It was once thought that not to notify a Generally Recognized As Safe (GRAS) conclusion implied the factual support of the safety of the GRAS substance was of dubious rigor and avoidance of FDA scrutiny was the goal; and while for several years there were no consequences for a rejection by FDA (i.e. the substance could still be marketed). This all changed with the August 2016 guidelines, which stipulated that a substance once determined by FDA as not having met [the GRAS standard] could not be marketed.[1]
As we shall see, this common misconception of a GRAS “loophole” allegedly allowing unsafe substances shelter, can be turned on its head as there are as many legitimate reasons for not submitting even the most thorough GRAS for review by FDA as there are for going through the GRAS notification process.
However, before we leap into the subject of GRAS Notification, how does GRAS Notification compare to GRAS self-affirmation, self-GRAS and FDA GRAS and GRAS Affirmed, the latter two of which are provided for in the Code of Federal Regulations? Further, if we GRAS an additional use of a GRAS Affirmed or FDA GRAS substance, should we notify?
How did the concept of GRAS come about and what is the category of GRAS Affirmed?
Astoundingly, it took until the early 1950’s for Congress to realize that food ingredients should be proven safe before they were added to food. There was resistance in favor and against by various activist groups, but the most daunting aspect was the huge number of unvetted ingredients; somewhere between 800 and probably >3000 if all flavors and spices were to be included. Even by the standards of the time, a thorough testing regimen for each ingredient would require six to nine months and realistically another two months (320 hours) for review of each ingredient by FDA staffers – hours for 800 to 3000 ingredients would amount to 25,600 – 960,000 hours for review alone – too much for all to be vetted by FDA.
However, a pragmatic Congress determined that because many of the ingredients had been in use for tens or even hundreds of years (such as spices) and as such had already proven their safety, could be allowed for addition to food without testing, if they were determined to be generally recognized as safe (GRAS) by individuals “qualified by training and experience” and if the ingredient was in use in food prior to January 1, 1958. For those ingredients not in use prior to the January 1, 1958 date, qualified individuals, using “scientific procedures” could make a GRAS determination as well. The law was written to ensure that there was no requirement for informing FDA of the determination of a substance to be GRAS. These fairly liberal rules led to a practice called “GRAS self-affirmation” or “self-GRAS”.
Congress added that a substance not GRAS was, by default, a food additive and the decision of its safety and use in food would be a decision made exclusively by FDA; however, this dictate was not absolute. Later, in the regulations, to ensure pragmatism when assessing ingredients, FDA made it clear that “it is impracticable to list all substances that are generally recognized as safe…by way of illustration...food ingredients [such] as salt, pepper, vinegar, baking powder…”. That is, just because a substance is not a list of GRAS substances, does not mean it cannot be GRAS or, on the other hand is, by default, a food additive.
From the start date of the new provision of the law in January of 1958 until the mid-1970’s, manufacturers and their consultants declared many substances to be GRAS and issued letters to that effect. Many manufacturers wrote to FDA and requested an “opinion letter,” in which Agency officials would render an informal opinion on the GRAS status of use of a substance. Although convenient and expedient, these opinion letters were often available only to the requestor. Moreover, these opinion letters were not binding on FDA even at the time they were issued and letters issued before April 9, 1970, were in fact revoked (21 CFR 170.6; 35 FR 5810; April 9, 1970).
Finally, in the mid-1970’s, because of the discovery that cyclamate, a GRAS substance, was carcinogenic, President Nixon ordered a review of GRAS substances. This task was undertaken by the Select Committee on GRAS Substances (SCOGS) formed under a contract with FDA by the Federation of American Societies for Experimental Biology (FASEB). Several hundred substances were vetted by SCOGS and reports were submitted to FDA, whereupon many were accepted as GRAS Affirmed.
This affirmation created two distinct classes of GRAS substances which now appear in the revised Code of Federal Regulations: “Substances Generally Recognized As Safe” [21CFR182 et seq. (human food) and 21CFR582 et seq. (animal food)] and “Direct Food Substances Affirmed as Generally Recognized As Safe” [21CFR184 et seq. and 21CFE186 et seq. (human food) and 21CFR584 et seq. (animal food); that is, the old GRAS list and the new GRAS Affirmed list, the latter being those ingredients vetted by the SCOGS committee and subsequently affirmed as GRAS by FDA. The difference here between 182, 582 and 184, 584; is that the designations ending in “2” are the original GRAS substances which, when re-evaluated in the future, may be placed in the “GRAS Affirmed” or food additive categories or, forbidden for use as unsafe. Although the substances placed in the 182 or 582 categories “temporarily”, none have found a new home since original placement in these categories in 1977.
Many manufacturers who, having avoided the food additive petition route because of the length of time involved, were finding that their customers wanted more assurance than the word of the manufacturer that their substance was GRAS. Because 21CFR184.1 allowed manufacturers to submit their substances for GRAS affirmation review, this became a route for vetting “self-GRAS”, because once something was GRAS Affirmed, FDA took ownership of the safety decision. Eventually, this was realized as being a poor option because FDA became bogged down with inconsistent and inadequate GRASes, to the point where the understaffed system became overloaded and affirmations ground to a halt.
There was still a gap in the system whereby FDA was not still fully informed; that is, although the regulations allowed for GRAS Affirmation (21CFR184.1), the law did not require that FDA be informed of independent conclusions of GRAS. This lack of information transfer led to some embarrassing moments for FDA; for example, when it found an additional substance was being added to food in the absence of FDA’s knowledge. Even though FDA sponsored a food ingredient survey from 1972 through 1987 there was still no guarantee that new substances would be reported in the survey. Even now with GRAS Notification, this gap in the system exists – FDA simply does not know the identity of everything that is added to food. A compliant food product would have the substance listed on the ingredient section of the label, but the FDA does not have the resources to cross-check food labels and lists of compliant substances.
GRAS Notification is born.
Because the GRAS affirmation system ground to a halt, it was abandoned, but a replacement was needed to provide users with some assurance that a substance met the minimum requirements for GRAS, thus the GRAS Notification process came into being in 1997. All GRAS Affirmation petitions were converted to GRAS Notifications.
The Notification process is not an affirmation and as the process now exists, a Notification determines if a GRAS meets the requirements for a GRAS as determined by FDA. Some critics might construe the Notification process as a back-door method for pre-market approval, something that the authors of the statute wanted to avoid, but in reality, the submitter is volunteering for a review of his substance as having met the requirements of GRAS as interpreted by FDA.
Part of the secret sauce for avoiding conflict with the law, is that FDA does not take “ownership” of the GRAS such as it would for a food additive petition or a GRAS affirmation; this sleight of hand allows FDA to declare that it “has no questions” or that “Notice does not provide a basis for a GRAS determination”.
Must all GRAS substances be notified?
In as much as some activists might believe that in order to protect the public, all GRAS determinations should be notified, there are many valid reasons for some manufacturers to withhold notification.
First, however, why would some manufacturers feel compelled to go through the Notification process? In general, these are small manufacturers that want to sell their product to a wide variety of users and some, especially large dominant players in a category such as Coca-Cola® or Oreo® cookies, that purchase ingredients from outside vendors, want assurance that FDA does not have any objection to the use of the GRASed substance – after all, the name of the substance will appear on the product label and a recall could cause the producer to lose sales and shelf-space. A “no questions” letter from FDA should assuage all doubts about questions on the safety and legitimate use of the substance.
If an ingredient is not notified, but an additional use is approved via a GRAS and notification is desired, the notifier will have to take a step back and notify the original substance, not just the new use.
On the other hand, a notification may not be the right move for every manufacturer, such as a vertically integrated company that may not want to tip off their competition to the use of a new ingredient. For example, Frito Lay® is vertically integrated, from developing a proprietary potato variety for contract farmers to grow, to making chips and delivering the finished product to the grocery store in their own trucks. This is a company that traditionally does not buy ingredients from outside vendors but develops ingredients in-house and while the name of the ingredient may appear on the label of the bag of chips, competitors have no idea of the concentration, use, manufacture or specifications of the ingredient, something they might learn from a GRAS Notification.
A parallel situation may be one in which a food product manufacturer has an exclusivity agreement; that is, an ingredient manufacturer has a substance that confers a great advantage to a particular product and the product manufacturer, realizing the advantage conferred by this substance wants exclusivity, purchasing all the substance that can be made and/or having an agreement with the ingredient manufacturer not to sell to anyone else. The advantage to not notifying in these circumstances helps maintain the proprietary nature of this key ingredient.
Conclusion
No GRAS substance requires notification, notification is voluntary. New GRASes modifying a previous GRAS-self affirmation or self-GRAS could be notified, but not just the modification, everything about the previously GRASed substance must be included in the notification.
Should an FDA GRAS (21CFR182) or GRAS-affirmed substance (21CFR184) or even a food additive or a modification of a member of either of these classes be notified? Yes, if the substance is eligible for a GRAS, it can be modified, but again, the entire substance with all its uses must be part of the GRAS and the notification.
Are there circumstances in which a GRAS substance should not be notified? Never, on the basis of a lack of safety data, but withholding a notification on the basis of proprietary interest is allowed.
Final note
President-elect Trump has shown his contempt for guidelines and rule-making that serve to defeat the will of the public by regulatory agencies. In his first term, President Trump issued Executive Order 13891, “Promoting the Rule of Law Through Improved Agency Guidance Documents,” which could have had a devastating effect on the guidance practiced by FDA, totally changing how substances are approved; however, this Order was overturned by President Biden. A second factor, the defeat of Chevron Deference by the Supreme Court could have no less of an effect on procedures at FDA. As a result, we might see a totally different process initiated soon after January 20, 2025.
[1] Rhetorical question: Does this meet the level of a requirement for pre-market approval from which GRAS substances are supposedly exempt?
At Burdock Group, we combine unparalleled expertise with meticulous attention to detail in every GRAS notification we handle. Our team of seasoned professionals brings decades of scientific, regulatory, and industry knowledge to the table, ensuring that each submission meets the highest standards of accuracy and compliance. By staying at the forefront of regulatory developments and tailoring our approach to each client's unique needs, we deliver consistently successful results, earning us the trust and respect of clients and regulators alike.
