In the Paperwork Reduction Act section of the proposed rule published on 11 August 2026, FDA puts a number on the part of the US food supply it cannot see: 2,000 independent conclusions of GRAS status, 1,885 of them in human food, held across 1,028 unique firms — plus a further 1,740 substances concluded GRAS by association expert panels, chiefly the Flavor and Extract Manufacturers Association. Set that against the notified universe: as of March 2025, FDA’s Human Foods Program had filed more than 1,200 GRAS notices in total since 1998, and the Center for Veterinary Medicine 75 since 2010.
The un-notified pile is larger than everything FDA has reviewed in twenty-eight years. That is the whole argument for the rule, and it is FDA’s own arithmetic, stated in its own document.
For anyone shipping a fermentation-derived ingredient into the US on a self-affirmed determination, the operative facts are these. Docket FDA-2025-N-3262, RIN 0910-AJ02, 21 CFR Parts 170 and 570, 48 Federal Register pages (51834–51881). Comments close 9 December 2026. There is no grandfathering clause. And the substitute for one — a streamlined submission under a brand-new subpart F — is open for exactly one year after the final rule’s effective date, then closes permanently.
What proposed § 170.205 actually says
The current § 170.205 is titled “Opportunity to submit a GRAS notice.” The proposed rule retitles it “Submission of a GRAS notice” and replaces the operative sentence. Proposed § 170.205(a), verbatim from the regulatory text:
Any person introducing a substance into interstate commerce under the GRAS provision of section 201(s) of the Act must notify FDA of the basis for their conclusion that the substance is GRAS under the conditions of its intended use, except as provided under paragraph (b) of this section.
Two things in that sentence do the work. “Must” replaces “may.” And “introducing a substance into interstate commerce” is present-tense and continuous — FDA states explicitly in the preamble that the requirement “would include substances already in the food supply and those being marketed for food use for the first time.”
Paragraph (b) then lists seven exceptions. None of them is “already on the market.”
| Exception | Proposed cite | What it covers | Does it help a self-affirmed fermentation ingredient? |
|---|---|---|---|
| Existing “no questions” letter | § 170.205(b)(1) | The same substance under the same conditions of intended use | Only if you hold the letter, or the conditions of use match one that exists. FDA warns that a different identity, manufacturing process, food category, use level or specification takes you outside it |
| Listed or affirmed in Parts 182, 184, 186 | § 170.205(b)(2) | Substances FDA has already put into regulation | No. Recombinant proteins are not in those parts |
| Pre-1958 natural biological origin, or GMP-only affirmation | § 170.205(b)(3) | § 170.30(d) and proposed § 170.30(i)(1) substances | No. Precision-fermented proteins have no pre-1958 history of common use |
| Considered through an established FDA process | § 170.205(b)(4) | Voluntary Premarket Consultations and Meetings for new plant varieties; Animal Cell Culture Consultations | Only for cultivated-cell and biotech-plant developers whose public FDA documentation does not identify a need for a GRAS notice. Informal technical assistance does not count |
| Threshold of regulation exemption | § 170.205(b)(5) | Uses cleared under § 170.39 | Not applicable to a bulk protein ingredient |
| Effective food contact notification | § 170.205(b)(6) | Food contact substances, and only for the manufacturer or supplier named in the FCN | Not applicable to a direct ingredient |
| Time-limited streamlined submission | § 170.205(b)(7) | Substances in interstate commerce before the final rule’s effective date, submitted under new § 170.305 and posted on a public FDA list | Yes — this is the one. And it expires |
Note the mechanism in the seventh row: the exception is not triggered by making the submission. It is triggered by FDA posting the submission on a public list, and it evaporates if FDA later “issues a determination that a GRAS notice or food additive petition must be submitted.” The exception is revocable by the agency at any time.
Practical consequence: if your ingredient ships today on a self-affirmed determination, stop describing your position as “GRAS in the US.” Under the proposal it is “eligible for a one-year window that has not opened yet, after which the position is revocable.” To a diligence lawyer those are different things.
The dates, in the order they will happen
FDA does not propose a calendar date for compliance. It proposes a chain of relative dates, each keyed to the previous one. Assembled:
| Step | Proposed timing | Fixed or floating |
|---|---|---|
| Comment period closes | 9 December 2026, 11:59 p.m. ET on regulations.gov | Fixed |
| Final rule published | No date proposed. FDA does not state a target | Floating |
| Final rule effective | 60 days after publication of the final rule | Floating |
| Subpart F streamlined submission window opens | Effective date of the final rule | Floating |
| Subpart F window closes — submissions “will not be accepted beyond” it | One year after the effective date, per proposed § 170.305(c)(3) | Floating |
| §§ 170.205 and 570.205 compliance date | 18 months after the effective date | Floating |
FDA explains the six-month gap between the two deadlines directly: it needs the year of streamlined submissions in hand and posted publicly before the compliance date arrives, “to inform industry whether the exception in proposed §§ 170.205(b)(7) and 570.205(b)(7) applies.” The public list is meant to work as a lookup table — and FDA says explicitly that “any person could rely on the inclusion of the submission on a public list maintained by FDA for the same conditions of use of a substance.” That clause is easy to miss and commercially significant: a streamlined submission creates no exclusivity. Whoever files first for a given substance and set of conditions builds a shield a competitor can stand behind for free.
Practical consequence: the earliest plausible close of the subpart F window is roughly two years and two months out, and only if FDA finalises immediately after the comment period. Plan it as a 2028–2029 event; treat the comment deadline as a 2026 one. And price in that a streamlined submission may do a competitor’s regulatory work.
No grandfathering — and two ways to be disqualified from the substitute
The word does not appear in the proposed regulatory text, and the structure rules it out. Proposed § 170.305(a) offers, for a substance introduced into interstate commerce before the effective date, the option to “submit information regarding the substance and its conditions of use in accordance with this subpart instead of submitting a GRAS notice.” Instead of — not in addition to, and not permanently.
What a streamlined submission must contain is light. Under § 170.305(c)(1): submitter name and address; the name of the substance; the conditions of intended use including foods, use levels and purpose; evidence of presence in interstate commerce before the effective date; and the GRN number of any prior notice FDA ceased to evaluate at your request. FDA is “not proposing to require that submissions under proposed subpart F include underlying data or information pertaining to a conclusion of GRAS status.” Its burden estimate reflects that: 32 hours for a streamlined submission against 180 hours for a full GRAS notice.
But proposed § 170.305(b) closes the door in two cases:
| Disqualifier | Cite | What you must file instead |
|---|---|---|
| The conditions of use are the subject of an insufficient basis letter | § 170.305(b)(1) | A new, full GRAS notice |
| FDA has determined the substance is not GRAS under those conditions of use | § 170.305(b)(2) | FDA says it “would expect to receive a food additive petition”; a GRAS notice is required if you contend the data support a GRAS conclusion |
A cease to evaluate letter is not on that list. Companies that withdrew a notice mid-review and then went to market on self-affirmation can use the streamlined path — but § 170.305(c)(1)(v) forces them to hand FDA the old GRN number, and FDA says why: “safety issues raised during our evaluation of a GRAS notice that we ceased to evaluate may warrant consideration as a higher priority.” That is a disclosure requirement with a triage function attached. We covered one such closure in our piece on GRN 1268.
Practical consequence: pull your own file now. An insufficient basis letter for the conditions of use you are shipping closes the streamlined path entirely — 180 hours plus a live FDA review. A cease to evaluate letter leaves it open, but you will be flagging yourself.
The scale of what FDA expects to receive
FDA’s PRA estimates are the most useful forward-looking numbers in the document, because they show what the agency thinks the rule will do to submission volume.
| Measure | Today | Under the proposed rule | Source |
|---|---|---|---|
| Firms submitting a human food GRAS notice annually | 100 (voluntary) | 194 (100 voluntary + 94 due to rulemaking) | PRIA table 15, via 91 FR 51870 |
| Firms submitting an animal food GRAS notice annually | 12 (voluntary) | 16 (12 + 4) | PRIA table 15 |
| Hours to prepare one GRAS notice | 180 | 180 | PRIA table 14 |
| One-time streamlined submissions, human food | Not applicable | 2,418 (967 respondents × 2.5) | PRIA table 10 |
| One-time streamlined submissions, animal food | Not applicable | 155 (62 respondents × 2.5) | PRIA table 10 |
| Hours per streamlined submission | Not applicable | 32 (10–25% of a GRAS notice, central estimate 17.5%) | PRIA table 10 |
| Total 10-year cost, present value at 3% | Not applicable | $89.6M (range $34.9M–$210.0M), 2024 dollars | 91 FR 51867 |
FDA’s review-timeline changes tell you it expects strain. Proposed § 170.265(a)(1) gives the agency 45 days to decide whether to file a submission at all; § 170.265(b)(1) keeps the 180-day response clock but adds a second optional 90-day extension, so a notice can legitimately run 360 days after filing, plus 45 days before it. Gibson Dunn reads the second extension the same way we do — as an anticipated capacity problem — and notes that FDA “does not estimate the staffing or other resources required to absorb the increase in GRAS notices.”
Two further mechanics matter. Under § 170.265(a)(2) the notification requirement is met only when FDA files your submission, not when you send it; and under amended § 170.265(b)(3), if FDA ceases to evaluate your notice, “we will not consider the notification requirement of § 170.205 to be met.” You cannot discharge the obligation by submitting and then withdrawing. Separately, proposed § 170.220(c) requires an “accurate and complete English translation” of any foreign-language material submitted in or referenced by a notice — relevant given that of FDA’s more than 1,200 filed notices, 617 came from foreign firms and 503 of those from countries where English is not the primary language.
Practical consequence: budget 405 days of FDA clock for a 2027-or-later notice, not 180. If your dossier leans on non-English toxicology or manufacturing records, put translation on the critical path now.
The named ingredient this rule would move: Helaina’s human lactoferrin
We reported on 18 August 2026 that Helaina’s recombinant human lactoferrin, effera, has no FDA GRAS letter. Re-verified independently against the FDA GRAS Notice Inventory as it stood on 18 August 2026:
- A search of the inventory for “Helaina” returns zero records. FDA’s own search notes state that results include terms found in the full record, not only the substance name shown on the results page.
- A search for “lactoferrin” returns 15 records. The three that ever covered the human protein — GRN 162 and GRN 235 (Ventria Bioscience, rice-expressed) and GRN 189 (bovine-milk-purified) — all closed with “At the notifier’s request, FDA ceased to evaluate this notice.”
- The only recombinant lactoferrins with “FDA has no questions” letters are bovine: GRN 1219 (TurtleTree Inc., Komagataella phaffii M020, closed 7 May 2025) and GRN 1284 (All G Co Holdings Pty Limited, K. phaffii Ppas_337, closed 25 March 2026).
AgFunderNews reported in July 2025, from an interview with founder and CEO Laura Katz, that Helaina “expresses it in a genetically engineered strain of yeast and has self-affirmed the ingredient as GRAS.” Nestlé announced a partnership with the company in June 2026, focused on early-life nutrition. Our fuller treatment is here.
The second example is cleaner still, because one company is running both routes at once. Vivici B.V., the Fonterra/dsm-firmenich venture, holds GRN 1200 for β-lactoglobulin produced by K. phaffii strain VIPLA, closed “FDA has no questions” on 28 February 2025. Its precision-fermented lactoferrin, by contrast, “received self-affirmed GRAS status in the US in February 2026 and was launched commercially in the US market,” per DairyReporter. An inventory search for “Vivici” returns exactly one record — GRN 1200. The lactoferrin is not in it.
| Company | Ingredient | US regulatory basis | Verified how |
|---|---|---|---|
| TurtleTree Inc. | Recombinant bovine lactoferrin (K. phaffii M020) | GRN 1219, “FDA has no questions,” 7 May 2025 | FDA GRAS Notice Inventory detail page |
| All G Co Holdings Pty Limited | Recombinant bovine lactoferrin (K. phaffii Ppas_337) | GRN 1284, “FDA has no questions,” 25 March 2026 | FDA GRAS Notice Inventory detail page |
| Vivici B.V. | β-lactoglobulin (K. phaffii VIPLA) | GRN 1200, “FDA has no questions,” 28 February 2025 | FDA GRAS Notice Inventory detail page |
| Vivici B.V. | Precision-fermented lactoferrin | Self-affirmed, February 2026; no GRN in the inventory | DairyReporter, 8 July 2026; inventory search for “Vivici” returns one record only |
| Helaina | Recombinant human lactoferrin (effera) | Self-affirmed; no GRN in the inventory | AgFunderNews, 21 July 2025; inventory search for “Helaina” returns zero records |
Under the proposed rule, the first three rows are done — § 170.205(b)(1) covers them for the conditions of use in their letters, and nothing more. The last two have to act: streamlined submission inside the one-year window, or a full GRAS notice. Neither carries a disqualifier we can see, since an insufficient basis letter or a not-GRAS determination would have to attach to a substance that had been through FDA, and neither appears in the inventory at all.
Practical consequence for a buyer: the diligence question changes from “do they have a GRAS letter?” to “which of the seven exceptions do they sit in, and if it’s (b)(7), have they filed?” For infant formula the GRAS question was never the binding constraint anyway — 21 CFR Part 106 is — and we set that sequencing out in our jurisdiction comparison. The clearances themselves, 2018 to 2026, are catalogued in our database.
The counter-argument, stated properly
Three arguments cut against reading this rule as the end of self-affirmation, and they are not weak.
First, FDA may not have the authority. The agency proposes this under sections 201, 402, 409 and 701 of the FD&C Act — not under a statute that says “notify us.” Its theory is that sections 409(a) and (d), which let the Secretary propose a food additive regulation on his own initiative, imply a power to demand the information needed to do so, citing Southeast Minerals, Inc. v. Harris, 622 F.2d 758, 767 (5th Cir. 1980). Gibson Dunn reports that Acting FDA Commissioner Kyle Diamantas described the rule as closing a decades-old information gap while “respecting the limitation to our authority,” referring to commentary that FDA lacks statutory authority to mandate GRAS reporting. That is an unusual concession to make near your own rulemaking, and it signals litigation risk.
Second, the enforcement consequence is soft. Covington’s read: “FDA does not assert that failure to submit a GRAS notice would render the food adulterated or otherwise in violation of the [FD&C Act].” What the proposal says is that noncompliance “would be a factor in FDA’s prioritization of food substances for post-market review.” That is a real cost — it moves you up a queue — but it is not seizure and it is not an unapproved food additive charge. The statutory position is unchanged: a substance that genuinely is GRAS under the conditions of its intended use is not a food additive, whether or not you told FDA.
Third, FDA is not creating premarket approval, and says so. The preamble is explicit that “a company may continue marketing a purported GRAS substance before submitting a GRAS notice or after submitting a GRAS notice before it is filed by FDA.” The rule changes what you must disclose, not when you may ship.
Fourth: this is a proposal. Section VI invites comment on alternatives that would reduce burden and names one FDA is evidently open to — “allowing streamlined submissions for all substances purported to be GRAS,” not just those already in commerce. Adopt that, and the 180-hour full notice largely goes away and the rule becomes a registry rather than a review gate. FDA has also found a significant economic impact on a substantial number of small entities, estimating impact “more than 3 percent of annual revenue” for them — exactly the finding that generates the most forceful comments.
Practical consequence: file a comment. The alternative in section VI is the single highest-leverage thing an ingredient developer can influence before 9 December 2026, and FDA has asked for data to support it. As of 20 August 2026, the Federal Register page for the document reports 393 comments received — nine days into a 120-day period.
What we could not establish
- When FDA intends to finalise. The document proposes no target date, and every downstream deadline floats off it. Any specific year attached to the compliance date is inference, not FDA’s statement.
- The annual rate of new self-affirmed determinations. FDA’s 2,000 is a stock, not a flow, and the 1,885/2,000 human-food split comes from PRIA table 6, which sits in the docket and which we did not retrieve. The only flow proxy is FDA’s estimate of 98 additional firms submitting annually.
- The provenance of the 1,000-substance figure. FDA’s exact wording is that “some sources estimate that, as of January 2011, there were more than 10,000 additives in use in food, including an estimated 1,000 human food substances for which firms had claimed independent conclusions of GRAS status,” citing References 6 and 7 — and it immediately adds: “Although we cannot verify the accuracy of these estimates.” The figure is fifteen years old and FDA disclaims it. We repeat it only with that caveat.
- Whether the 1,740 association expert-panel substances overlap with the 2,000. FDA presents them in separate PRIA tables and assumes one respondent covers all 1,740. We could not determine from the Federal Register text whether the sets are disjoint. Do not add them.
- HHS’s own framing. The HHS fact sheet returned a 403 to our fetch, so we have not read it. The Diamantas quotation above is reported by Gibson Dunn, not verified by us against a primary source.
- Whether Helaina or Vivici have taken a position on the rule. Nothing in the company materials we fetched mentions it. Helaina’s site does not use the word GRAS on its home, effera or technology pages.
- Whether either self-affirmed lactoferrin would clear a full GRAS review. The three historical human-lactoferrin notices were withdrawn rather than refused, which tells you FDA had questions but not what its answer would have been.
What to watch
Five testable claims, each of which will resolve on the public record.
- The comment count on docket FDA-2025-N-3262 at close on 9 December 2026. 393 as of 20 August. A five-figure count would signal organised opposition and push the final rule further out.
- Whether FDA adopts the section VI alternative and extends streamlined submissions to all purported GRAS substances, not only those already in commerce. That is the difference between a registry and a review gate.
- Whether Helaina files a GRAS notice for effera before the rule is final. With Nestlé attached and infant formula as the destination, a voluntary notice now — while the queue is 100 firms a year rather than 194 — beats a streamlined submission later. Watch the inventory for a “Helaina” record.
- Whether Vivici notifies its lactoferrin. It has already run that route successfully for β-lactoglobulin. If it does not, that is evidence the self-affirmed route stays commercially rational in the interim.
- Whether the authority question reaches court. Watch trade-association comments for a developed argument that sections 409(a) and (d) do not support a mandatory reporting requirement. A well-built record now is a brief later.
The rule does not abolish self-affirmation — FDA is explicit that “firms would still be able to render their own GRAS conclusions.” What it abolishes is the ability to keep one to yourself. For a sector whose entire US market-access position rests on a determination nobody outside the company has ever read, that is the change that matters.