What is the Best Approach to Obtain FDA Clearance for Food Contact Substances?

May 1, 2004

Since the Food Contact Notification program was fully implemented in January 2000, the FCN has become the route of choice for obtaining official FDA clearance for substances used in contact with food. The advantages over the old Food Additive Petition process, in terms of the time from filing of the submission to final clearance, are obvious. As a result, FDA's inventory of effective notifications now lists close to 400 successfully filed notifications. By contrast, only a handful of petitions for food-contact substances have been granted in the same period, and FDA's inventory of threshold of regulation exemptions lists no new exemptions since 2000.

However, it is important to know that both the threshold of regulation and food additive petition remain routes for obtaining FDA clearance for food-contact substances. Indeed, in certain situations, it may be most appropriate – or even necessary – to clear a new use of a food-contact substance through the submission of either a TOR request or an FAP. Following are some suggestions for when to file each of the three types of submissions for food-contact substances.

Threshold of Regulation Request

As discussed elsewhere in this month's focus articles, the threshold of regulation remains a viable approach for obtaining FDA clearance for a food-contact substance. You should consider filing a TOR request when the calculated concentration of your food-contact substance in the diet resulting from your intended use does not exceed 0.5 parts per billion, the threshold that applies for most food-contact substances. Remember, the threshold applies to the dietary concentration, not the migration level. The dietary concentration is calculated by applying appropriate reduction factors (i.e., food-type distribution and consumption factors) to the measured or calculated worst-case migration values. Thus, in many instances, the threshold of regulation can be met even if the migration level is much higher than 0.5 ppb.

In limited cases, a TOR request can be submitted even if the exposure level exceeds 0.5 ppb. If the substance in question is already cleared by FDA as a direct food additive (i.e., it's listed in Part 172 of the food additive regulations), and the dietary intake that results from the substance's use in food packaging is no more than 1% of the total allowable intake, then the substance may qualify for a TOR exemption.

In general, the data requirements are somewhat less burdensome for a TOR request than for an FCN, consistent with the concept that substances that meet the threshold criteria pose little if any threat to health. Most significantly, there is no need to generate toxicity data on a substance that meets the threshold criteria. In addition, much of the detailed chemistry information required for an FCN need not be provided in a TOR submission. Moreover, although there is no strict limit on FDA's review time, it may be possible to obtain a determination from FDA on a TOR exemption in less time than the 120 days FDA has to review an FCN.

Two things to consider before filing a TOR request: First, because of the less extensive review, there can be no reason to suspect that the food-contact substance may be carcinogenic, and any substance that contains a relatively potent carcinogen as an impurity should not be the subject of a TOR request. (This would apply, for example, to a polymer produced from certain carcinogenic monomers.) Also, a TOR exemption does not confer any proprietary rights on the submitter; thus, once the TOR is granted, anyone can manufacture or use the cleared substance under the conditions of the TOR.

Food Contact Notification

If the criteria for a threshold of regulation exemption cannot be met – generally, because the dietary exposure to the substance is too high – the preferred alternative will be to submit a food contact notification. An FCN may be submitted for any substance that is properly classified as a "food-contact substance" (the main criterion being that the substance does not have a technical effect in food) except for some substances for which the calculated dietary exposure exceeds 1 part per million.

Generally speaking, for substances whose dietary intake exceeds 0.5 ppb, some amount of toxicity data will be needed to demonstrate the safety of this level of exposure. For low dietary intakes – up to 50 ppb in the diet – this means submitting reports of in vitro genotoxicity assays such as an Ames test and mouse lymphoma or chromosome aberration study. These can be studies performed by the notifier or obtained from the public literature. Of course, if these studies do not provide uniformly negative results, this will complicate the review process. In such a case, it's a good idea to include in the FCN a thorough analysis of the data and a rationale for your conclusions regarding the safety of the substance for the intended use.

If the dietary exposure is higher than 50 ppb, it may be necessary to submit more extensive toxicity data, including a subchronic oral study in rats and, possibly, the same study in dogs. In this case, it's important that these studies demonstrate a clear no-observed adverse effect level (NOAEL) and that this NOAEL exceeds the calculated dietary exposure by a safe margin. Generally speaking, the minimum safe margin of exposure determined from subchronic studies should be 1000-fold.

In contrast to the traditional petition process, FDA has only 120 days from the filing of an FCN to complete its review of the notification. In the absence of an explicit FDA objection by day 120, the notification automatically becomes effective. Moreover, the notification only clears the food-contact substance of the manufacturer/supplier listed in the FCN. Note, however, that this does not prevent others from submitting their own notifications to clear competitive products.

Food Additive Petition

In some cases, it may be necessary to clear a food-contact substance by the submission of a food additive petition. Usually, this will only be an issue for substances with very high estimated dietary exposures. Specifically, if the substance is estimated to enter the diet at a level in the parts-per-million range, and FDA has not already established an allowable dietary intake high enough to encompass the new use, the Agency could prefer that the substance be cleared through the petition route.

The rationale here is that for a dietary intake in excess of 1 ppm, FDA recommends much more extensive toxicological data to ensure safety. This can include, e.g., two-year studies in rodents for chronic toxicity and carcinogenicity, multigeneration reproductive toxicity studies also in rodents, and/or a one-year toxicity study in dogs. Such extensive testing can require a more time-consuming review by FDA than the types of data ordinarily reviewed in an FCN, which can be difficult to complete in a 120-day review period. In some cases, even if a high estimated dietary exposure is not entailed, if extensive toxicological data is available on the substance, and it has never been reviewed by FDA, the Agency may still request submission of a petition to allow for the time necessary to complete a thorough review.

Thus, if the studies have not previously been reviewed by FDA, it may not be feasible to submit them as part of an FCN. This is most likely to be a problem if there is any doubt as to whether the studies support the safety of the substance at the estimated dietary exposure level – say, if the NOAEL is questionable or there is some evidence of a carcinogenic effect.

Because the limits on FDA's review time for petitions are much more flexible than the limits for FCN reviews, it is always wise to consider whether there is any basis on which to file an FCN rather than a petition, even when the dietary exposure will be high. If the substance is already cleared for some uses, it's a good idea to obtain information from FDA about the established acceptable dietary intake level. It's possible that the Agency has already reviewed adequate data to justify your new use of the substance. Another possibility is to demonstrate that your substance, upon being ingested, is metabolized to substances for which high dietary exposures have been shown to be safe. If there is no alternative to submitting extensive new toxicology data to support your use of the substance, FDA may still allow the substance to be cleared through submission of an FCN if you submit the new toxicity data prior to filing the FCN to allow the Agency additional time to review the studies.

In sum, there are three viable routes for obtaining FDA sanction for new uses of food-contact substances. While the FCN will be the preferred route in most cases, it is certainly worth considering whether you have the option of filing a TOR request. Moreover, even if the dietary exposure to your substance is calculated to be greater than 1 ppm, it still may be possible to use the FCN approach. While a food additive petition is certainly an option in such cases, you almost always will obtain your clearance more quickly by means of the notification procedure.

Finally, this entire discussion presupposes that you already have determined that explicit FDA clearance for your substance is needed. There remain a number of ways in which to establish that a food-contact substance does not have to be cleared by FDA prior to its use in contact with food. If you can make such a determination for your substance, there is no need to file any submission with FDA unless your customers demand the added assurance of an FDA sanction.