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Food and Drug Administration Presents Toxicology Update

May 1, 2004

The Food and Drug Administration implemented the Food Contact Notification (FCN) program on October 22, 1999 and the final rule regarding this program published in May of 2002 (Federal Register, 67(98):35724). To date, 424 FCNs have been received by the Office of Food Additive Safety (OFAS). Although over four years old now, the program is still in its infancy and is continuing to evolve in all areas based on experience as well as feedback from our stakeholders. Moreover, though we have published several guidance documents and held stakeholder meetings, numerous FCNs are not acceptable in their original form. For example, to date 81 FCNs were either withdrawn or not accepted while, of those effective, 28% required the issuance of a new receipt date due to deficiencies noted during the preliminary review. It is worthwhile noting that this percentage dropped to nearly 21% for calendar year 2003. Though there are several facets of an FCN, this article will address possible solutions to avoid deficiencies regarding the toxicology portion of an FCN and highlight recent developments in the review process.

Although statistics are not being kept on which deficiencies are seen most often, some of the more basic ones can be easily avoided. For instance, a detailed safety narrative (SN) and comprehensive toxicology profile (CTP) should address the safe use of the food contact substance (FCS) as well as any potential impurities. Very often notifiers adequately address the FCS in the SN and CTP. However, what is usually deficient is the safety analysis of the impurities. At the very least, this causes problems in the review process as the toxicologist does not know what to focus on during the preliminary review. At the most, assuming the chemist cannot determine the migrants and/or their dietary concentrations, this leads to non-acceptance. Another frequently noted deficiency is the lack of supporting documentation. Accordingly, in addition to summarizing the findings of studies, notifiers need to support their conclusions with full submissions of the pivotal studies.

Any submission can benefit from communication between FDA and the notifier. As a result we have been advocating the use of prenotification consultations (PNC). Our goal for PNCs is to alert notifiers of concerns that would arise during the initial review of the submission due to deficiencies in data or our previous knowledge of the compound. In addition, potential notifiers are encouraged to submit draft protocols regarding toxicology testing to FDA to ensure that concerns are raised and testing parameters, including animal models, have been designed adequately. This pre-testing protocol review is especially important when dealing with FCSs that are mixtures or when testing will be conducted on oligomeric material. With regard to data reporting, FDA recently released numerous toxicology templates that, though not required for use, outline our method of review documentation. We believe that the use of these templates to supplement full study reports will facilitate the preparation of FCNs by helping notifiers identify and address the questions that FDA reviewers are likely to have.

In an effort to utilize all existing resources in safety review, our office is continuing to use and expand our knowledge of structure activity relationship (SAR) analysis data and tools. These programs and databases, when validated, are extremely useful in determining the need for testing. Our future goals include the continual pairing of these data with biological data submitted on a substance and extracting our own data files. One problem we face is the completeness of our databases. In order to maximize the use of SAR and modeling programs it is critical that FDA have confidence that its data set is as complete as possible. In order to build good modeling programs, one needs a more balanced set of data. Accordingly, we continue to emphasize our ability to serve as a repository for confidential data that can be extracted and useful in modeling programs.

Lastly, though multiple avenues for approval are available for FCSs where all dietary concentrations of ≤ 0.5 µg/kg (ppb), our safety evaluation is equivalent whether submissions are reviewed under Threshold of Regulation (TOR, 21CFR§170.39) or as FCNs. In such cases, impurities are handled in a more qualitative manner based on manufacturing information sufficient to conclude they are present at ≤ 0.5 µg/kg and carcinogenic risk is accessed by comparison of an appropriate Tumor Dose 50 value to that described in the regulation. Though our safety approach is identical, the processes differ in exclusivity and time frame, both of which a notifier should consider when making a submission to FDA.

As the FCN process continues to evolve, we will continue to explore every avenue to communicate with stakeholders to facilitate the submission process. Furthermore, as mentioned, we continue to explore the wealth of existing data to examine and refine our data recommendations.

Michelle L. Twaroski was a Toxicology Group Leader, Division of Food Contact Notifications, Office of Food Additive Safety, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, when she wrote this article.