Establishing Safety for Novel Methane-Reduction Feed Additives

Characterizing the safety implications of new and newly applied substances to ruminant feed for reducing agricultural emissions

To reduce the levels of greenhouse gases produced by agriculture, the use of novel feed additives and feed materials designed to reduce methane emissions from ruminant livestock is gaining momentum. As with any substantial change to the food chain, introducing new chemical and biological substances comes with associated safety considerations for the animals, environment, farm workers, and consumers who may be exposed to potential residues in products like milk, meat, and cheese.

To gain regulatory approval for these novel products, or for novel applications of established products, feed additive manufacturers are required to thoroughly characterize the safety concerns that can arise from the use of methane-reducing agents, whether synthetic or biologically derived. Demonstrating the safety of a new product or product use requires conducting a rigorous, application-specific safety assessment, ideally early in the development process, as well as anticipating the need for additional safety assessments that account for increasingly sophisticated analytical methods that detect contaminants and residues in animal products with greater and greater sensitivity.

Factors driving the use of methane inhibitors

According to the UK's official greenhouse gas figures for 2022, the agriculture sector accounted for 12% of all UK emissions, 58% of which were methane emissions. These figures are broadly similar for the EU, with approximately 50% of agricultural emissions attributed to methane between 2005 and 2021.

Due to these large figures, and as highlighted in a recent report by the Food and Agriculture Organization of the United Nations (FAO), agrifood systems are under significant pressure to increase food outputs for a growing global population while simultaneously decreasing their environmental footprint and contribution to climate change.

The Bovaer example and other chemical solutions

Solutions for reducing methane in ruminant livestock have primarily focused on additions to feed that alter digestion in the rumen - the large first stomach compartment of ruminant animals - which can actively inhibit methane production. Examples include chemical solutions, such as the feed additive 3-NOP, and biological derived solutions, such as the use of Asparagopsis seaweed as feed material or as a concentrated additive. Previously authorized feed materials such as nitrate salts have been shown to be effective in reducing methane as well and are now marketed as such.

One of the most well-known commercial methane-reduction feed additives was recently developed by the Dutch company Royal DSM. 3-NOP, also known as 3-nitrooxypropanol or Bovaer, is a synthetically derived compound that has been shown to reduce methane emissions from dairy cows by roughly 30% when added to feed at trace (parts per million) concentrations. It works by inhibiting enzymes in the rumen that form methane during digestion.

To bring Bovaer to market as a novel zootechnical feed additive, approved by both the European Union (EU) after a robust safety assessment by the European Food Safety Authority (EFSA) in 2022 and the UK Food Standards Agency (FSA) in 2023, Royal DSM was required to provide extensive safety evidence, including studies on genotoxicity, carcinogenicity, reproductive toxicity, environmental impact, target species tolerance, and agricultural worker health impacts. Additionally, establishing 3-NOP's absorption, distribution, metabolism, and excretion (ADME) profile was crucial to the approval process, revealing that 3-NOP readily metabolises in ruminants to endogenous compounds and 3-nitrooxypropionic acid (NOPA), which was detected in trace (parts per billion) amounts in cow's milk.

Further toxicology data on NOPA and a subsequent conservative exposure assessment indicated that predicted consumer exposure to NOPA was significantly lower than the derived acceptable daily intake (ADI), resulting in the EFSA and FSA's conclusion that the product is safe for consumers. The regulatory agencies also found no safety concerns for the target species, workers, or the environment at intended use concentrations, and Bovaer was subsequently authorized for use as a feed additive in the EU for dairy cows and cows for reproduction and in the UK for all ruminants for milk production and reproduction; further large beef cattle trials are currently underway. The agencies' environmental safety conclusions were based on the fact that 3-NOP is extensively metabolized into endogenous compounds (e.g., lactose, glucose, and constituents of amino and fatty acids) and ultimately excreted as carbon dioxide. Their conclusions further emphasize the importance of ADME studies to confirm minimal new residues in the environment.

Industry safety evaluation challenges

Measured against the urgent need to address greenhouse gas emissions with high-performing methane inhibitors, the Bovaer example illustrates the scope of the challenges involved in ensuring the safety of new and newly applied substances.

In many cases, it can take two to three years for a new substance to receive EU and GB market authorization post-dossier submission, not including the months to years it can take to prepare the submission. Safety assessments for new methane inhibitors are likely to face a lack of existing safety and ADME data, requiring comprehensive studies that bring together:

• Veterinary expertise to support the design of target species "tolerance" studies and interpret their results

• Toxicology support, including genetic and reproductive toxicology, to assess and characterize hazards using acute and chronic studies

• Analytical chemistry to characterize substances, support ADME assessments, plan the experimental design for the collection of residue data, undertake the analysis, and review results

• Dietary exposure assessments to calculate exposure among population groups and ultimately characterize consumer risk

• Worker (operator) exposure assessments to characterize toxicological risk for employees, including for skin, eyes, and respiratory impacts

• Environmental risk assessments to determine the effects of excreted residues or pertinent metabolites on soil and water

New evaluations for existing substances

For chemicals already authorized for use in the food chain for other functions (as listed in the FAO report) that may inhibit methane production if used in feed (e.g., chlorinated phenols authorized as pesticides or nitrogen-based compounds authorized as food additives), a new evaluation must still be undertaken to understand the safety implications when the substance is used under different conditions or in a different feed application. Any new or changed concentrations in residues may have critical effects on the target animals, consumers, or the environment. Other complex factors, some of which may significantly alter the fate and behavior of a substance in the animal system and result in new residues (of the chemical itself or pertinent metabolites), include:

• Considerations of use at different inclusion rates

• Factoring in use with different species

• Factoring in use with different complementary feed

Evaluations for biologically derived substances

The use of biological, rather than synthetic, materials can be just as challenging, if not more so. When derived from natural materials (e.g., Asparagopsis seaweed), the final product may be a complex chemical mixture of other plant secondary metabolites along with the desired active compounds that can inhibit methane production. Completing a rigorous safety assessment can include:

• Thorough characterization of any mixture to understand both the ADME and toxicity of the naturally derived active compounds that express methane-inhibiting effects (e.g., bromoform) and all pertinent secondary metabolites

• State-of-the-art analytical chemistry that accounts for the lack of internationally recognized standardized methods, addressed through:

  • Careful consideration of experimental design

  • Verification by experienced analytical chemists in the field of complex mixture non-targeted bio-chemical profiling

  • Robust and valid QC processes

Given the pressures on the agriculture sector to reduce greenhouse gas emissions, and the significant contribution represented by livestock, solutions for methane reduction will continue to be at the forefront of options to reduce agricultural emissions. By leveraging relevant toxicological experimental design, applying advanced analytical chemistry techniques, and implementing rigorous validation and quality control measures, industry stakeholders can identify and obtain the data needed to demonstrate safety for workers, animals, the environment, and consumers when introducing new products into livestock feed and the food supply chain.

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