Pivotal and emerging issues in FDAs approach to safety assessment

2.5.1 Consumer exposure

Exposure estimates, developed from migrant levels in food and information on food contact uses, determine the amount of toxicological information needed to support the proposed use of an FCS. Limitations on use conditions may be imposed by the notifier, possibly at the suggestion of FDA, to reduce exposure to either the FCS or to a constituent due to safety concerns identified during the review. This approach can be advantageous to the notifier. For example, if the available toxicological information is limited and, thus, supports only a low exposure in accord with the tiered testing scheme, a notifier may submit an FCN for a narrow or limited use. As additional chemistry or toxicological data become available, the notifier may submit another FCN for expanded use of the FCS. As another example, consider two monomers used in the manufacture of polymeric food contact articles, one of which is commonly used as a 'base' monomer and the other used as a minor monomer. Through its evaluation of numerous submissions that the FDA has processed, FDA has determined that some polymeric articles, manufactured from certain monomers, are used only in such niche or specialty applications that they are not expected to see wide use in food packaging. As such, they usually require minimal data to ensure safety at their respective exposures. This approach to safety assessment allows the FDA not only to fine tune the safety assessment for the particular notification in question, but also to reassess the safety assessment of FCSs and their constituents on a continuing basis. If concerns are raised in the reassessment, they may result in post-market action on any permitted uses of the FCS.

Exposure estimates derived from packaging factors are 'averages' across the U.S. population and may be thought of as 'per capita' estimates. FDA believes that this 'per capita' -based approach to estimating exposure to food packaging components is appropriate because consumer selection of food is not generally dependent on the type of packaging; rather, it is dependent on the eating habits and spending preferences of the consumer. In fact, one criticism of FDA's approach to consumer exposure for packaging materials is the assumption that a food(s) eaten by a given consumer will have been packaged with the same material 100% of the time. For example, if a notifier proposes use of an antioxidant in high-density polyethylene, the consumer is assumed to ingest the selected food(s) only if it is packaged in the high-

density polyethylene with the antioxidant, even though the food(s) may be packaged in other materials as well. With regard to selecting or developing an appropriate CF for a FCS for use in refining an exposure estimate, the FDA encourages the submission of marketing or other information that may be used to subdivide packaging markets. Given the exclusive nature of the FCN process, FDA continues to explore new methods to utilize marketing information in exposure refinement. On occasion, exposure estimates for packaging components may be derived based on the intake of a particular food, with focus on the 'mean' intake of the particular food rather than the 90-plus percentiles. This approach can be used when an FCN identifies use only with specific foods, such as for polymeric absorbent pads used only for raw chicken or fruit.

2.5.2 Dose related toxicity

In applying the hazard information gained in toxicology testing to a safety evaluation, it is essential to assess the hazard based on the exposure resulting from the use(s) of a substance in food contact articles. In many cases, only limited information may be available on a substance; however, if the substance has a large toxicological data base of information, the safety assessment may be made using the data deemed most relevant to the exposure level being evaluated. As an example, consider the proposed use of a substance with a dietary concentration of one microgram per kilogram food consumed and supporting data consisting of genetic toxicity tests and a subchronic study. At one microgram per kilogram food consumed, the genetic toxicity studies would be thoroughly reviewed because they can provide information relevant at such a low level while the subchronic study would be subjected to a preliminary review. If the preliminary review of the subchronic study indicates a safety concern based on the margin of exposure, the study would be thoroughly reviewed to establish an acceptable daily intake value. An acceptable daily intake value need not be calculated if the exposure and preliminary review do not warrant an extensive evaluation of the additional data to ensure safety.

2.5.3 Continuous monitoring

The exclusive nature of the FCN process allows for a safety assessment for the FCS and its constituents in each and every FCN submitted by each and every notifier. The safety assessment may be for a new FCS or constituent or may be an updated assessment for a FCS or constituent that the FDA has evaluated previously. Thus, the FDA can monitor all safety information on FCSs and their constituents on a continuing basis and quickly address any safety concerns in the process. Moreover, as noted above, this process allows the FDA to acquire and maintain knowledge of the manufacturers/suppliers of the FCS or articles manufactured from the FCS. In addition, because the notifier/supplier is bound by the limitations and specifications of the FCS as submitted in the effective FCN, including the manufacturing process, any substantive changes in the manufacturing process should be assessed by FDA to determine compliance. Notifiers must contact FDA regarding details as to the manufacturing changes for review and determination of whether the resultant changes require the submission of a new FCN. These correspondences are usually handled in a prenotification consultation, allowing FDA to provide detailed guidance on compliance or future submissions. This knowledge base contrasts the previous 'generic' food additive petition process and affords FDA the ability to more quickly respond when post-market issues arise, have a more detailed knowledge of the regulated industry and its practices, and allows FDA to continually evaluate the key steps used in its approach to the safety assessment of food contact articles.

2.5.4 Constituents

Another important aspect of the safety assessment is the evaluation of constituents of food additives, which include impurities and byproducts, as well as the low molecular weight oligomeric fraction of polymeric substances. For example, the safety evaluation for every FCN encompasses all components that would be expected to migrate to food, including the FCS, the food additive, and constituents of the food additive. This assessment is complex and the lack of proper evaluation and supporting documentation on all substances is the most common deficiency.

Polymerization aids constitute one specific class of substances that is frequently the subject of a constituent safety evaluation. Polymer manufacture necessarily requires the use of various substances, such as catalysts, initiators, and chain transfer agents, to aid in the polymerization process but that are not essential in the final polymer. These substances are used at low levels and are typically incorporated into the polymer during polymerization or are removed during the final manufacturing steps. Solvents are also generally used in the manufacturing process and are removed during the final steps.

Under the food additive petition process, polymers were either generically listed as unique entities e.g., 21 CFR 177, or by way of the monomer building blocks used in the manufacture of certain polymers, such as polyester container coatings under ยง175.300. The FDA could not anticipate every polymerization aid that might be used by manufacturers as a result of a generic regulation listing. Polymerization aids were considered to be part of the base polymer and were, in most cases, not subjected to an independent regulation. This concept, often referred to by the regulated industry as the 'basic resin doctrine', does not apply to substances that are not essential to the polymerization reaction. In any case, safety assessments are conducted on all substances that might become components of food, including polymerization aids, monomers and oligomers.

Under the FCN process, polymerization aids and solvents are also subjected to an independent safety assessment along with the monomers and polymer and are also typically not included in the language in the notification letters. However, as the FCN is exclusive to the notifier, the identity and manufacturing information contained in the FCN apply to the FCS whether or not such information is included in the language in the notification letter or website listing of effective notifications. FCNs have been submitted for catalysts as an FCS.

2.5.5 Polymeric FCSs

A challenging issue with regard to the safety assessment of food contact articles is the safety evaluation of the low molecular weight oligomeric fraction of polymeric FCSs. For most polymeric FCSs, the primary focus is on the low molecular weight oligomeric fraction that might become a component of food, primarily due to the expected low solubility (in food or food simulants) and/or the low diffusivity (in the polymer matrix) of higher molecular weight oligomers. Toxicological evaluation of the low molecular weight oligomeric fraction of a polymeric FCS can be problematic due to the additional cost of fractionation and concentration of sample and/or the development of facsimiles for testing. Currently, FDA evaluates representative structures based on structure activity relationship analysis and the available data on the monomeric components, with consideration given to the oligomers that are unique to the specific FCS and the molecular linkages and steric changes that may have occurred during polymerization. This information and the assumptions used to generate the conclusions of the toxicology review are weighted with the exposure estimate to determine if additional data are necessary to ensure safety.

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