and developmental toxicity (CMR), acute toxicity (category 1 or 2), or skin sensitization.
Step 3: Assess whether the flavoring compound induces local effects such as respiratory irritation, ciliary shedding, mucus thickening, or has an effect on the lungs by inhalation. Substances that cause respiratory irritation through local cytotoxic effects are classified as STOT SE category 3. Substances that cause corrosion in the respiratory tract are classified as STOT SE Category 1 or 2, depending on the dose level required to cause toxicity. The RD50 value is closely related to the lowest level of observed deleterious effect (LOAEL), which is a standard measure of human sensory stimulation, and 0.03xRD50 may be considered as the stimulation threshold for humans. It is believed that many flavorings found in e-cigarette liquids would be considered "moderate" irritants if the RD50 was less than 1000 ppm. If the flavoring compound has been classified as specific target organ toxicity, it should be documented.
Step 4: Assess whether inhalation versus ingestion of the chemical would result in different target organ toxicity affecting the whole body, taking into account any different metabolic profiles. If systemic toxicity is observed through the oral route of exposure, it must be determined whether inhalation also produces toxic effects. Kinetic data on absorption, metabolism, distribution, and excretion (ADME) should be compiled to assess whether, and at what levels, chemicals and/or metabolites are likely to enter the systemic circulation following inhalation and oral exposure. It is especially important to understand the metabolism of flavoring compounds, as first-pass metabolism may occur after ingestion but not after inhalation. In some cases, this may result in the absence of reactive metabolites after inhalation. Conversely, metabolism may inactivate flavoring compounds, so exposure through inhalation may lead to greater systemic toxicity. Information related to repeated-dose toxicity can also be obtained from data on other endpoints, route-to-route extrapolation from oral studies, structural analogs, and physicochemical properties. Through repeated exposure, readouts can also be used to predict target organ toxicity.
Step 5: Assess whether exposure levels through e-cigarette use are higher than exposure levels through culinary use. The flavoring compound is not expected to cause health effects if exposure is similar to or lower than when cooking.
Output results when each step is completed
Step 1: If flavoring compounds, degradation and/or reaction products are different from those produced during cooking and there is insufficient information to apply a risk assessment framework, then the TTC method should be used for assessment and inter-route extrapolation based on oral values. The TTC should be included as part of the weight of evidence assessment of flavour use in e-cigarette liquids. Those compounds that exceed their appropriate TTC values should be evaluated for suitability in e-cigarette liquids, and those not exceeding TTC values do not cause health problems. In step 4 of the framework, flavour compounds, degradation and/or reaction products that do not differ from those produced by culinary use should be assessed for similarity in systemic toxicity through oral or inhalation exposure or difference.
Step 2: Flavoring compounds with a CMR or Harmonized European Classification of Acute Toxicity (Class 1 or 2) or Skin Sensitivity (Class 1) should be assessed for suitability for use in e-liquids. The severity and incidence of effects should be considered. A risk assessment should be carried out, possibly using a limit of exposure (MOE) approach. Based on the mechanism of action (MOA) and other relevant toxicological information, if IARC classifies a flavoring compound as a carcinogen, its suitability in e-liquid should also be considered. A risk assessment of the compound should be considered if the other data sources above or other available evidence based on the weight of evidence and expert judgment suggest that the flavoring compound may produce CMR, acute toxicity, or skin sensitization. If the flavoring compound is not classified as a CMR, acute toxin, or skin sensitizer, local effects on the lungs should be considered (step 3).
Step 3: For STOT REs with skin or respiratory sensitivities, respiratory irritation, or lungs as target organs, a harmonized European classification of flavoring compounds for their suitability in e-cigarette liquids should be considered. The severity and incidence of effects should be considered. A risk assessment should be performed, possibly using the MOE approach. If flavored compounds are on the shortlist based on respiratory sensitivity, their suitability in e-liquids should also be considered, according to the MOA and other relevant information. If other data suggest that flavoring compounds may produce respiratory sensitization, the compounds may also be undesirable based on the weight of evidence and expert judgment. For sensitization effects, the human No Expected Sensitization Induction Level (NESLS) can be used to determine a threshold below which the risk of sensitization will be very low. If the flavoring compound does not have local effects on the lungs, the systemic effects of inhalation and ingestion should be assessed according to Step 4, taking into account differential metabolism.
Step 4: Repeat-dose toxicity potential should be used in weight-of-evidence judgments along with data from other endpoints. If edible flavoring compounds produce different toxicity by inhalation versus ingestion, the severity and incidence of effects should be considered. A risk assessment should be performed, possibly using the MOE approach. If the toxicity of the edible flavoring compound through inhalation is similar to that through ingestion, the exposure levels through e-cigarette use should be considered in step 5.
Step 5: If exposure levels from e-cigarette use are higher than those from culinary use, the exposure levels should be compared to relevant health guidance values (HBGV) or TTC values. Those compounds that exceed their appropriate HBGV/TTC values should be evaluated for suitability in e-cigarette liquids. Those viruses that do not exceed the HBGV/TTC value do not cause health problems. If exposure levels through e-cigarette use are similar or lower than those from culinary use, the flavoring compound is not expected to cause health problems for users. An assessment of bystander risk requires appropriate estimates of exposure for comparison with HBGV/TTC.
Some sources of toxicology data acquisition are included in the framework, including assessments by authoritative bodies (eg IARC, EU Harmonized Classification) or substances on the SVHC Candidate List, and non-animal data can also be used for QSAR modelling and TTC methods.
As one of the European markets that highly accept electronic cigarettes, the United Kingdom has become increasingly strict with product safety controls to ensure that the products provided to consumers are safe. Notifiers of vaping products should carefully assess the safety toxicology data for each constituent in e-liquids and the impact of their associated emissions on their products in order to meet their responsibilities under UK Tobacco Products Law and General Consumer Safety Law.
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