Transparency data

Workshop on assessing the safety of biomass-derived dietary proteins discussion paper

Updated 9 September 2026

Committee Paper for Discussion - ACNFP/178/04

Advisory Committee For Novel Foods and Processes

Workshop on assessing the safety of biomass-derived dietary proteins discussion paper

Issue

As part of the wider work on novel food applications for precision fermented products including biomass fermented proteins, a question has emerged on interpretation of evidence to identify the safe use levels of these foods. The Committee is invited to consider the paper and provide views on the interpretation of Margin of Safety, the use of supporting evidence where conventional toxicological datasets are limited, and the development of principles to support robust and proportionate assessment of novel proteins and their safety under the proposed uses.

Background

1. Biomass-derived dietary proteins present challenges for the application of traditional toxicological risk assessment approaches, particularly when determining whether proposed uses and levels of consumption can be considered safe.
2. The rapid emergence of biomass-derived proteins (e.g. microbial, fungal, fermentation-based) presents new challenges for risk assessment. These products often: - Are consumed at relatively high dietary intakes - Have complex compositions (whole biomass vs isolated protein) - May exhibit study limitations (e.g. inability to achieve high doses in animal studies without nutritional imbalance or artefacts)
3. In a number of assessments, toxicological studies have not identified adverse effects at the highest dose tested, but practical or nutritional constraints have limited the ability to investigate substantially higher dose levels. As a result, uncertainty can arise regarding the adequacy of the Margin of Safety (MoS) and the confidence that can be placed in the available data.
4. While a default MoS of 100 is commonly applied in toxicological risk assessment, it is unclear whether this approach is always appropriate for biomass-derived proteins. Questions remain regarding the circumstances in which a MoS below 100 may still provide sufficient reassurance of safety and what factors should be considered when reaching such conclusions. These factors may include the nature of the protein, product characterisation, human data, history of safe use, nutritional considerations, and other supporting evidence.
5. A workshop paper has been prepared to facilitate discussion on the assessment of biomass-derived dietary proteins and to explore approaches for consistently determining whether proposed uses and levels of consumption can be considered safe.

The workshop

The workshop will aim to:

• Establish a structured approach for evaluating the adequacy of Margins of Safety (MoS)
• Identify factors that may increase or decrease the level of concern associated with a product or dataset.
• Promote consistent interpretation of study limitations and data gaps.
• Define decision-making criteria for determining when additional data or information may be required.
• Consider how toxicology, nutrition, allergenicity, exposure, and other relevant evidence streams can be integrated into an overall safety assessment.
• Explore the applicability of traditional toxicological assessment frameworks to biomass-derived proteins and consider when alternative approaches or case-specific considerations may be needed to support risk characterisation and interpretation of margins of safety.

6.  The overarching objective is to ensure consistency in interpreting data in assessments of biomass-derived proteins considered in GB, while ensuring that ACNFP recommendations remain evidence-based, proportionate to the level of risk, and protective of UK consumers.

Structure of the workshop

7.  To facilitate a structured discussion, the workshop has been organised into three interrelated themes: (1) the interpretation and adequacy of margins of safety and exposure, (2) the evaluation of study limitations and the role of supporting evidence, and (3) the application of scientific evidence within regulatory safety assessment. The questions set out below are intended to stimulate discussion, identify areas of consensus and uncertainty, and explore whether general principles can be established to support future assessments.

8.  The objective is not necessarily to reach definitive answers for every scenario, but rather to develop a shared understanding of the factors that should be considered when evaluating biomass-derived proteins and to identify approaches that promote consistency, transparency, and scientific robustness in risk assessment.

9.  To support these discussions, Annex A provides a series of examples where the calculated Margin of Safety (MoS) was below 100 for one or more population groups. The annex is intended to move the discussion beyond theoretical considerations and provide practical case studies illustrating the types of evidence that have been submitted to support safety assessments in such circumstances. For each example, a brief summary of the application is provided alongside the key toxicological studies, exposure information, and other relevant supporting data submitted by the applicant.

Session 1 - Assessing the Adequacy of Margins of Safety

10.  The interpretation of MoS values is central to risk characterisation. For many novel foods, toxicity studies provide a reference point such as a NOAEL, which is compared with estimated human exposure to assess whether an adequate margin exists between anticipated consumption and doses associated with adverse effects.

11.  However, determining what constitutes an adequate margin is not always straightforward for biomass-derived proteins. Existing uncertainty factors were largely developed for chemical substances and may not always account for the distinctive characteristics of highly nutritious food ingredients. Furthermore, the confidence that can be placed in a margin depends not only on its numerical value but also on the quality of the underlying data, biological relevance of the findings, certainty of the reference point, and overall strength of the evidence base.

12.  This section seeks to explore how margins should be interpreted in practice, when deviation from default approaches may be scientifically justified, and how assessors should evaluate situations where the available reference point is associated with substantial uncertainty.

Key Questions

• What factors, evidence, or product characteristics should be considered when determining whether a MoS is adequate for biomass-derived proteins?

• Under what circumstances could a MoS below the standard 100 be scientifically justified, and what evidence would provide sufficient confidence to support acceptance of a reduced margin?

Examples may include:

• Extensive human data.
• Strong history of safe use.
• Robust mechanistic understanding.
• Highly characterised products.
• Consistent evidence across multiple independent datasets.
• Should products consisting of a single protein, or a limited and well-characterised range of proteins with few other constituents, be considered differently when assessing uncertainty and MoS requirements?
• How should uncertainty be characterised and incorporated into overall risk assessment conclusions?

• To what extent should considerations beyond toxicology, such as nutrition, allergenicity, product composition, and anticipated exposure, influence decisions on MoS adequacy?

• To ensure biological relevance is considered. How should the interpretation of MoS be influenced by:
  • Mode of action
  • Biological plausibility
  • Human relevance of observed findings
  • Species differences
  • Toxicokinetic considerations

Session 2 - Study Limitations, Reference Points and Supporting Evidence

13.  A recurring challenge in the assessment of biomass-derived and other novel protein products is the interpretation of toxicological studies where testing at progressively higher doses is constrained by practical or nutritional factors. Unlike conventional chemicals, increasing dietary inclusion rates may result in nutritional imbalance, altered diet composition, reduced food consumption, palatability issues, or physical bulk effects before adverse effects attributable to the test substance are observed. Consequently, studies may reach the maximum feasible dose rather than a biologically meaningful threshold for adverse effects.

14.  This can make it difficult to establish clear dose-response relationships, identify suitable toxicological points of departure, and determine the level of confidence that can be placed in the available data when setting safe levels of consumption. These challenges raise questions regarding how maximum feasible dose studies should be interpreted, whether additional uncertainty should be applied, and the extent to which alternative lines of evidence can strengthen confidence in the overall assessment.

15.  This section aims to explore how constrained datasets should be interpreted and the role that additional evidence may play in strengthening confidence in safety conclusions.

Key Questions

Maximin Feasible Dose Challenges

• When a study reaches the maximum feasible dose, under what circumstances can this be considered sufficient to support a safety conclusion?

• How much confidence should be placed in a NOAEL when it is driven by study design limitations rather than a biologically derived threshold?

• How should studies be interpreted when the highest dose is constrained by:
  • Nutritional imbalance
  • Palatability issues
  • Physical bulk effects
  • Altered dietary composition
  • Reduced food consumption
• Should the inability to achieve higher doses automatically increase uncertainty within the risk assessment?
• What level of confidence can be placed in a study that does not achieve meaningful dose-response?

Alternative and supporting evidence

• Which types of supporting evidence are most informative when conventional toxicological studies cannot establish a clear point of departure, and what combination of evidence would provide sufficient confidence to establish a safe level of consumption in the absence of robust dose-response data?

• When conventional toxicological studies are constrained, what role should be given to other sources of data such as:

• Human studies
• History of safe use
• Read-across approaches
• ADME data
• Digestibility studies
• Nutritional studies
• Mechanistic evidence
• Weight-of-evidence approaches

• Under what circumstances should additional toxicological studies, including reproductive or developmental toxicity studies, be requested to address residual uncertainties in the assessment of biomass-derived proteins?

• To what extent can supporting evidence compensate for limitations in toxicological datasets, and what would constitute an adequate evidence package for establishing a safe level of consumption under these circumstances?
• Which uncertainties can be accommodated through uncertainty factors, and which require additional evidence?

Session 3 - Regulatory Safety Assessment Practical Considerations

16. This section focuses on the practical application of scientific evidence within the regulatory process, exploring how ACNFP might approach recurring challenges, identify circumstances that warrant additional data, and establish decision-making principles that can be applied across future assessments of biomass-derived proteins and other emerging protein sources.

Key Questions

• What overarching principles should guide ACNFP when assessing biomass-derived proteins where standard toxicological approaches provide limited certainty?

• What circumstances should trigger requests for additional data, and when can residual uncertainties be managed through a weight-of-evidence approach?

• Can a set of general principles be identified to support consistent, transparent, and proportionate decision-making across future assessments of biomass-derived proteins and other emerging protein sources?

• How should recent EFSA guidance and relevant international regulatory experience be interpreted and applied when assessing biomass-derived proteins?

Use of workshop outcomes

Where appropriate, outputs from the workshop may be used to inform future discussions within the ACNFP and support the development of internal approaches and shared principles for interpreting margins of safety, assessing study limitations and uncertainties, and evaluating the role of supporting evidence in the safety assessment of emerging protein sources.

Committee action required

• The Committee is asked to consider the questions raised in the paper.
• To comment on how the points raised in the workshop should influence the assessment of biomass novel foods and identification of safe levels of consumption.

Secretariat

September 2026

Annexes

Annex A – Examples of Margin of Safety Considerations in Novel Food Risk Assessment