Bibra Toxicology Advice and Consulting | Toxicology News: BfR reports…

Toxicology and Regulatory News in November covers key developments across e-cigarettes, non-animal-based methods, cannabidiol (CBD), the Threshold of Toxicological Concern (TTC), and more.

In this month’s update:

BfR reports on coolants in e-cigarettes

Coolants are used in e-cigarettes to trigger a cooling and refreshing sensation in the mouth and throat during vaping. BfR has issued three reports that discuss this use, the third of which compares potential exposure levels and health risks. For eleven such cooling agents that might be inhaled from e-cigarettes (including eucalyptol and menthol), the Institute has estimated the Derived-No-Effect Levels (DNELs) for systemic effects from chronic inhalation by the consumer. These range from 0.04 mg/m3 for WS-23 to 13 mg/m3 for each of menthol and menthyl acetate. Exposure estimates indicate a potential health risk due to systemic effects associated with most of these coolants, the toxicological safety margins being breached for some at an average daily e-liquid intake level of 5 mL/day. BfR therefore continues to advise against their use in e-cigarettes. In the case of menthol, its diverse uses in foods and medications mean that a portion of the daily safe intake can already be reached before e-cigarette use is considered. BfR noted that, due to the lack of robust inhalation toxicology data, the risk assessments rely on data from feeding studies in laboratory animals, with considerable uncertainties around the degree of absorption. Furthermore, BfR was unable to comment on the possibility of local damage to the respiratory tract.

Reference: BfR and BfR

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ICMRA statement on non-animal-based methods

Under the International Coalition of Medicines Regulatory Authorities (ICMRA), several international medicines regulators (including the EMA, the MHRA, the Irish Health Products Regulatory Authority and Swissmedic) have issued a joint statement calling for the advancement and implementation of alternative methodologies and approaches. The statement sets out the long-term goal of replacing in vivo laboratory animal testing at every stage of a human medicine’s lifecycle, from initial screening and early development, through non-clinical testing, to licensing and post-authorisation activities.

Reference: ICMRA

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EFSA evaluation of Cannabidiol (CBD) and Cannabis sativa extract as novel foods

The NDA Panel has evaluated the safety of synthetic CBD as a novel food intended for use in food supplements at a maximum daily dose of 2 mg, for adults over 25 years of age excluding pregnant and breastfeeding women. The Panel identified the liver as a key target organ in a 90-day subchronic rat study and derived a Benchmark Dose Lower Confidence Limit (BMDL10) of 10.5 mg/kg bw/day based on increased relative liver weight in the females. Due to the remaining data gaps, particularly concerning reproductive and developmental toxicity, the Panel applied an uncertainty factor of 400 to establish a safe intake level of 0.026 mg/kg bw/day (equivalent to 2 mg/day for a 70-kg adult). EFSA concluded that the novel food is safe under the proposed conditions of use, with the exception of individuals taking medication for whom safety could not be established.

The Panel also evaluated the safety of C. sativa L. extract and of CBD isolated from C. sativa, both as novel foods. However, it was unable to reach a conclusion on either due to data gaps for which no additional information was provided by the applicant.

Reference: EFSA and EFSA

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The Threshold of Toxicological Concern (TTC)

In this era of analytical sophistication and regulatory risk aversion, where would we be without TTC to help navigate the choppy water of human health risk assessment? We are all waiting for the next exciting development, Expert Groups validating the commendable US Food and Drug Administration (FDA) efforts to double up on those original three Cramer classes of non-genotoxin. There is though, another TTC fashion bubbling away, with various groups developing what they hope will become authoritative sector-specific TTC values. One such sector-specific initiative has recently been published, focusing on a TTC said to be applicable for the assessment of botanical extracts used in cosmetics. Some hard labour has been invoked by the team from the Ewha Womans University of Seoul, as the resulting TTC values are based on their scrutiny of over 500 studies of these complex mixtures. Is there any chance that these endeavours will be embraced by the Scientific Committee on Consumer Safety (SCCS) of the EU? Possibly not, as the Committee already has a liberal approach to botanicals, and it will perhaps be reluctant to lower its guard any further. Whilst the chemical characterisation of an extract will often be incomplete, the Committee will allow any known component to be assessed against the Cramer III TTC benchmark (of 90 µg/day) as long it does not exhibit a structure that triggers genotoxicity suspicion. The Seoul endeavours hint that the non-genotoxic TTC could be increased to 250 µg/day for the whole botanical extract.

Reference: Science Direct

DECOS looks at ethylene glycol's reproductive/developmental toxicity

DECOS has finalised its evaluation of the reproductive and developmental effects of ethylene glycol. Classification (under CLP) as a developmental toxin (Repr. 1B) was recommended, based on its effects in rodents on foetal body weight, skeletal development, post-implantation losses, and numbers of live foetuses. The data were considered too limited to inform on whether it might adversely affect fertility.

Reference: The Health Council of the Netherlands