November 10, 1999

(202) 434-4110

heckman@khlaw.com

The Society of the Plastics Industry, Inc.

Food, Drug, and Cosmetic Packaging Materials Committee

Dear Ladies and Gentlemen:

The purpose of this letter is to provide you with the latest information available from the Food and Drug Administration (FDA) about the working of the new Premarket Notification (PMN) program for food contact substances. In a way you might consider this a preview of the presentation we expect FDA staff to give at the Semi-annual Meeting of the SPI Food, Drug and Cosmetics Packaging Materials Committee in Charleston on December 2^nd. We do apologize for the length of this report but believe that many of you will find the material of direct interest and value. The report was prepared with a great deal of help from Holly Foley of our office since we asked her to attend the meeting on which we are reporting. Incidentally, you may also notice that it would appear the comments we have been making to FDA on the Food Contact Notification program for the past couple of years have had considerable impact on the directions it is taking.

On November 8, 1999, FDA representatives provided details on how the Agency envisions administering the program, and clarification of several issues outstanding from the draft guidance documents issued earlier this year, during the "Future-Pak 99" Sixteenth International Schroeder Conference on Packaging Innovations in Houston, Texas. Speaking for FDA were Drs. Mitchell Cheeseman, Allan Bailey, and Francis Lin, as well as Consumer Safety Officer Vivian Gilliam. These details are discussed below.

A. Revised Draft Guidelines

First, with regard to the draft chemistry and toxicology guidelines, the Agency has now updated these guidelines and indicated that they will be publicly available within the next few days. We have copies of the current versions of these documents on hand and will be happy to

provide copies upon request. FDA intends to announce the availability of these documents in the Federal Register this week, and will once again seek comments on the guidance documents.

As for the administrative guidance, an updated version of this document is not yet available. We understand it will be made public within the next few weeks, simultaneous with the Agency publishing a Notice of Proposed Rulemaking in connection with the PMN system.

In large part, the revised chemistry and toxicology guidelines remain similar to the documents issued in March of this year. The chemistry guidelines have been revised to contain some useful additional information on estimating exposure to food-contact substances. Notable additions in this regard include updated consumption factors and a discussion of alternatives to migration testing (including worst-case calculations assuming 100% migration as well as use of accepted diffusion modeling).

The most significant change to the toxicology guidelines is in the limit on exposure in relation to the toxicity data. As you will recall, the previous draft guidance suggested that food-contact notification would not be the appropriate route to establishing suitable FDA status for a substance in cases where the acceptable daily intake (ADI) exceeds the cumulative estimated dietary intake (CEDI) by a factor of less than five. In our comments on the draft guidelines, we argued forcefully against this incorporation of an additional five-fold safety factor in an already conservative safety assessment process. The Agency appears to have adopted our reasoning since this notion has been dropped as a limiting factor for PMNs. However, the toxicology guidelines do retain the advice that a pre-submission conference may be warranted in cases where the ratio of the ADI to the cumulative EDI is less than five to make sure there are no differences in data interpretation that could result in the EDI exceeding the acceptable intake.

The other major points of the draft toxicology guidelines remain intact. Thus, as expected, the requirement for genotoxicity testing in place of acute oral toxicity testing remains in place. Specifically, for substances with a cumulative intake above 0.5 part per billion (ppb) but not greater than 50 ppb, the Agency is recommending a bacterial mutagenicity assay plus an in vitro cytogenetic damage or mouse lymphoma assay; where the intake exceeds 50 ppb, a third study in the form of an in vivo chromosomal aberration study is recommended. With respect to demonstrating the safety of polymers, while the FDA toxicologists have not dispensed entirely with the notion of conducting genotoxicity testing on the oligomeric fraction, there clearly will be some flexibility in determining when such testing will be required. Rather than issuing any sort of blanket exception for polymers (such as that genotoxicity testing on the oligomers will not be required if the monomers themselves present no toxicity concern), it appears FDA will be open to reasoned arguments on a case-by-case basis.

In addition to the revised draft chemistry and toxicology guidance documents, FDA has now issued a detailed form that may be used to report the major points of information needed to support a food-contact substance PMN. This document, identified as FDA Form 3480, bears a striking resemblance to the reporting form we developed last year and urged the Agency to consider for this purpose. Use of the form is intended to help ensure consistency of the format and information submitted in PMNs and to facilitate FDA's review. It is expected that all supporting data and study reports that would previously have been submitted in a food additive petition will be submitted as appendices to the PMN form. (The FDA staff indicated that the form does not yet have formal approval and, thus, its use is not yet required; however, the form may be used once the Agency begins to accept submission of food-contact notifications.)

We also can report that the Agency has made significant progress towards putting together a database that will list the current estimated dietary levels of all regulated food-contact substances. This, of course, will be critically important to ensure that notifications for additional uses of existing substances can be readily prepared since the notifier will be required to address cumulative intake from all current plus proposed additional uses of the substance. (At this point, we understand the Agency has determined the current EDIs for 1400 out of a total of 4500 substances.) There also are plans to establish databases that will provide the current ADIs for food- contact substances and, eventually, potency factors for carcinogenic constituents.

One further point on data requirements for PMNs: While a final decision is still being considered as to the need for an environmental impact review, the Agency's expectation at present is that the PMN program will likely be subject to the same environmental analysis requirements — and, thus, eligible for the same range of categorical exclusions from the need for the same — that are currently in place for food additive petitions. On the other hand, the FDA staff do not expect to object to a food-contact PMN on purely environmental grounds. Since a number of petitions have been held up at FDA for reasons that do not go beyond environmental impact issues, it remains to be seen how this aspect of the PMN will be handled, but at least there are clear indications that environmental concerns such as possible impacts on recycling will not be viewed by FDA as constituting grounds for objection.

B. Scope of PMN Program

We also have now obtained some additional information on the expected scope of the PMN program. First, we are pleased to report in particular that, in addition to classical "indirect" food additives, the program is expected to extend to those additives classified as "secondary" direct food additives that are not intended to have a technical effect on food. Examples of such materials include boiler water additives and ion exchange resins. Second, while a final decision has not yet been made on this point, it appears likely that the Agency will accept submission of PMNs for formulations in addition to those intended to cover single compounds.

We also now have some additional information on the Agency's current thinking with regard to those situations in which the use of a food-contact substance should be cleared through the food additive petition process rather than by submission of a PMN. As you will recall, the previous indication from the Agency was that the petition process is more suited to those cases in which the cumulative dietary intake exceeds 1 part per million (ppm). This position has been eased somewhat by the realization that there are cases in which the safety determination is fairly straightforward despite the relatively high intake level.

Some examples of cases in which submission of a premarket notification may be appropriate for substances with cumulative intake above 1 ppm include the following: (1) substances for which FDA has previously determined an ADI of greater than 1 ppm, provided this ADI has not been revised downward due to new concerns being raised; (2) substances that are closely related to compounds for which a large toxicological database is available, where the existing data indicate that the unregulated substance is of equal or lower toxicity; and (3) substances that are not absorbed to a significant extent or that are converted upon consumption solely to substances that are clearly of no toxicological concern.

As to substances for which a carcinogenicity bioassay has been conducted but has not been reviewed previously by FDA, a premarket notification may be submitted if the results of such a study are clearly negative (that is, if the results provide no evidence of carcinogenicity). If the study did not yield clearly negative results, it might be necessary to submit a food additive petition (or confer about the matter with the FDA staff prior to filing a notification, e.g., to try to settle on a suitable timetable for filing an acceptable notification) for such a substance since the Agency's evaluation of such data is necessarily complex.

C. Administrative Process

While the updated administrative guidance document is not yet available, we have been able to obtain some additional details on how the premarket notification process is expected to be handled by FDA. The Agency is creating a new position, known as the Notification Control Assistant (NCA), to whom notifications will be submitted. The NCA will be responsible for assigning PMNs to the Consumer Safety Officers and for keeping the website updated as to effective notifications.

For purposes of starting the 120-day review clock, the first day will be the day of receipt of the notification by FDA; if there is any question about this, the NCA may be contacted to confirm the receipt date. It is expected that no initial letter acknowledging FDA's receipt of a notification will be provided. Rather, the Agency expects to determine within 30 to 45 days of receipt whether the PMN is likely to prove ultimately sufficient. A letter then will be sent to the notifier confirming the date of receipt and the date upon which the notification will become effective; this letter also will confirm the scope of the notification, i.e., the identity and intended use of the substance and the notifying party. If any "deficiencies" in the notification are found after this letter is sent out, the notifier will be contacted immediately (by phone or e-mail) so that whatever additional information is needed may be provided. Because the 120-day review clock will not stop at this point, the notifier is expected to be given only a very short time to respond to this request; the time allotted is expected to be no more than 1 to 2 weeks to ensure FDA has adequate time to review the notifier's response.

It is important to note that if such a "deficiency" in a notification is significant — generally, if any new data must be generated — so that it is not possible to provide the necessary additional information to ensure safety within the time allowed by the Agency, the notifier can withdraw the PMN and resubmit it when the new information is available. (This, of course, will re-start the 120-day clock.) If the notification is withdrawn before FDA formally objects, neither the data submitted in the notification nor FDA's basis for objecting to it will be made public. However, should the notifier not withdraw the submission and FDA issues its formal objection due to the unaddressed safety concerns, the data in the notification and FDA's reasons for the objection will be publicly available. (Incidentally, in any case FDA will not make any data submitted in a notification public during the 120-day review time.)

Another important issue, of course, is how the Agency intends to acknowledge that a notification has become effective following the successful completion of its review of a PMN and the termination of the 120-day review period. It appears that this point is still being considered internally, but the current FDA thinking is that it will issue a final letter to the notifier. The letter is likely to state words to the effect that, "Your food contact notification number ____ is effective as of [date]." As we have been reporting, a list of effective PMNs is expected to be made available on the Agency's website; to ensure the usefulness of this listing, FDA expects it to be updated on a weekly basis.

We are quite certain that this report will leave some of you with important questions. It will no doubt be in order to raise such questions at the December 1^st and 2^nd sessions. In the meantime, of course, please feel free to contact us with any questions.

Sincerely yours,

Jerome H. Heckman

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