On October 19, 2026, the U.S. Food and Drug Administration (FDA) announced the availability of its final guidance, New Dietary Ingredient (NDI) Notifications and Related Issues; Identity and Safety Information About the NDI. The guidance establishes FDA’s current recommendations for documenting ingredient identity, evaluating historical use and other evidence of safety, and supporting safety conclusions in New Dietary Ingredient Notifications (NDINs).
The guidance finalizes Sections VI.A, VI.B, and VI.C of FDA’s 2016 revised draft guidance. It addresses technical considerations including manufacturing processes, ingredient specifications, botanical characterization, toxicological studies, exposure assessments, and the scientific justification supporting an ingredient’s intended conditions of use.
For dietary supplement manufacturers and ingredient suppliers, the significance is primarily scientific and procedural. The underlying statutory requirement to submit an NDIN at least 75 days before marketing, when applicable, remains unchanged. However, the finalized recommendations provide a more definitive reference for assessing whether an NDIN contains sufficient information to support a reasonable expectation of safety.
Companies developing new ingredients or preparing notifications should evaluate the relevance and completeness of their identity data, safety studies, historical-use evidence, and exposure calculations. Existing development programs may also benefit from a gap assessment against the finalized guidance before additional testing or regulatory submissions proceed.
The New Dietary Ingredient notification framework was established under the Dietary Supplement Health and Education Act of 1994 (DSHEA), which amended the Federal Food, Drug, and Cosmetic Act (FD&C Act). Under section 413 of the FD&C Act, a dietary ingredient not marketed in the United States before October 15, 1994, is considered an NDI. Manufacturers and distributors must generally submit a premarket notification at least 75 days before introducing a dietary supplement containing an NDI into interstate commerce, unless a statutory exception applies.
The notification must provide the scientific basis for concluding that the dietary supplement containing the NDI will reasonably be expected to be safe under its intended conditions of use. FDA’s implementing regulation, 21 CFR 190.6, specifies the information required in the notification, including ingredient identity, conditions of use, and history of use or other evidence of safety.
In August 2016, FDA issued its revised draft guidance on NDI notifications, providing detailed recommendations concerning NDI classification, notification procedures, and safety substantiation. Although the guidance offered an extensive framework for preparing submissions, its draft status meant that the recommendations had not been finalized.
FDA’s October 2026 guidance finalizes the portions of that framework addressing identity and safety information. The agency has also updated its remaining draft guidance to identify sections that have been finalized separately, while retaining other topics in draft form.
The distinction between law and guidance remains important. The final guidance does not establish new legally enforceable requirements or prescribe a universal testing program. Rather, it describes FDA’s current scientific recommendations for demonstrating compliance with existing statutory and regulatory requirements. Alternative scientific approaches remain permissible when they satisfy applicable law.
The October 2026 guidance finalizes and reorganizes the identity and safety portions of FDA’s 2016 revised draft guidance. Many topics were already addressed in the draft, so the final document should not be interpreted as introducing an entirely new set of expectations.
The following table summarizes key topics covered by the final guidance and their practical relevance to NDIN preparation.
| Area | Final guidance: coverage and practical implications. |
| Regulatory status | These sections are finalized as FDA’s current thinking. They remain nonbinding recommendations. |
| Ingredient identity | Provides organized, ingredient-specific recommendations for chemical entities, botanicals, extracts, enzymes, fermentation products, and microorganisms. |
| Manufacturing information | Explains the relevance of manufacturing steps, controls, specifications, and process-related variability to the safety assessment. |
| History of safe use | Elaborates on the quality of historical evidence, including consumption levels, duration, frequency, population, and comparability with proposed use. |
| Toxicological evidence | Provides detailed recommendations on genetic toxicity, repeat-dose studies, subchronic toxicity, reproductive endpoints, and interpretation of toxicological results. |
| Alternative methods | Expressly discusses new approach methodologies (NAMs), including scientific validity, reliability, and fitness for purpose. |
| Human studies | Discusses circumstances in which clinical safety studies may be useful, including study design and dose selection. |
| Safety narrative | Describes a comprehensive, integrated scientific narrative connecting identity, historical use, toxicology, exposure, and intended conditions of use. |
| Exposure and safety calculations | Provides dedicated discussion of safety factors, margins of safety, NOAELs, and estimated daily intake. |
| Emerging ingredient technologies | Includes dedicated recommendations for microbial NDIs and ingredients involving nanotechnology. |
Source: FDA’s 2016 revised draft guidance and October 2026 final guidance. The comparison describes areas of clarification and finalization; it does not imply that every recommendation was newly introduced in 2026.
The principal development is the availability of finalized recommendations describing how different types of evidence should be evaluated together. For companies preparing NDINs, this provides a clearer basis for determining whether existing studies adequately support the specific ingredient, manufacturing process, formulation, and proposed conditions of use.
Establish a Clear and Verifiable Ingredient Identity
Ingredient identity is foundational to an NDIN because the relevance of safety evidence depends on whether the substance evaluated is representative of the ingredient intended for commercialization.
Section IV of the final guidance describes information FDA recommends for characterizing an NDI, including its composition, physical and chemical properties, manufacturing process, and specifications. The guidance also provides ingredient-specific recommendations for botanicals, extracts, chemical derivatives, enzymes, and microbial ingredients.
For botanical NDIs, relevant information may include taxonomic identification, plant parts used, extraction conditions, and compositional characteristics. Manufacturers should be able to explain how processing affects the ingredient and whether the resulting material is comparable to substances evaluated in supporting safety studies.
For example, a manufacturer developing a concentrated botanical extract may possess published safety evidence concerning consumption of the whole plant. However, extraction can alter the relative concentrations of constituents, including potentially toxic components. The manufacturer must therefore evaluate whether the published evidence adequately represents the extract’s composition and proposed exposure.
FDA’s recommendations make the relationship between ingredient characterization and safety substantiation particularly important. Specifications and analytical data should establish not only what the ingredient contains, but also whether the material described in the notification is representative of the ingredient that will be manufactured and marketed.
Evaluate Historical Use Against the Proposed Conditions of Use
A documented history of human consumption can provide substantial evidence supporting the safety of an NDI, but its relevance depends on the relationship between historical exposure and the proposed use.
Section VI of the final guidance discusses the information FDA recommends when relying on historical use, including the identity and composition of the consumed material, the quantity consumed, frequency and duration of consumption, and characteristics of the exposed population.
For example, evidence that an ingredient has traditionally been consumed intermittently does not necessarily establish its safety when used daily over an extended period. Similarly, historical consumption at relatively low levels may not support a substantially higher proposed daily intake without additional scientific justification.
FDA also addresses the use of traditional medicine as supporting evidence. Such information may be relevant, but differences in preparation, composition, intended population, and duration of use must be evaluated before drawing conclusions about the safety of a modern dietary supplement.
Importantly, the guidance recognizes that additional toxicological testing may not be necessary when sufficiently documented historical evidence supports the proposed conditions of use. When the intended dose, frequency, duration, and population are adequately covered by historical evidence, additional studies may provide limited incremental value.
The practical implication is that manufacturers should assess the strength and applicability of historical-use evidence before commissioning new safety studies. A scientifically defensible comparison between historical and proposed exposure can help identify whether meaningful safety data gaps exist.
Determine When Additional Toxicological Studies Are Necessary
The final guidance describes a risk-based approach to selecting safety evidence, rather than requiring an identical testing program for every NDI.
Section VII discusses several types of studies that may support a safety assessment, including genetic toxicity, repeat-dose toxicity, reproductive and developmental toxicity, and human clinical safety studies. The appropriate evidence depends on the ingredient’s characteristics, existing scientific information, potential hazards, and intended conditions of use.
For ingredients lacking sufficient historical-use evidence, a 90-day oral toxicity study may help identify adverse effects and establish a no-observed-adverse-effect level (NOAEL). However, supporting long-term daily use requires consideration of study duration, species coverage and appropriate uncertainty factors. FDA strongly discourages relying solely on a single rodent subchronic study to support chronic human use without supporting historical-use data, although it describes circumstances where this may be acceptable with a larger safety factor and additional justification.
The guidance also explains that human clinical studies are not universally required to establish the safety of an NDI. Their relevance depends on whether existing evidence adequately supports the proposed use and whether additional human data would address unresolved safety questions.
For example, a novel ingredient with limited human consumption history and no adequate repeat-dose toxicity data may require additional testing before a reasonable expectation of safety can be established. Conversely, an ingredient supported by extensive, relevant human exposure data may not require the same toxicological program.
Manufacturers should therefore begin with a structured review of existing evidence and identified hazards. This allows additional studies to be selected according to the specific uncertainties they need to resolve, rather than relying on a predetermined testing package.
Consider New Approach Methodologies in Safety Assessments
The final guidance expressly addresses the potential use of new approach methodologies (NAMs) as supporting evidence in NDI safety evaluations. These approaches may include in vitro testing, computational modeling, and other methods intended to reduce, refine, or replace animal testing.
FDA recognizes the potential value of these methods but also identifies limitations in their ability to predict complex biological responses. Accordingly, when NAMs are used to support an NDIN, the agency recommends demonstrating that the selected methodology is scientifically valid, reliable, fit for purpose, and appropriate for the safety question being evaluated.
For example, an in vitro assay may provide evidence concerning a specific toxicological mechanism but may not adequately characterize systemic toxicity associated with repeated oral exposure. Such results may support the overall safety assessment without necessarily replacing evidence needed to address other relevant endpoints.
Manufacturers considering NAMs should therefore evaluate their applicability during study planning. The objective is to select scientifically appropriate methods that address identified data gaps while avoiding unnecessary or duplicative testing.
Establish a Quantitative Basis for Safety Conclusions
A safety assessment must demonstrate how the available scientific evidence supports the proposed conditions of use. Section IX of the final guidance provides recommendations concerning the quantitative interpretation of toxicological findings, estimated daily intake (EDI), safety factors, and margins of safety.
FDA recommends using the NOAEL from relevant studies when appropriate and explaining the scientific rationale for selecting the critical study and endpoint. Where multiple studies identify different NOAELs, the safety narrative should justify the value selected for subsequent calculations while addressing the broader evidence.
For example, a manufacturer may identify a NOAEL from a 90-day oral toxicity study and compare it with the anticipated maximum daily intake of the ingredient. This comparison can help establish a margin of safety, although the adequacy of that margin depends on factors such as interspecies differences, individual variability, study duration, and the completeness of the toxicological database.
The guidance also discusses the use of estimated daily intake relative to acceptable daily intake, where applicable. These calculations provide a quantitative framework for interpreting the relationship between exposure and available safety evidence.
Manufacturers should not assume that a particular numerical margin automatically establishes safety. The calculations must be interpreted alongside the ingredient’s characteristics, study limitations, intended population, and other relevant evidence.
Develop an Integrated Safety Narrative
The safety narrative is a central component of the NDIN because it connects the available scientific evidence to the conclusion that the dietary supplement containing the NDI will reasonably be expected to be safe.
Section V of the final guidance recommends presenting an objective evaluation of historical use, toxicological evidence, estimated exposure, and relevant safety concerns. This evaluation should consider the intended conditions of use and the composition of the finished dietary supplement, including other ingredients that could influence the safety profile.
For example, a notification containing several favorable toxicological studies may still require further explanation if the test materials differ substantially from the commercial ingredient. Similarly, an ingredient-specific safety assessment may not adequately address potential interactions or exposure considerations associated with a multi-ingredient finished product.
FDA also recommends explaining the relevance of supporting studies, addressing conflicting or unfavorable findings, and identifying limitations in the available evidence. A comprehensive safety narrative should therefore provide a scientific interpretation of the evidence rather than simply compiling study reports.
The practical objective is to establish a traceable relationship between ingredient identity, scientific evidence, anticipated exposure, and the proposed conditions of use. Each component should contribute to a coherent and defensible safety conclusion.
The finalization of FDA’s identity and safety recommendations provides an opportunity for manufacturers and distributors to evaluate existing development programs and strengthen the scientific basis of planned NDIN submissions.
Companies should begin by confirming whether their ingredient qualifies as a dietary ingredient, whether it is an NDI, and whether a notification is required. These determinations remain governed by the applicable statutory and regulatory provisions, while other sections of FDA’s broader NDI guidance continue to address classification and notification applicability.
Once the appropriate regulatory pathway has been established, preparation should focus on four connected activities:
1. Review ingredient identity and manufacturing documentation. Confirm that the ingredient’s composition, specifications, analytical methods, and manufacturing information adequately characterize the material intended for commercialization.
2. Assess the available safety evidence. Evaluate the relevance of historical-use information, published literature, toxicological studies, and human data to the proposed dose, duration, frequency, and target population.
3. Identify and address scientific data gaps. Determine whether existing evidence supports a reasonable expectation of safety or whether targeted analytical, toxicological, or clinical studies would strengthen the assessment.
4. Prepare a scientifically integrated notification. Ensure that the safety narrative clearly explains how the evidence supports the proposed conditions of use, including the rationale for exposure calculations, study selection, and safety conclusions.
For companies with NDINs already submitted or ingredients currently marketed, the final guidance does not itself create a general obligation to resubmit notifications. However, reviewing the relevance of the finalized recommendations may be appropriate when considering formulation changes, revised conditions of use, new manufacturing processes, or additional product applications.
Companies should also distinguish the 75-day statutory premarket notification period from the time needed to prepare an adequate scientific dossier. Ingredient characterization, literature evaluation, and additional safety studies can require substantial development time, particularly where existing evidence does not adequately address the proposed exposure.
The most effective preparation begins before submission. Establishing a regulatory strategy and identifying evidence gaps early in ingredient development can reduce the likelihood of unnecessary testing, incomplete submissions, and commercialization delays.
dicentra provides regulatory consulting and scientific support to manufacturers and distributors developing new dietary ingredients for the U.S. dietary supplement market. Our NDI consulting and NDIN services cover the regulatory pathway from initial ingredient classification and safety evaluation through notification preparation and FDA correspondence.
Our approach begins with a regulatory eligibility assessment to determine whether an NDIN is required and whether alternative regulatory pathways should be considered. We then conduct scientific literature reviews and gap analyses to evaluate the available identity, manufacturing, and safety evidence against applicable FDA requirements and recommendations.
Where additional evidence is necessary, dicentra’s integrated regulatory, toxicology, and clinical research capabilities support the development of targeted testing strategies, including toxicological assessments and study coordination. Our team also prepares scientifically supported safety narratives, exposure evaluations, and NDIN dossiers consistent with 21 CFR 190.6.
As FDA finalizes its recommendations concerning ingredient identity and safety substantiation, manufacturers should ensure that their development programs reflect the agency’s current scientific expectations.
Whether you are evaluating a novel ingredient, preparing an NDIN, or assessing gaps in an existing safety dossier, dicentra can help establish an appropriate regulatory and scientific strategy.
Learn more about dicentra’s NDI consulting and NDIN services.