GRAS Notification Procedure: Will It Work for Food-Contact Substances?

A rule proposed by the U.S. Food and Drug Administration has significantly altered the procedure for providing information to the agency on substances that are claimed to be "generally recognized as safe" (GRAS) and thus not regulated as food additives under Section 201(s) of the Federal Food, Drug, and Cosmetic Act (FD Act).

Under this new procedure, FDA no longer affirms the GRAS status of an ingredient; rather, a voluntary notification procedure has replaced the cumbersome GRAS affirmation petition process. The notification process allows a company to notify FDA that a particular use of a substance is considered to be GRAS and provide information regarding the basis upon which this conclusion is reached. FDA reviews this information and sends a responsive letter to the notifier indicating whether or not the agency has any questions regarding the notifier's self-determined GRAS position.

The GRAS notice provision was intended to replace the antiquated and resource-intensive GRAS affirmation procedure. Based on industry's experience thus far, the GRAS notification program has had the intended effect of expediting the agency's confirmation of a manufacturer's self-determined GRAS position. Below, we briefly outline the origins of the GRAS provision as it relates to food and food additives, and discuss FDA's programs that have been in place over the years to confirm a manufacturer's self-determined GRAS position.

Although the definition of GRAS applies equally to direct additives and food-contact substances, it is not at all clear that FDA would accept a GRAS notice for a food packaging material. As explained more fully below, a manufacturer in need of a specific clearance from FDA for a food-contact substance would likely find the filing of a food-contact notification to be more expeditious and straightforward.

History of GRAS Determinations by FDA

The FD Act requires that substances meeting the definition of a "food additive" be the subject of a food additive regulation or covered for the intended use in an effective food-contact notification. However, the Act specifically exempts from the definition of a "food additive" substances that are considered GRAS.

Shortly after passage of the food additives amendment, FDA clarified the regulatory status of a multitude of food substances that were used in food prior to 1958, and amended its regulations to include a list of food substances that, when used in accordance with current good manufacturing practice, are GRAS. This list was incorporated into the agency's regulations as 21 C.F.R. § 121.101(d) (now parts 182 and 582).

As part of the rulemaking that created this list, FDA acknowledged that it would be impracticable to list all substances that are GRAS for their intended use. (See 21 C.F.R. § 182.1(a).) In that regard, FDA added other categories of substances (e.g., spices, seasonings, and flavorings) to this "GRAS list" in subsequent rulemakings.

Many substances that were considered GRAS by the food industry were not included in the FDA's GRAS list. Although agency review and approval was not legally required for GRAS substances, as a practical matter, manufacturers occasionally needed FDA's concurrence that the self-determined GRAS position was justified before customers would buy their products. In these cases, manufacturers frequently wrote to FDA and requested an "opinion letter," in which agency officials would render an informal opinion on the GRAS status for the use of a substance. Although convenient and expedient, these opinion letters were often available only to the requestor. Moreover, opinion letters were not binding on the agency and were in fact formally revoked in 1970.

After the agency stopped issuing GRAS opinion letters, FDA conducted a rulemaking to provide a voluntary mechanism whereby an individual could petition FDA to review and affirm the GRAS status of substances. This process, known as GRAS affirmation, involved the administrative rulemaking process, and required FDA to:

1. publish a notice of filing in the Federal Register;
2. request comments on the petitioned request;
3. conduct a comprehensive review of the petition's data and information (as well as deal with the comments received) to determine whether the evidence established that the petitioned use of the substance was GRAS; and
4. publish a final rule in the Federal Register explaining why the use was GRAS (as compared to just being safe).

Also, once the GRAS petition was "accepted for filing," petitioners were able to market their products, so there was little incentive for the agency to complete the process. In practice, the significant delays associated with the GRAS affirmation process deterred many from petitioning the agency to affirm independent GRAS determinations.

On April 17, 1997, FDA published a proposed rule creating a new program to deal with the agency's review of manufacturers' self-determined GRAS positions. The resulting GRAS Notification System greatly simplified FDA's process. Under the new procedure, the manufacturer simply notifies FDA of its self-determined position that a particular use of a substance is GRAS. The submitted notice contains specific information about the GRAS determination, including a description of the notified substance, the applicable conditions of use, and a detailed discussion regarding the basis for the GRAS determination (i.e., through scientific procedures or through experience based on common use in food).

Although the proposal has not yet been made final, FDA began accepting GRAS notices in 1998. The proposed rule requires FDA to respond to the notifier in writing, advising whether or not the agency has identified any problems with the notification. Although the proposed rule requires FDA to review the notification within 90 days, FDA currently does not consider the 90-day timeframe to be binding because the rule has not been made final.

In practice, FDA's responses fall into one of the following categories:

1. The agency does not question the basis for the notifier's GRAS determination;
2. The agency concludes that the notice does not provide a sufficient basis for a GRAS determination (e.g., because the notice does not include appropriate data and information or because the available data and information raise questions about the safety of the notified substance); or
3. The response letter states that the agency has, at the notifier's request, ceased to evaluate the GRAS notice.

Although FDA does not state affirmatively that the agency agrees with the notifier's GRAS determination, its decision not to disagree is tantamount to its acquiescence on this point. In practice, response letters issued by the agency are all that a supplier has available to market its product to food companies.

To date, FDA has received 118 GRAS notices. Of these, FDA has had "no questions" on 76; 15 did not provide a sufficient basis for a GRAS determination (three of which were resubmitted as new GRAS notices); 16 have been withdrawn by the notifier (six of which were resubmitted); and 11 GRAS notices are still pending before the agency.

Does Notification Program Apply to Food-Contact Substances?

The GRAS notification proposal predates the Food Contact Notification (FCN) system. It is not clear whether FDA would accept a GRAS notice for a food-contact substance, although the proposed GRAS notice procedure does not prohibit such action.[1] It is quite possible that FDA would administratively convert a GRAS notice for a food-contact substance to an FCN and conduct the review under that system.

Unlike the FCN procedure that has a statutorily defined review period of 120 days, FDA is not currently bound by a specific review period for GRAS notices. Thus, the agency can take as much time as it needs to review a GRAS notification to make the determination as to whether the agency questions the notifier's GRAS position. (In fact, one GRAS Notice (GRN000094) has been pending at the agency for nearly a year.)

Also, to allow an FCN to become effective, FDA need only conclude that the proposed use of a substance is safe to a reasonable certainty—not that experts in the scientific community agree that the proposed use is generally recognized as safe. Thus, data provided in a food-contact notification need not be published and there does not need to be a consensus in the scientific community regarding the asserted safety conclusion. Consequently, manufacturers of food-contact substances are likely to be better served by submitting data to FDA in an FCN rather than under the proposed GRAS notification procedure.

FOOTNOTES

[1] It is interesting to note that GRAS Notice No. 62 (GRN000062) is related to food packaging. The subject of the notice is chlorine dioxide generated from "particles (less than 30 micrometers) composed of sodium polyphosphate, magnesium sulfate, sodium silicate and sodium chlorite" that are incorporated into low density polyethylene (LDPE) food-packaging films, at levels not exceeding 17.5 micrograms chlorite/in2 of finished package film. Based on the information in the GRAS notice, as well as other information available to the agency, FDA did not question the notifier's conclusion that the intended use of the substance was GRAS.