FDA’s Cumulative Effects Mandate: Understanding “Chemically and Pharmacologically Related Substances” in Food Additive Safety Assessments

Introduction  

The U.S. Food and Drug Administration (FDA) recently posted a scientific review designating four ortho-phthalates as “chemically or pharmacologically related substances” for the purpose of a future cumulative risk assessment, noting that the grouping approach may guide the Agency in future pre- and post-market reviews of substances added directly or indirectly to food [1]. This article discusses what constitutes “chemically and pharmacologically related substances” and how such evaluations could impact future FDA risk assessments.

Legislative and Regulatory Context

FDA’s evaluation of food additives under the Federal Food, Drug, and Cosmetic Act (FD&C Act) considers whether “the proposed use of the food additive, under the conditions of use . . .will be safe [2].” While attention is often placed on toxicological studies for individual substances, the FD&C Act directs FDA to consider, “in determining . . . whether a proposed use of a food additive is safe, . . . the cumulative effect of such additive in the diet of man or animals, taking into account any chemically or pharmacologically related substance or substances [3].”

The Food Additives Amendment of 1958 established the modern framework for safety evaluations, introducing a risk-based approach that remains the cornerstone of FDA reviews today. Under FDA’s regulations, safety does not require establishing “with complete certainty the absolute harmlessness of the use of any substance [4].” Rather, a food additive would be considered safe when “there is a reasonable certainty in the minds of competent scientists that the substance is not harmful under the conditions of its intended use [5].” This approach recognizes that scientific assessments inevitably involve some degree of uncertainty and that safety determinations rely on the weight of available evidence. Although FDA’s framework for assessing the safety of food additives has been in place since the 1958 Food Additives Amendment, advances in exposure science, chemistry, toxicology, and cumulative risk assessment methodologies have spurred renewed interest in how related substances may be grouped for such evaluations.

Consistent with this framework, FDA evaluates food additives by considering several factors, including anticipated dietary exposure to the substance, potential exposure to substances that may be formed as a result of the additive’s use, and appropriate safety factors to account for uncertainties in the available data. Importantly, the framework also recognizes that consumers are rarely exposed to a single substance in isolation. Thus, FDA’s safety assessment paradigm includes consideration of the cumulative contribution of chemically or pharmacologically related substances that may already be present in the diet.

Congress incorporated this cumulative effects concept in the FD&C Act after recognizing that dietary exposure can stem from multiple sources, and that substances with shared chemical structures or biological activities can collectively drive up overall exposure. Although early safety assessments lacked today’s advanced analytical tools, the inclusion of cumulative effects language in the statute and FDA’s definition of “safe or safety” proved visionary. The concept recognizes that true food safety requires looking at the broader, real-world context of dietary exposures to individual substances.

Historically, FDA’s safety evaluations have focused on substance-specific data and intended conditions of use. Nevertheless, the cumulative effects provision remains a vital component of the statutory safety framework and continues to provide a foundation for evaluating how related substances may be considered within modern food additive and food contact safety assessments.

Why is This Topic Receiving Renewed Attention?

The concept of “chemically or pharmacologically related substances” has been part of the food additive safety framework for decades; however, it is attracting renewed attention through FDA’s current emphasis on post-market reviews of substances in the food supply. As noted in footnote 1, FDA recently proposed a grouping strategy for certain food-contact ortho-phthalates to evaluate whether they should be considered chemically or pharmacologically related substances for purposes of a future cumulative risk assessment. In doing so, the Agency examined factors such as chemical structure, toxicokinetics, and toxicological effects to determine whether certain ortho-phthalates could appropriately be evaluated as a group rather than solely as individual substances.

While FDA’s most recent review focused on ortho-phthalates, this scientific evaluation highlights the continuing relevance of the statutory requirement to consider chemically or pharmacologically related substances and illustrates how modern tools, such as in silico modeling, can inform assessments of cumulative effects.

What are “Chemically and Pharmacologically Related Substances”?

The statute does not explicitly define the phrase “chemically or pharmacologically related substances,” and its interpretation may depend on the scientific context and available data.

From a toxicological perspective, “chemically related” substances may include compounds that share structural similarities, common functional groups, comparable physicochemical properties, related metabolic pathways, or common degradation products. Such similarities and differences can provide insight into how substances behave in biological systems and whether they may produce comparable toxicological profiles.

“Pharmacologically related” substances may comprise compounds that produce similar biological effects, even when their chemical structures differ. For example, substances may affect the same target organ, interact with similar biological pathways, or produce comparable adverse outcomes through related molecular mechanisms or toxicity pathways. Evaluating similarity among chemical substances typically involves not only chemistry, but also how substances behave with biological systems.

In practice, determining whether substances are chemically or pharmacologically related involves a weight-of-evidence evaluation that integrates information from chemistry, metabolism, toxicology, exposure science, and mechanistic analyses. The degree of similarity necessary to support grouping may vary depending on the regulatory question being addressed and the strength of the supporting scientific evidence.

Evolving Scientific Approaches

Scientific approaches for evaluating food chemical safety have evolved considerably since Congress enacted the Food Additives Amendment in 1958. Advances in analytical chemistry, toxicology, exposure science, and computational modeling have expanded the tools available to characterize the substances in the food supply and evaluate potential relationships among them.

One notable development has been the emergence of New Approach Methodologies (NAMs), a broad term describing scientific methods that complement traditional toxicology studies. Examples include:

• Structure–activity relationship (SARs) and quantitative structure–activity relationship (QSAR) models, which use chemical structure to predict biological activity;
• Read-across approaches and methods, which leverage data from analogous substances to fill data gaps;
• In vitro or in chemico assays, which provide information on biological activity, key molecular events, and potential mode of action of chemicals;
• Adverse Outcome Pathways (AOPs), which describe the biological events linking an initial chemical interaction to subsequent molecular effects at subcellular, cellular, tissue, organ, or whole-body levels leading to an adverse health outcome;
• Toxicogenomics and physiologically-based pharmacokinetic (PBPK) modeling, which provides insights into biological responses, metabolism, and internal exposure; 
• Data from High-Throughput Screening (HTS), High-Content Screening (HCS), transcriptomics, metabolomics, and phenotypic profiling technologies to identify analogues or confirm bioactivity similarity; and
• Integrated Approaches to Testing and Assessment (IATA), which combine multiple lines of evidence to support safety evaluations and decision making, including the targeted generation of new data if needed [6].  

Collectively, these tools provide a more comprehensive understanding of similarities and differences among substances than may be possible through analyses of chemical structure alone. As a result, they can help inform evaluations of whether substances may be chemically or pharmacologically related and whether grouping approaches would be scientifically appropriate.

FDA has recognized the potential value of these methods through its initiatives such as the Predictive Toxicology Roadmap and the Roadmap to Reducing Animal Testing in Preclinical Safety Studies. These initiatives reflect FDA’s broader commitment to advancing regulatory science by incorporating a range of scientifically robust tools and data streams into safety evaluations. Depending on the regulatory context and scientific questions the Agency is aiming to address, the Agency may consider information generated using NAMs alongside data from traditional toxicology studies to support a robust, weight-of-evidence assessment.

As experience with NAMs continues to grow, these methodologies may provide additional opportunities to evaluate chemical relatedness, biological activity, and other factors relevant to cumulative safety assessments. The advances underscore the value of a multidisciplinary approach to food additive and food contact safety evaluations.

Practical Considerations for Industry

As cumulative assessment approaches continue to evolve, companies may benefit from proactively considering whether potentially related substances could become relevant in future regulatory discussions or safety evaluations. Although the specific scientific considerations may vary depending on the substances at issue and their intended uses, a thorough understanding of potential relationships among chemicals can strengthen the overall safety assessment across a company’s portfolio.

In some situations, early consideration of similarities among chemical substances may support food additive petitions, food contact notifications, Generally Recognized as Safe (GRAS) evaluations, and broader stewardship activities. Also, incorporating these considerations early in product development may help identify data needs and facilitate more efficient regulatory submissions.

Looking Ahead

The statutory concept of “chemically or pharmacologically related substances” has existed for decades, yet scientific methodologies for evaluating grouping chemicals and evaluating their cumulative effects continue to evolve. Advances in exposure, toxicology, computational methods, and mechanistic research are providing new opportunities to evaluate relationships among substances and to better understand the impacts of cumulative exposures.

As FDA, stakeholders, and the scientific community continue to discuss cumulative assessment approaches, companies operating in the food and food contact sectors may benefit from staying informed on emerging scientific considerations and regulatory developments. Understanding how chemistry, toxicology, exposure science, and mechanistic information intersect can help support scientifically grounded and strategically informed safety assessments. As these scientific approaches continue to advance, the multidisciplinary team at Keller and Heckman LLP remains committed to helping clients navigate evolving regulatory expectations and develop scientifically sound approaches to food and food contact safety assessments. 

[1] U.S. Food and Drug Administration, FDA Review of Select Ortho-Phthalate Food Contact Substances as Chemically or Pharmacologically Related (CPR) Substances, Docket No. FDA-2026-N-5776 (May 27, 2026), https://www.regulations.gov/document/FDA-2026-N-5776-0001. FDA’s review, conducted on eight ortho-(o)-phthalates currently cleared by FDA as plasticizers for food contact (diisononyl phthalate (DINP), diisodecyl phthalate (DIDP), di(2-ethylhexyl) phthalate (DEHP), dicyclohexyl phthalate (DCHP), butylphthalyl butyl glycolate (BPBG), diethyl phthalate (DEP), ethylphthalyl ethyl glycolate (EPEG), and diisooctyl phthalate (DIOP)), concluded that a CPR grouping for DEHP, DCHP, DIOP, and DINP was appropriate for purposes of a future Agency cumulative risk assessment.  

See also our Packaginglaw.com article at FDA Proposes Grouping Strategy for Post-Market Assessment of Food-Contact Phthalates, Extends Public Comment Period.

[2] 21 U.S.C. 348(c)(3)(A).

[3] 21 U.S.C. 348(c)(5)(B); 21 C.F.R. 170.3(i).  

[4] 21 C.F.R. 170.3(i).

[5] Id.

[6] OECD (2025), Guidance on Grouping of Chemicals, Third Edition, OECD Series on Testing and Assessment, No. 418, OECD Publishing, Paris, Guidance on Grouping of Chemicals, Third Edition (EN).