Bibra Toxicology Advice and Consulting | Toxicology and Regulatory…

July’s Toxicology and Regulatory News brings together key developments across medical device toxicology, chemical safety, food contact materials and occupational exposure.

In this month’s update:

Oral-to-parenteral Uncertainty Factor for medical device constituents

At a glance

Topic: route-to-route extrapolation
Relevant area: medical device constituents
Key reference: ISO 10993-17
Method used: in silico PBPK modelling
Main takeaway: the analysis suggested an evidence-based default UF of 7 for oral-to-parenteral extrapolation, compared with the ISO default UF of 10

Route-to-route extrapolation is often a key component of toxicological risk assessment. This is particularly the case for extractables and leachables from medical devices, where the intended exposure route is often parenteral and the relevant hazard database typically oral. ISO 10993-17 specifies a default Uncertainty Factor (UF) of 10 for oral-to-parenteral extrapolation. While the guidance permits use of other values, the requisite bioavailability data are often lacking for such chemicals.

An industry scientist has published an analysis of around 7700 medical device constituents, using in silico Physiologically Based Pharmacokinetic (PBPK) modelling to estimate oral bioavailability. Single oral and intravenous exposures were simulated from physicochemical inputs using the Integrated Chemical Environment PBPK tool, developed by the US National Toxicology Program, and bioavailability was calculated by the ratio of plasma area under the curve values.

Oral bioavailability was generally moderate to high, with almost half of the chemicals having values above 90%, while a further third exceeded 50%. The lowest 5th percentile of the distribution was 14.56%, which suggested an evidence-based default UF of 7 for oral-to-parenteral extrapolation, slightly lower than that noted in the ISO guidance.

Several limitations were noted, including that the analysis likely underestimated the extent of chemical space represented, given that modelling was not possible for more than half of the overall database of chemicals.

Reference: Science Direct

Glyphosate carcinogenicity classification and labelling update

ECHA’s Risk Assessment Committee (RAC) has started discussing the Harmonised Classification and Labelling (CLH) of glyphosate following a request from the European Commission for ECHA and the European Food Safety Authority (EFSA) to assess a 2025 (https://pubmed.ncbi.nlm.nih.gov/40490737/) by the Ramazzini Institute.

Reference: ECHA

EFSA assessment of Food Contact Material additive L-aspartic acid, N-benzoyl-, disodium salt

The Panel on Food Contact Materials (FCMs) assessed the safety of L-aspartic acid, N-benzoyl-, disodium salt for use in plastic FCMs, ruling out a concern for genotoxicity for the substance itself and for other impurities/reaction products.

The Panel concluded that the additive is not of safety concern when used at up to 0.07% w/w in polypropylene homo- and co-polymers to manufacture FCMs, so long as migration does not exceed 0.05 mg/kg food.

However, it should not be used in FCMs for human milk, infant formula, or water that could be used to reconstitute infant formula.

Reference: EFSA

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EC roadmap towards phasing out animal testing in chemical safety assessments

At a glance

Topic: non-animal approaches in chemical safety
Organisation: European Commission
Scope: EU legislation requiring animal testing for chemical safety
Key focus: moving from traditional animal testing to non-animal approaches
Main takeaway: the roadmap sets out objectives and actions for reducing animal testing while maintaining protection for human health and the environment

In 2023, the EC committed to developing a roadmap towards phasing out animal testing for chemical safety assessments. Now published, the roadmap sets out the clear objectives and steps needed to make the transition from traditional animal testing methods to innovative non-animal approaches, whilst ensuring that these non-animal approaches still deliver an equivalent level of protection for human health and the environment.

Applicable to all pieces of European Union legislation that require animal testing for chemical safety, the roadmap sets out a plan of action focusing on three “pillars”:

making the change happen (towards phasing out animal testing)
innovation, research and development to support the change
stakeholder engagement (including public engagement) in both the EU and wider global scientific communities

An accompanying Staff Working Document (SWD) has also been released providing more detailed information on each of the “pillars”, notably describing for each toxicological endpoint the current state of the science regarding non-animal testing, actions/changes that can be taken now to phase out animal methods, and future opportunities to do so.

References: European Commission Communication and European Commission Working Paper

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DECOS report on wood dust exposure and occupational health risks

At a glance

Topic: occupational exposure to wood dust
Organisations involved: DECOS and the Nordic Expert Group
Key target: upper respiratory tract
Reported concern: nasal adenocarcinoma and respiratory symptoms
Exposure values discussed: HBC-OCRVs of 0.1, 0.8 and 2.9 mg/m³
Main takeaway: DECOS has finalised its report on the adverse effects of occupational exposure to wood dust

The upper respiratory tract is the key target, with a strong link reported between exposure and nasal adenocarcinoma. Health-Based Calculated Occupational Cancer Risk Values (HBC-OCRVs) were derived on the basis that any exposure could, in theory, increase the risk of this tumour type. Occupational exposures for 40 years to HBC-OCRVs of 0.1, 0.8 or 2.9 mg/m3 were expected to result in four additional cancer cases per 100,000, 10,000 or 1000 workers, respectively. These concentrations refer to the inhalable fraction of wood dust, measured as a Time-Weighted Average (TWA) over an 8-hour working day.

It was noted that other respiratory symptoms (such as coughing, sneezing, throat symptoms and asthma development) can also occur at wood dust exposures in the range of the HBC-OCRVs.

Reference: The Health Council of the Netherlands

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