TECHNICAL ADVISOR'S REPORT TO THE FOOD, DRUG, AND COSMETIC PACKAGING MATERIALS COMMITTEE

June 9, 2000

Lester Borodinsky, Ph.D.

Ladies and Gentlemen:

It is a great pleasure for me to be with you once again in the role of the Committee's Technical Advisor. This report will describe one of the current technical issues we are dealing with in establishing satisfactory regulatory positions for plastic food-contact materials. Specifically, this report will provide observations and comments on technical issues that have arisen with the Food and Drug Administration's (FDA) implementation of the Agency's Food-Contact Notification (FCN) program.

Food-Contact Notifications

As we have been reporting to you, FDA officially set its FCN program into motion on January 18, 2000. As you will recall, FDA issued draft guidance documents regarding the chemistry and toxicology needs for Notifications entitled "Preparation of Premarket Notifications for Food Contact Substances: Chemistry Recommendations" and "Preparation of Premarket Notifications for Food Contact Substances: Toxicology Recommendations," respectively, in September 1999. However, FDA has not yet revised the administrative procedures guideline it issued in March 1999, nor has it promulgated pertinent amendments to the regulations to implement the program. Despite the absence of such implementing regulations and final versions of the guidance documents, the program is "up and running." The FCNs that FDA has been evaluating to date primarily have been pending food additive petitions that have been "converted" to FCNs. Although the official guidance documents and regulations are not formally in place, the procedures and parameters of the system are beginning to take shape on a case-by-case basis. In fact, several notifications already have become effective; these effective notifications are tabulated on the Agency's website at the following address: http://vm.cfsan.fda.gov/~dms/opa-fcn.html. The tabulation includes the following information: (a) the FCN Number; (b) the identity of the food-contact substance (FCS); (c) the Notifier and manufacturer of the FCS; (d) intended use; (e) specifications/limitations; and (f) effective date.

The FCN Number is a means of identifying the notification per se, and is merely a running, consecutively issued number. Thus, the first FCN that became effective is FCN Number 1, etc. However, the consecutive order of the FCN Numbers does not correlate perfectly with the associated effective dates, e.g., the effective date for FCN Number 5 is earlier than the effective date for FCN Number 4. This is likely due to the manner in which food additive petitions were converted to FCNs. We anticipate that the order of the FCN Numbers will track more closely with the effective dates as the system matures. In addition, while the tabulation includes up to FCN Number 19 (as of the writing of this report), several FCN Numbers currently are absent - FCN Numbers 11, 15, 16, and 18.

The identifications all are explicit chemical names of the cleared material; in one instance, a tradename also is included. The use so far of chemical names appears to be a continuance of way in which the generic food additives (including threshold of regulation clearances) are identified. As the FCNs are proprietary clearances, we have been interested in learning of FDA's position on the issue of listing products by tradename only for effective notifications; as of the moment, FDA has not indicated that it would list materials only by tradenames.

The intended use and specifications/limitations are very much like the corresponding items of information in food additive regulations.

FCN Technical Issues - Chemistry

While not explicitly represented in this way, the draft "Chemistry Recommendations" document is, in essence, an updating of the Agency's "Recommendations for Chemistry Data for Indirect Food Additive Petitions" (June 1995), the most recent version of FDA's Chemistry guidelines. The new guidelines are most recent version of a series of such guidelines dating back to a guideline document entitled "FDA Guidelines for Chemistry and Technology Requirements of Food Additive Petitions," issued in August, 1966. These Guidelines were divided into three sections: (I) "Protocol for Direct Additives," (II) "Protocol for Indirect Additives," and (III) "Protocol for "Radiation and Radiation Sources." Since that time the Chemistry guidelines have been reissued in the ensuing time in March 1976 as "FDA Guidelines for Chemistry and Technology Requirements of Indirect Food Additive Petitions," in September 1988 as "Recommendations for Chemistry Data for Indirect Food Additive Petitions," and in June 1995, again titled Agency's "Recommendations for Chemistry Data for Indirect Food additive Petitions." With each revision, FDA has made it more clear as to the specific recommended information that is needed to evaluate a clearance request and, in most instances, the reasons behind the recommendations.

While it has always been important to pay close attention to such guidelines in preparing to assemble a FCN, this is especially critical in an environment in which FDA will apparently hire new reviewers to handle the increased work-load that the Agency anticipates with the implementation of the FCN program. It is a common trait of new reviewers to be more conservative and more rigid in their interpretation of the guidelines than are the "veteran" reviewers. While FDA has not yet hired new reviewers specifically for the FCN program, there are, nonetheless, perennially new staff reviewers at FDA, and such new staff reviewers often request information that has heretofore not been deemed necessary for the evaluation of chemistry data. Such is the current situation; the following is an example of such an interpretation we have experienced coincidental to the implementation of the FCN system.

As you are aware, the chemistry information needed in an FCN includes migration data. FDA's default assumption for food packaging is that 10 grams of food contacts each square inch of the packages surface area. To coincide with this use parameter, the "Chemistry Recommendations" notes that migration testing using a solvent volume-to-surface area ratio of 10 mL/in2 is acceptable. Other ratios may be acceptable, provided the migration level observed does not reach the solubility limit; the guidelines indicate that precipitation or cloudiness of the extract solution is an indication that the limit has been reached. In fact, it has been a long standing practice in providing migration data in food additive petitions to use a slightly lower ratio so as to effectively improve the analytical sensitivity or to minimize the amount of solvent that must be evaporated (where such a procedure is needed). Our recent experience is that one or more of the newer chemistry reviewers has been raising a question about the use of ratios slightly lower than 10 mL/in2 and, in fact, has suggested that solubility studies might be necessary. It is clear to me that such information is generally not necessary.

Specifically, in instances in which the analyses are performed in the food simulating solvent, the calibration phase of the study will need to bracket the detected levels and, in this way, demonstrate that greater levels than those observed in the study are soluble. In addition, the validation portion of the study is usually performed by spiking-and-recovery studies which are performed at several spiking levels, one of which is a multiple of the maximum detected level (two times the detected level is recommended). Thus, provided that such data are included in the filing, additional information should not be necessary for FDA to complete its review.

Another unusual comment we have received recently is with regard to testing of uncoated or pigment-coated paper and paperboard. Specifically, we are aware of a recent suggestion from FDA that components of uncoated or pigment-coated paper and paperboard may be restricted to room temperature use only when testing is performed in accordance with the recommended times and temperatures set forth in the guideline documents. FDA's recommended testing for uncoated or pigment-coated paper calls for the used of 10% ethanol and either 50% ethanol or a food oil at 40 C for 24 hours. This combination of time and temperature is quite different than the times and temperatures recommended for virtually all other food-contact applications - in most instances, the recommended testing is 40 C for 10 days (or even 30 days, in some instances), often preceded by a higher temperature phase of relatively short duration (e.g., 66 C or 121 C for 2 hours). In the predominant cases, the latter type of testing is performed using the two combined phases to reflect the actual use of the packaged food - the phase at 40 C for 10 days (or 30 days) is intended to serve as an accelerated simulation of long term room temperature shelf storage, while the initial elevated temperature (66 C, 121 C, etc.) Is designed to simulate thermal processing of the packaged food. The principal reason for the different testing scheme for uncoated or pigment-coated paper is that such unprotected paper cannot generally survive the rigors of prolonged contact or elevated temperature contact with actual aqueous or fatty food. In most instances in which a paper-containing package is used for long term shelf storage or at elevated temperatures, there is a polymeric barrier coating. In such instances, migration of components of the barrier coatings are properly performed by the more conventional migration conditions (i.e., 40 C for 10 days preceded by a higher temperature phase, where necessary).

As can be seen from the foregoing discussion, there is a distinction between uncoated or pigment-coated paper and polymer-coated (barrier) paper because of the actual anticipated conditions under which the food-contact materials will be used. In the case of uncoated or pigment-coated paper, these are used to hold primarily dry food; in these cases, exposure of the test samples to the food simulating liquids at 40 C for 24 hours is undoubtedly an exaggeration, as the test sample (unprotected paper) is a permeable material that usually would be saturated by the solvents and not truly represent the environment of the packaged food in real use. While we recognized that there may be instances in which the temperature may exceed 40 C, these uses will clearly constitute a minute fraction of the food-contact uses of uncoated or pigment-coated paper, especially when one considers that FDA's default consumption factor for uncoated and pigment-coated paper and paperboard is 10%, which is quite a large fraction of an individual's packaged food. Therefore, for the above reasons, it appears to me that it should not be necessary to impose a restriction on the use of uncoated or pigment-coated paper manufactured employing an additive that has been tested in accordance with FDA's "Chemistry Recommendations."

One of the information requirements not previously required by FDA for food additive petitions that has been "institutionalized" with the implementation of the FCN program is the need for cumulative estimated dietary intake (CEDI) values. In the review of food additive petitions, the petitioner is required to provide information from which to calculate an estimated dietary intake (EDI) for the proposed use of the substance. In conjunction with the EDI thus calculated, FDA's reviewers of the petition often also considered all prior clearances of the particular substance (if any) along with the EDIs for the prior cleared uses - the total of the EDI for the proposed use and the EDIs for the existing uses is referred to as the CEDI. Under the FCN program, the guidance documents indicate that the applicant needs to not only calculate the EDI fro the notified use but also include the CEDI. The change in this instance is that the Notifier, not FDA, is responsible for the CEDI. This is an extremely difficult set of circumstances, as it is only FDA that is generally in a position to determine the EDI for the currently-cleared applications. It is our understanding, however, that FDA will provide such information upon request and that, eventually, such EDI information will be included on FDA's web-page. In the meantime, however, this additional data requirement will make it more challenging to prepare a Notification in instances where there is one or more existing clearance for the substance of interest.

FCN Technical Issues - Toxicology

Turning to toxicology-related matters, as you know from our previous reports, the "Toxicology Recommendations" is FDA the first formal set of toxicology guidelines for food-contact substances. With the issuance of the "Toxicology Recommendations," FDA has for the first time formally indicated that genotoxic testing is needed for substances with an exposure level above 0.5 parts per billion (ppb) but lower than 50 ppb; the purpose of these screening tests is to assess the potential for the substance to be carcinogenic. The specific tests recommended are (1) a test for gene mutations in bacteria (i.e., the Ames test) and (2) an in vitro test with cytogenetic evaluation of chromosomal damage using mammalian cells or an in vitro mouse lymphoma tk+/- assay. For dietary exposures greater than 50 ppb but lower than 1 part per million (ppm), in addition to the two genetic toxicity tests noted above, FDA indicates that the substance should be evaluated by another genetic toxicity test - an in vivo test with cytogenetic evaluation of chromosomal damage using using rodent hematopoietic cells - as well as two subchronic (90-day) oral toxicity tests, one in a rodent species and one in a non-rodent species.

Our experience thus far with the new toxicology data recommendations regarding genetic toxicity studies has been reasonably positive in that FDA has been interpreting the available data in a reasonable fashion. In fact, FDA has been willing to rely solely on one genotoxicity study - the Ames test - under certain circumstances and not require the second in vitro study. Thus, it appears that an Ames test only may suffice where (1) the CEDI is at the low end of the 0.5-50 ppb range, (2) there are no structurally concerning aspects of the substance, and (3) the Ames test results are clearly negative.

In addition to the new reliance on genetic toxicology, the "Toxicology Recommendations" has ushered in a change in the manner in which the toxicology data need to be presented. Until recently, it has been sufficient to simply provide a conclusory summary of a given toxicology study, or even of a collection of toxicology studies for the substance of interest. Now, however, an FCN needs to include a far more expansive section summarizing the toxicology data. In essence, a "comprehensive toxicology profile" needs to be included, wherein each study is explicitly summarized and each of the summaries spells out the details of how the study was performed and as well as the details of the observations. While this is not technically difficult to accomplish, it does mean that more attention to detail and effort are needed in the preparation of an FCN.

FCN Technical Issues - Environmental Assessments With regard to the Environmental Assessment (EA) sections of the Notifications, conversations with Dr. Buzz Hoffman, head of the Environmental Review Team, indicate that, until general guidance is issued, the environmental assessment needs for notifications must be determined on a case-by-case basis. Since the regulations on categorical exclusions from the need for an EA have not yet been amended to apply to notifications, an EA will be required for every notification. The amount of information required, however, will depend on various factors. Although it has been our experience that the amount of environmental information needed is not significant for a notification that would qualify for a categorical exclusion if it were a petition, FDA has indicated that, until amending regulations are issued, prospective filers of notifications should submit to the Agency a description of the substance, the intended use, and the environmental information that would be required if the filing were not categorically excluded. FDA will then respond with advice on the required content of the environmental assessment. In the case of pending petitions or threshold or regulation requests that have been converted, FDA itself has been handling environmental assessments to allow the notifications to become effective; however, we understand that FDA has indicated that it will be discontinuing its EA preparation for converted petitions.

Concluding Comments

In summary, it is important, as it has always been, to pay close attention to FDA's guidance documents for the collection of the data needed in an FCN. Furthermore, some of the information elements of Notifications require that more time and effort be expended in their preparation; despite this additional "burden," the factor of the relatively short 120-day timeframe may compensate for the additional work needed.

As with the establishment of any new system, it will take time to more fully evaluate the effectiveness of the FCN program. However, it appears that the FCN program is running reasonably well. Nonetheless, it is important to pay attention to the details to ensure that FDA continues to evaluate Notifications in a consistent and rational way.

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