A new dietary ingredient needs a documented safety case before it is marketed, and FDA's reply to a notification is not an approval
FDA's October 2026 final guidance covers what an NDIN should say about identity, history of use and the safety conclusion. When a notification is required remains in draft guidance.
Status. EUTECNIQ is in formation and has prepared no notifications, run no studies and holds no master files. Studies would be run by qualified laboratories; legal conclusions belong to counsel.
Academy fundamentals: Course 2, The untapped botanicals · Course 9, Toxicology and dose
An NDIN is a premarket safety notification, and FDA does not approve it
“FDA does not approve NDI notifications; no FDA approval is required or issued at any point in this process.”
Text version of the figure
The notifier, the manufacturer or distributor of the NDI or of the supplement, concludes that the supplement will reasonably be expected to be safe and files the basis for that conclusion with FDA at least 75 days before marketing. FDA reviews the basis and replies with one of four kinds of letter.
An “acknowledgement letter without objection” means FDA's review found no reason to object to the notifier's basis for its safety conclusion. In FDA's words, it “does not constitute an independent finding by FDA that the NDI and the dietary supplement that contains the NDI are safe, or that they are not adulterated.” FDA's silence is not a safety finding either (21 CFR 190.6(f)).
Sources: 21 U.S.C. 350b; 21 CFR 190.6 (eCFR, current to Oct 21, 2026); FDA final guidance, NDI notification procedures and timeframes (March 2024), Section IV.D; FDA final guidance, NDI identity and safety information (October 2026), Sections II and VI.
Academy: explore FDA's NDIN list by year (Course 2)
Explanation, details and sources
A new dietary ingredient (NDI) is a dietary ingredient not marketed in the United States before October 15, 1994. A notification (NDIN) gives FDA the notifier's basis for concluding the supplement will reasonably be expected to be safe.
The October 2026 guidance finalizes three sections of FDA's 2016 draft; the questions about when a notification is needed remain draft
Text version: where each part of the 2016 draft went
Identity, history of use, basis for safety
Sections VI.A, VI.B and VI.C of the August 2016 revised draft. FDA now asks for one “safety narrative” in place of the earlier “comprehensive safety profile.” The material is reorganized into new sections, including safety calculations and microbial and nanotechnology NDIs.
Final guidance · Oct 2026Procedures and timeframes
How to submit, what FDA sends back and when, confidentiality, and pre-submission meetings. Finalized from Section V of the 2016 draft in March 2024 (89 FR 16003; docket FDA-2023-D-5280).
Final guidance · Mar 2024Whether a notification is needed
What counts as an NDI, pre-1994 documentation, “chemically altered,” “dietary substance,” the drug exclusion, definitions and the decision tree. Master files moved to a separate April 2024 draft.
Draft guidance · 2016 and 2024| 2016 revised draft | Now in | Status |
|---|---|---|
| Section VI.A (identity) | 2026 final, Section IV (identity) | Final |
| Q VI.B.1, VI.C.1, VI.C.3 | 2026 final, Section V (summary of the basis for safety, the “safety narrative”) | Final |
| Q VI.B.2–VI.B.10 | 2026 final, Section VI (history of use) | Final |
| Q VI.B.11–VI.B.39 (selected) and VI.C.4 | 2026 final, Section VII (other evidence of safety) | Final |
| Q VI.B.40–VI.B.42 | 2026 final, Section VIII (microbial NDIs, nanomaterials) | Final |
| Q VI.C.5–VI.C.8 | 2026 final, Section IX (safety calculations) | Final |
| Table 3 | 2026 final, Appendix A (Standard Safety Testing Table) | Final |
| Section V (procedures and timeframes) | March 2024 final guidance | Final |
| Master-file questions in Section IV and the “Master File” definition | April 2024 master-file draft guidance | Draft |
| Sections I–III, IV, VII (other definitions), VIII (decision tree) | Remain in the 2016 revised draft (October 2026 revision) | Draft |
Source: “Document History” in the October 2026 revision of FDA's draft guidance, Dietary Supplements: New Dietary Ingredient Notifications and Related Issues (docket FDA-2011-D-0376). The 2016 row ranges are abbreviated; FDA lists the individual questions.
Explanation, details and sources
FDA dated the final guidance October 19, 2026 and announced it in the Federal Register on October 20, 2026 (91 FR 66336; docket FDA-2025-D-6501). It is a stand-alone document with new section numbers.
The statute and 21 CFR 190.6 are binding; FDA's guidance documents are recommendations
Text version of the hierarchy
| Instrument | What it does | Status |
|---|---|---|
| FD&C Act § 413 (21 U.S.C. 350b) | Defines an NDI. Requires notification at least 75 days before marketing unless the food-supply exception applies; otherwise the supplement is deemed adulterated under § 402(f). | Statute Requirement |
| FD&C Act § 201(ff) (21 U.S.C. 321(ff)) | Defines “dietary supplement” and the dietary-ingredient categories; excludes certain articles first approved or investigated as drugs. | Statute Requirement |
| 21 CFR 190.6 | Sets timing, required contents, filing date, the effect of amendments, the 90-day confidentiality period, and that silence is not a finding of safety. | Final regulation Requirement |
| NDI notification procedures and timeframes (March 2024) | Submission mechanics, response letters, incomplete notifications, trade-secret marking, pre-submission meetings. | Final guidance Recommendation |
| NDI identity and safety information (October 2026) | Identity information, history of use, other evidence of safety, safety narrative and safety calculations. | Final guidance Recommendation |
| 2016 revised draft, remaining sections | When an NDIN is required, “chemically altered,” pre-1994 documentation, definitions and decision tree. | Draft guidance Not for implementation |
| NDIN master files (April 2024) | How master files and letters of authorization would work. | Draft guidance Not for implementation |
Explanation, details and sources
FDA states that its guidance documents “do not establish legally enforceable responsibilities” and should be viewed as recommendations unless they cite a statute or regulation. Draft guidance is labeled “not for implementation.”
A new dietary ingredient needs a notification unless every dietary ingredient in the supplement was in the food supply, chemically unaltered
Seven questions EUTECNIQ would answer before any study is commissioned
Text version of the seven questions
- Definition
Is it a dietary ingredient?
It must fit FD&C Act § 201(ff)(1): a vitamin, mineral, herb or other botanical, amino acid, dietary substance, or a concentrate, metabolite, constituent, extract or combination of these. If it does not, the supplement pathway is closed. Statute
- Before 1994
Was it marketed in the U.S. as a dietary ingredient before October 15, 1994?
If so, it is not a new dietary ingredient. The marketer should be able to document that marketing; FDA's views on acceptable documents are in draft guidance. Statute Draft guidance
- Food supply
Has it been present in the food supply as an article used for food, in a form not chemically altered?
When every dietary ingredient in the supplement meets this test, no notification is required (§ 413(a)(1)). Statute
- Processing
Has extraction, concentration or another process chemically altered it?
A chemically altered form can lose the food-supply exception. FDA's interpretation of “chemically altered” is in Section IV.B of the 2016 draft. Draft guidance
- Drug exclusion
Was it approved as a new drug, or authorized for investigation as one with substantial public clinical investigations, before it was marketed as a supplement or food?
If so, § 201(ff)(3)(B) excludes it from the dietary-supplement definition unless FDA issues a regulation finding it lawful. Statute
- Category
Is it meant for a supplement, a conventional food, a cosmetic or something else?
Each category has its own pathway. An NDIN covers use in dietary supplements only; food uses go through the food-additive or GRAS routes.
- Evidence
Do the data support the proposed dose, duration, population and conditions of use?
The gaps decide which studies are commissioned. A required notification is filed at least 75 days before marketing (21 CFR 190.6).
Sources: 21 U.S.C. 321(ff), 350b(a) and (d); FDA draft guidance, New Dietary Ingredient Notifications and Related Issues (October 2026 revision), Sections IV.A–IV.D.
Explanation, details and sources
Section 413(a) gives two routes. That a plant has been eaten for centuries does not by itself decide which applies, because form, part, processing and dose all matter.
Food-supply exception
The supplement “contains only dietary ingredients which have been present in the food supply as an article used for food in a form in which the food has not been chemically altered.” The exception is strict: one ingredient outside it brings the product into (a)(2).
StatuteHistory of use or other evidence of safety, notified 75 days ahead
There must be a history of use or other evidence of safety, and the manufacturer or distributor of the NDI or of the supplement must give FDA the basis for its conclusion at least 75 days before interstate marketing.
StatuteFDA's readings of “chemically altered,” pre-1994 documentation and “dietary substance” appear only in the 2016 draft (Sections IV.A, IV.B, IV.D). There FDA also takes the view that the “reasonably expected to be safe” standard applies when no notification is needed. Both are FDA's draft thinking, not settled law.
The 75-day clock starts on the day FDA receives a complete notification, and a substantive amendment restarts it
Text version of the timeline
- Optional pre-NDIN meetingVoluntary request for preliminary, non-binding FDA feedback
- SubmissionElectronic through FDA's online submission module, or on paper
- Filing date, day 0Date FDA receives the notification; FDA acknowledges receipt and assigns a number
- 75-day periodThe supplement may not enter interstate commerce; a substantive amendment sets a new filing date
- FDA response letterFDA states it intends to respond within 75 days of filing
- After day 90Notification and response posted on regulations.gov, minus trade secrets and confidential commercial information
Data table
| Year | Notifications | Median days | Answered by day 75 |
|---|---|---|---|
| 1995 | 2 | 58.5 | 1 |
| 1996 | 8 | 69 | 7 |
| 1997 | 14 | 42.5 | 12 |
| 1998 | 19 | 22 | 19 |
| 1999 | 24 | 43 | 22 |
| 2000 | 31 | 73 | 29 |
| 2001 | 19 | 84 | 8 |
| 2002 | 53 | 74 | 34 |
| 2003 | 64 | 74 | 47 |
| 2004 | 43 | 74 | 40 |
| 2005 | 57 | 74 | 46 |
| 2006 | 64 | 75 | 43 |
| 2007 | 73 | 79 | 8 |
| 2008 | 40 | 75.5 | 20 |
| 2009 | 47 | 72 | 37 |
| 2010 | 53 | 73 | 45 |
| 2011 | 49 | 72 | 48 |
| 2012 | 42 | 40 | 42 |
| 2013 | 33 | 55 | 33 |
| 2014 | 40 | 70 | 37 |
| 2015 | 48 | 69 | 42 |
| 2016 | 60 | 69 | 51 |
| 2017 | 93 | 63 | 87 |
| 2018 | 42 | 69.5 | 38 |
| 2019 | 33 | 70 | 32 |
| 2020 | 54 | 70 | 54 |
| 2021 | 37 | 66 | 36 |
| 2022 | 33 | 65 | 33 |
| 2023 | 45 | 68 | 45 |
| 2024 | 59 | 67 | 55 |
| 2025 | 71 | 69 | 59 |
| 2026 | 9 | 70 | 9 |
| All years | 1,359 | 71 | 1,119 |
Across 1,359 listed notifications FDA's median response came on day 71 after submission, and 82% came by day 75.
Explanation, details and sources
The list gives a submission date and the date of FDA's response, not the filing date or the kind of letter, so the interval is approximate: the filing date is the date FDA receives the notification (21 CFR 190.6(c)), and a substantive amendment sets a new filing date (190.6(d)). Responses after day 75 can reflect amendments. FDA's response is not an approval in any case.
What a notification must contain (21 CFR 190.6(b))
What a notification must contain (21 CFR 190.6(b)) Regulation
- Name and complete address of the notifier.
- Name of the NDI; for a botanical, the Latin binomial name including the author.
- Description of the supplement: the level of the NDI and the conditions of use in the labeling, or the ordinary conditions of use.
- The history of use or other evidence of safety, with copies of cited references and complete English translations of foreign-language material.
- Signature of a person designated by the notifier.
Text version of the response letters
Response letters FDA commonly sends Final guidance, March 2024
- Acknowledgement without objection. FDA found no reason to object to the notifier's basis; not an independent finding of safety.
- Incomplete. Required information is missing. FDA does not evaluate safety or identity in an incomplete NDIN, and an incomplete NDIN does not satisfy § 413(a)(2).
- Objection. Concerns about the identity or safety information, such as gaps in history of use.
- Other regulatory issues. For example, the substance is not a dietary ingredient, or the product is not a dietary supplement.
Sources: 21 CFR 190.6(a)–(f); FDA, Guidance for Industry: New Dietary Ingredient Notification Procedures and Timeframes (March 2024), Sections III–V.
FDA's public list holds 1,372 notifications since 1995, and it can be searched by ingredient name
A match only shows that someone notified FDA about a similarly named ingredient; identity, form and intake decide whether a new notification is needed.
Eighteen evidence packages, scaled to the ingredient rather than filled in by default
Not every package is needed for every notification; the ingredient, its process, its hazards and the exposure gap decide the scope.
What each package would contain
Ingredient identity
Latin binomial with author (required), plant part, common and trade names, authenticated reference material, vouchered specimen and where it is stored.
190.6(b)(2) · final IV.2, IV.10Source provenance
Geographic origin, wild or cultivated, propagation, harvest season and maturity, post-harvest handling, supplier records (GACP where available).
final IV.10–IV.11Manufacturing description
Process flowchart with controls, starting materials, solvents and processing aids, concentration or dilution ratio, purification, drying and blending.
final IV.3, IV.13Chemical characterization
HPLC/UPLC, LC-MS/MS, LC-HRMS, GC-MS, NMR, FTIR, HPTLC. Marker identity and content, each marker labeled as a toxicity marker or a surrogate marker.
final IV.2, IV.13Batch consistency
Representative batches, fingerprint similarity, controls or acceptable ranges for batch-to-batch variation, and how the extract is standardized.
final IV.2, IV.13Physical properties
Appearance, solubility or dispersibility, density, particle or droplet size, moisture, water activity, pH.
final IV.2Impurities and contaminants
Elemental contaminants, pesticides, mycotoxins, microbes, residual solvents, degradation products, toxins known in related species, and their quantitative limits.
final IV.2, IV.12, IV.13Analytical methods
Methods and reference materials, specificity, accuracy, precision, range, LOD/LOQ, and evidence that each method is fit for its purpose.
final IV.2, IV.4–IV.5History of use
Who consumed it, in what form, how much, how often and for how long, and how the historical article relates to the NDI.
final VIPublished safety evidence
Systematic review of toxicology, human studies, case reports and adverse events, with study quality appraised.
final VIINonclinical safety
Genetic toxicity battery, repeat-dose and 90-day studies, and reproductive studies when the target population calls for them.
final VII, Appendix AToxicokinetics
Absorption, distribution, metabolism and excretion; metabolites; systemic exposure in the test species compared with people.
final VII.1Human safety evidence
Single- or repeat-dose tolerability and ADME studies when they close a data gap, with safety endpoints collected.
final VII.1, VII.15–VII.18Interaction assessment
Other botanicals, medicines, metabolizing enzymes and transporters, and the other ingredients in the formula.
EUTECNIQ addition · final V.3 (several NDIs)Exposure assessment
Highest total daily intake under the proposed conditions of use (the EDI), serving size, frequency, duration, sensitive groups and other sources.
190.6(b)(3) · final IV.19, IXSafety conclusion
The safety narrative: weight of evidence, NOAEL selection, margin of safety, ADI and EDI/ADI, uncertainties and remaining controls.
final V, IXFinished-product relevance
Other ingredients and their food-grade purity, formulation, directions for use, and any difference from the material that was tested.
final IV.2, IV.20, VII.4Notification administration
Notifier details and signature, references and translations, trade-secret and CCI marking, amendments and correspondence.
190.6(b)(4)–(5) · March 2024 guidance“final” refers to FDA's October 2026 final guidance on NDI identity and safety information; “190.6” to 21 CFR 190.6. GACP: WHO good agricultural and collection practices for medicinal plants.
GLP governs how a nonclinical study is run; no current FDA rule or NDI guidance requires it for a notification
Text version of the figure
- Neither the October 2026 final guidance nor the remaining 2016 draft mentions GLP or Part 58.
- Part 58 applies to nonclinical studies supporting applications for research or marketing permits. Its list of covered submissions (§ 58.3(e)) includes food and color additive petitions and INDs; it does not include NDI notifications.
- FDA recommends recognized protocols such as the OECD Test Guidelines, cited and with any deviation explained. In FDA's words, “You do not have to use specific published protocols in your NDIN.”
- Reconstructable records. Protocols, raw data, quality-assurance audits and archives let a reviewer trace every result.
- Reuse in the U.S. The same study may later support a submission Part 58 does cover, such as a food additive petition or an IND.
- Reuse abroad. Under the OECD Mutual Acceptance of Data decision (1981), data from OECD Test Guidelines and GLP in one adherent country “shall be accepted” in others for assessment; each authority still interprets the results itself.
Submissions listed in § 58.3(e) include color additive petitions (Part 71), food additive petitions (Parts 171 and 571), GRAS affirmation data (§§ 170.35 and 570.35), investigational new drug applications (Part 312), new drug applications (Part 314), biologics license applications (Part 601), device IDE and PMA submissions, and food contact substance notifications (Part 170, Subpart D). None of the 21 listed types mentions dietary supplements or NDI notifications.
Text version: typical quality approach for each study
| Study or evidence | Typical quality approach | Why it matters |
|---|---|---|
| Literature and history-of-use research | Non-GLP; documented, reproducible systematic review | Establishes existing evidence and finds gaps |
| Botanical authentication | Qualified analytical and QC methods against authenticated reference material | Shows the tested material is what it claims to be |
| Chemical fingerprinting | Documented, fit-for-purpose methods; validated where results set specifications | Links test batches to commercial material |
| Contaminant screening | Laboratory quality system; ISO/IEC 17025 accreditation for the specific methods adds confidence | Measures known or foreseeable hazards |
| In vitro activity screening | Usually non-GLP exploratory research | Selects candidates; does not show efficacy |
| CYP and transporter screening | Exploratory first; higher-quality follow-up if a signal appears | Flags interaction liabilities |
| Exploratory PK and ADME | Often non-GLP at the discovery stage | Shows exposure and metabolism |
| Genetic toxicity battery | Commonly OECD test guidelines under GLP; required by Part 58 only for covered submissions | Hazard identification FDA's guidance recommends |
| Repeat-dose and 90-day toxicology | Commonly OECD test guidelines under GLP; required by Part 58 only for covered submissions | The NOAEL used in the safety calculations |
| Human tolerability studies | Human-subject protections (21 CFR Parts 50 and 56) and good clinical practice, not GLP | Human safety under study conditions |
| Manufacturing qualification | The applicable GMP: 21 CFR Part 111 for supplements, Part 117 for ingredient-only operations | Manufacturing consistency |
| Shelf-life studies | Stability protocols with stability-indicating methods | Product quality and dating |
| Integrated safety assessment | Documented regulatory-scientific review | The safety narrative |
Sources: 21 CFR 58.1 and 58.3 (eCFR); FDA final guidance (October 2026), Section VII.5; OECD, Decision of the Council concerning the Mutual Acceptance of Data in the Assessment of Chemicals, OECD/LEGAL/0194 (adopted May 12, 1981); FDA final guidance (October 2026), footnote 20 on safety-only clinical studies and Parts 50 and 56.
Explanation, details and sources
Good Laboratory Practice (21 CFR Part 58; OECD Principles of GLP) governs how nonclinical laboratory studies are planned, performed, monitored, recorded, archived and reported. It does not decide which studies an ingredient needs.
EUTECNIQ would design pivotal toxicology studies to GLP standards where the regulatory purpose or a later submission warrants it, and would present that as a data-quality choice. It is not an NDIN legal requirement.
The gap between historical and proposed exposure decides which studies FDA's guidance points to
Text version of the figure
A two-study battery (bacterial mutation plus an in vitro mammalian test) or a three-study battery that adds an in vivo test for chromosomal damage. The less history of use, the more studies FDA recommends. A positive result is “a clear but non-quantitative identification of a potential hazard” and calls for further testing, such as carcinogenicity studies.
FDA guidance VII.1, VII.6A 14-day study to set the maximum tolerated dose, then a 90-day oral study to find the no-observed-adverse-effect level (NOAEL) used in the safety calculations. A one-generation reproductive study applies when the product is for pregnancy, lactation or young children.
FDA guidance VII.1, Appendix AADME studies in animals or people show whether the test species was exposed in the way people will be. FDA notes that a human study can help “where available animal models are not ideal to represent human exposure.”
FDA guidance VII.1New approach methods, such as in vitro and in silico models, are “unlikely to be sufficient to demonstrate safety on their own” but can fill gaps when shown to be scientifically valid and fit for purpose.
FDA guidance VII.1, VII.3Show the table (7 rows): FDA Standard Safety Testing Table: studies that could fill a data gap for each combination
| Documented historical use | Proposed use of the NDI | Two-study genetic toxicity battery | Three-study genetic toxicity battery | Single-dose acute and/or ADME study, animals | 14-day repeat-dose oral study, animals | 90-day subchronic oral study, animals | One-generation rodent reproductive study ^ | Single-dose tolerability and/or ADME, humans * | Repeat-dose tolerability and/or ADME, humans * |
|---|---|---|---|---|---|---|---|---|---|
| Daily chronic | Intermittent, serving greater than historical | ● | · | ● a | · | ● | · | ● a | · |
| Daily chronic | Daily chronic, serving greater than historical | ● | · | ● a | · | ● | ● | ● a | · |
| Intermittent | Intermittent, serving greater than historical | ● | · | ● a | · | ● | ● | ● a | · |
| Intermittent | Daily chronic, serving less than historical | · | ● | · | ● | ● | ● | · | · |
| Intermittent | Daily chronic, serving greater than historical | · | ● | · | ● | ● | ● | · | ● |
| No history | Daily chronic | · | ● | · | ● | ● | ● | · | ● |
| No history | Intermittent | · | ● | · | ● | ● | ● | · | ● |
^ Only relevant if the product is intended for infants, children, or people who are pregnant or lactating. * Human tolerability or ADME studies are case by case, to address existing data gaps. a: an animal or a human single-dose study is equally relevant. FDA says history-of-use data alone should be sufficient when the proposed serving is less than historical use and the proposed pattern is the same or less frequent (daily chronic history with daily chronic or intermittent use; intermittent history with intermittent use). Source: FDA final guidance (October 2026), Appendix A.
EDI/ADI is at or below 1. Under FDA's guidance this supports, without proving, a reasonable expectation of safety at this intake, if the NOAEL and safety factor are justified.
Method, assumptions and limits
- What it calculates
- The estimated daily intake (EDI), margin of safety, acceptable daily intake (ADI), the EDI/ADI ratio, and the intake at which EDI/ADI equals 1, as described in Section IX of FDA's October 2026 final guidance.
- Equations
- EDI = I ÷ BW. Margin = RP ÷ EDI. ADI = RP ÷ SF. Ratio = EDI ÷ ADI. Intake at ratio 1 = ADI × BW. FDA uses the NOAEL as the reference point (RP).
- Variables and units
- I: highest total daily intake of the NDI under the proposed conditions of use, mg/person/day (0.1–10,000). BW: body weight, kg (10–120; FDA's worked example uses 70 kg). NOAEL and BMDL10: mg/kg bw/day (NOAEL 1–3,000). SF: combined safety factor, dimensionless.
- Safety factors
- FDA: usually 100 for a chronic study (10 between species × 10 within people); 1,000 when two 90-day studies in rodent and non-rodent species are extrapolated to chronic use; 2,000 for a single rodent 90-day study, which FDA “strongly discourages” without history-of-use support. FDA calls these approximate values that can move up or down with the data.
- Illustrative study
- Hill curve f(d) = 100 ÷ (1 + (ED50 ÷ d)²) with ED50 = (20/3) × NOAEL; LOAEL = (10/3) × NOAEL; BMD10 is the dose with a 10 % response; BMDL10 is set to 0.6 × BMD10 for display only. A real BMDL is a statistical lower bound from fitting dose–response models (EFSA 2022).
- Decision rule
- FDA: EDI/ADI ≤ 1 supports a conclusion that the proposed use will reasonably be expected to be safe; EDI/ADI > 1 means the study does not support it. FDA does not treat the ADI as a sharp line between safe and unsafe.
- What it does not establish
- It is not a safety determination. It does not choose or validate a NOAEL, weigh study quality, severity or human data, add intake from other sources, or quantify risk. EFSA's margin-of-exposure benchmark of 10,000 applies to substances that are both genotoxic and carcinogenic, with a BMDL10 from an animal study; it does not apply here.
- Verification
- Reproduces FDA's worked example (NOAEL 3,000 mg/kg bw/day, 1 mg/day, 70 kg, SF 2,000: margin 210,000; ADI 1.5 mg/kg bw/day; EDI/ADI 0.0095, which FDA rounds to 0.01). Seven cases are checked against an independent Python implementation (tests/numerics/ref/regulatory-ndin.py).
- References
- FDA final guidance, NDI identity and safety information (October 2026), Section IX; EFSA Scientific Committee, Guidance on the use of the benchmark dose approach in risk assessment, EFSA Journal 2022;20(10):e07584; EFSA Scientific Committee, statement on the margin of exposure approach, EFSA Journal 2012;10(3):2578.
FDA names the OECD Guidelines for the Testing of Chemicals, Section 4, the EPA OCSPP harmonized guidelines and FAO/WHO risk-assessment principles as protocol sources (final guidance VII.5). FDA's mouse lymphoma thymidine kinase assay preference corresponds to TG 490. ICH M3(R2) guides pharmaceutical programs and is not an NDIN test list. Titles from the OECD Section 4 listing as published by Germany's BfR.
Academy: reference points, uncertainty factors and human-equivalent dose (Course 9)
Explanation, details and sources
FDA recommends considering history of use first. Studies are added to fill the gap between what people safely consumed and what the product would deliver. Study design and dose–response methods are covered on Toxicology and exposure.
FDA's Standard Safety Testing Table FDA guidance, Appendix A
FDA built this table to illustrate studies that could fill the gap. Firms are “not required to complete and submit all the studies listed in a given row.” Choose a scenario to see its row.
Safety calculations: margin of safety, ADI and the EDI/ADI ratio Educational calculation
FDA recommends a margin of safety in every notification, even one based on history of use. The calculator applies FDA's Section IX arithmetic to an invented dose–response study.
| OECD test guideline | Title |
|---|---|
| TG 471 | Bacterial Reverse Mutation Test |
| TG 490 | In Vitro Mammalian Cell Gene Mutation Tests Using the Thymidine Kinase Gene |
| TG 473 · TG 487 | In Vitro Mammalian Chromosome Aberration Test · In Vitro Mammalian Cell Micronucleus Test |
| TG 474 · TG 489 | Mammalian Erythrocyte Micronucleus Test · In Vivo Mammalian Alkaline Comet Assay |
| TG 407 · TG 408 | Repeated Dose 28-day and 90-Day Oral Toxicity Studies in Rodents |
| TG 421 · TG 422 | Reproduction/Developmental Toxicity Screening Test, alone or combined with a repeated-dose study |
| TG 414 · TG 443 | Prenatal Developmental Toxicity Study · Extended One-Generation Reproductive Toxicity Study |
| TG 417 | Toxicokinetics |
A new extract is not covered by an old safety package until comparability is shown
Text version of the workflow
- Original extract. 40 % aqueous ethanol; characterized batches; existing safety studies.
- Changed extract. New solvent and purification; higher concentration; safety coverage unknown.
- Comparability assessment. Chemical-fingerprint comparison; marker and non-marker constituents; impurity and degradation-product profiles; batch-to-batch equivalence; comparative bioaccessibility and exposure; process change-control review; toxicological data-gap evaluation.
- Bridge justified. Documented reasons why the existing studies apply to the new material.
- New studies needed. Targeted studies for the gaps the comparison found.
Example: a supplier holds safety studies on an extract made with 40 % aqueous ethanol, then introduces a more concentrated extract made with another solvent. EUTECNIQ would not assume the original package applies. FDA's own example accepts data on a dried ground root for an isopropanol extract of the same root only if the extract's components are present at the same or lower levels than in the root that was fed. Proposed workflow FDA guidance VII.4
Explanation, details and sources
FDA generally recommends that the test article be identical to the NDI. When it is not, FDA asks for a qualitative and quantitative comparison, and warns that “the more different the composition of the test article … the more difficult it will be to demonstrate that the study provides relevant safety evidence.”
A master file lets an ingredient owner authorize others to rely on its data unseen, under guidance that is still a draft
Text version of the figure
- Owner submits the master fileCover letter, contents, authorized parties and any limits; a U.S. representative if the owner is abroad
- No standalone reviewFDA “does not intend to conduct a scientific review” of a master file without a corresponding NDIN
- Letter of authorizationThe owner authorizes a notifier to reference named sections, sent to FDA with a copy to the notifier
- Notifier files an NDINThe NDIN incorporates the authorized sections by reference and includes the letter
- FDA reviews both togetherFDA checks the authorization, then reviews the referenced data as part of the NDIN
A right of reference “does not include the right to see or copy the Master File.” Conditions of use in the NDIN should match those in the master file, or the data may not apply. Closing a file stops future references; earlier NDINs keep it.
Draft guidanceSubmitting a master file, and any receipt FDA sends for it, is not an FDA review, authorization, endorsement or safety finding. EUTECNIQ would never describe a master file as “FDA-reviewed” or “FDA-accepted.”
Draft guidance Wording riskThere is “no presumption” that master-file contents are trade secret or confidential commercial information; FOIA and 21 CFR Part 20 decide. An NDIN itself becomes public after 90 days, minus protected information. Pre-submission meeting materials can be requested under FOIA.
Draft guidance RegulationExplanation, details and sources
FDA's April 2024 draft describes an NDIN master file as identity, manufacturing and/or safety information that the owner submits “for use in evaluating a potential future NDIN” by the owner or by people it designates. Nothing in the draft is binding until finalized.
Document ownership Proposed contract terms
- Contracts would state who owns study reports, raw data and the dossier; by default, the client that funds the work.
- They would name who may file the NDIN or master file and who may grant rights of reference, for which sections and for how long.
- Trade-secret and confidential commercial information would be marked, with the basis explained, as FDA recommends.
- EUTECNIQ would hold client data under confidentiality agreements and claim no ownership unless agreed in writing.
Commercial model under consideration: a supplier holds its dossier as a master file and authorizes U.S. customers to reference it (see the proposed offering). It relies on draft guidance and on contracts; a right of reference does not replace a compliant notification or guarantee FDA's response. Proposal · relies on draft guidance
Safety data on a conventional ingredient are unlikely to cover its nanoscale version
The final guidance has a section on NDIs that contain nanomaterials or otherwise involve nanotechnology. It matters for nanoemulsions and other engineered delivery forms.
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FDA describes such ingredients by a nanoscale dimension or structure (about 1 to 100 nm) and by properties attributable to their dimensions, which can extend up to 1,000 nm. FDA states that “the non-nanotechnology data alone are unlikely to address safety concerns specific to the nanomaterial- or nanotechnology-modified version.”
The safety narrative should explain how the nanoscale form changes the ingredient's biological and physical behavior. FDA recommends contacting it before submitting such a notification. Whether a given nano-enabled form is itself an NDI is a case-specific legal question for counsel.
Explanation, details and sources
For EUTECNIQ's proposed delivery work, this means characterizing droplet or particle size distribution and stability, and planning nano-specific safety evidence early. See emulsions and colloids and delivery technologies.
Safety dossiers for international ingredient suppliers would be a proposed EUTECNIQ service
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- Assess NDI status questions and flag those that need counsel
- Run a gap analysis against 21 CFR 190.6 and FDA's 2026 guidance
- Build the identity, specification and contaminant package
- Plan, select and oversee external studies
- Draft the safety narrative and safety calculations
- Prepare a master file under the draft mechanism, if the client chooses
- Run GLP toxicology at contract research organizations
- Run human studies under IRB oversight
- Perform analytical testing until EUTECNIQ has its own laboratory
- Give legal opinions on NDI status and labeling
- Any notification filed, acknowledged or objected to
- Any FDA approval; FDA does not approve NDINs
- That a dossier guarantees FDA's response
- Any client, study or master file to date
Explanation, details and sources
An overseas manufacturer can hold well-made material without the U.S. evidence a notifier needs. EUTECNIQ proposes to close that gap with a documented, notifier-ready dossier. See the supplier pathway.
Planning a new dietary ingredient?
Start with the eligibility questions and a gap analysis against FDA's 2026 guidance. EUTECNIQ is in formation and welcomes early conversations with suppliers and brands.