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

June 21, 1999

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 review and provide commentary on the Food and Drug Administration's (FDA) "Draft Chemistry Information Prepared for the March 12, 1999 Stakeholders Meeting on Premarket Notification for Food-Contact Substances" and "Draft Toxicology Information Prepared for the March 12, 1999 Stakeholders Meeting on Premarket Notification for Food-Contact Substances," both issued in March, 1999. While not explicitly represented in this way, the "Draft Chemistry Information" 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 "Draft Toxicology Information" document is the first publicly available toxicology guidance document specifically on components of food-contact materials. This report will discuss the utility of guidance documents as well as provide summaries of the new elements set forth in both the "Draft Chemistry Information" and "Draft Toxicology Information" documents, referred to hereinafter as the Chemistry guidelines and Toxicology guidelines, respectively.

Utility of Guidance Documents

As many of you know, Section 409(b) of the Federal Food, Drug, and Cosmet-ic Act (the Act) permits any person to petition FDA to issue a regulation prescribing the conditions under which a food additive may be safely used. The Act sets forth the types of information required to support a petition, and the procedures and substan-tive parameters to be followed by FDA in considering a petition. These information requirements and procedures are spelled out in a general way in Part 171 of the Food Additive Regulations (Title 21 of the Code of Federal Regulations). Such a petition must include several categories of information to clear the use of any specific material in food-contact applications: (a) the composition and method of manufacture for the substance, (b) its intended condition of use, (c) the quantity of substance likely to become a component of food under the intended conditions of use, (d) an estimate of the concentration of the additive in the human diet, and (e) toxicological data supporting the safety of the intended use. In addition, information on the potential environmental impact of the manufacture, use, and disposal of the material must be submitted. FDA's Chemistry guidelines address the above items (a), (b), (c), and (d), but in far greater detail than the general description in Section 171.1. However, the Chemistry guidelines are useful for much more than for the submission of food additive petitions.

Specifically, FDA's "Threshold of Regulation," set forth in Section 170.39 ("Threshold of regulation for substances used in food-contact articles"), is the Agency's "process" for clearing substances without the need for a formal food additive petition. Appropriate and substantive migration data, of the quality described in the Chemistry guidelines are needed to serve as the basis for the determination.

In addition, for many years, since 1968 when the so-called "Ramsey Proposal" was first advanced, we have been advising you that we believe it is appropriate to take the position that a substance is not a food additive, i.e., may not reasonably be expected to become a component of food, if it is undetectable when suitable extraction studies are performed, followed by a proper analysis with a validated method of appropriate sensitivity. Furthermore, when a substance is indeed demonstrated likely to be a food additive, or when the need arises because of the nature of the marketplace, petitioners file food additive petitions to have their substances listed as food additives. As in the other regulatory realms described above, the data needed to make the determinations must be of the suitable quality based on the principles and particulars outlined in FDA's Chemistry guidelines.

History of FDA's Chemistry Guidelines

As noted above, Part 171 of the Food Additive Regulations delineates the types of data needed in a petition to permit the agency to establish the safe use of a food additive. However, while such a framework of petition requirements has been in place since 1959, the Sections in Part 171 do not provide practical guidance on the quality and the nature of the data required for petitions. Because questions began almost immediately regarding the kinds of data and other information which would satisfy FDA's needs for evaluating food additive petitions, FDA first set forth its guidelines in this area in "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."

Questions continued to arise after the issuance of the 1966 Guidelines, and FDA had also acquired a greater appreciation of the subtleties involved with evaluating components of food packaging materials. As a result, the Guidelines were revised to address indirect food additives alone and issued in March 1976 as "FDA Guidelines for Chemistry and Technology Requirements of Indirect Food Additive Petitions."

The Agency's next issuance of guidelines involved two "amendments" rather than the revision of the Guidelines per se. Specifically, in May, 1981 FDA issued "Validation Guidelines," which outlined the general criteria for validation of analyses presented in indirect food additive petitions, and in June, 1981 FDA issued its seminal "Procedures for Estimating Exposure to Indirect Food Additives," FDA's first public "paper" describing the exposure estimating approach it "invented," which employs consumption factors and food-type distribution factors.

The Agency next revised its guidelines after the completion of exploratory research on the nature of food simulating solvents and testing temperatures and times conducted on its behalf by contract laboratories. Along with these new items of knowledge, the two amending guidelines were included in the Agency's "Recommendations for Chemistry Data for Indirect Food Additive Petitions" in September, 1988.

The guidelines were next revised in June, 1995, again titled Agency's "Recommendations for Chemistry Data for Indirect Food additive Petitions." The introductory portion of the 1995 "Recommendations" indicated four items the Agency considered to be the highlights of the revised edition: (1) migration testing protocols for high temperature applications were included; (2) the use of Miglyol 812™ as an alternative fatty-food simulant was discussed; (3) in the spirit of international harmonization, FDA recommended testing with 10% ethanol (instead of 8% ethanol) to simulate aqueous, acidic, and low-alcohol foods, and indicated acceptance of testing at 40 C (instead of 49 C) to model long-term storage at ambient temperatures; and (4) the Chemistry criteria relating to reviews under the Threshold of Regulation were addressed. In addition to these, however, there were other changes that were noteworthy; all of these modifications were addressed in the December 1995 Technical Advisor's Report.

Revisions to Chemistry Guidelines

As an introductory page to the revised guidelines, the new "Recommendations" lists three items the Agency considers to be the highlights of the 1999 guidelines: (1) alternative approaches to estimating migration level to food, such as migration modeling are presented; (2) Consumption Factors (CF) for several specific polymer packaging categories have been updated; and (3) testing for "wet-end" additives used in the manufacture of paper and paperboard is addressed. In addition to these, however, there are other changes that are noteworthy. All of the changes, including the four itemized by FDA, will be considered below.

Format

The format in the 1999 Chemistry guidelines is virtually the same as that in the 1995 "Recommendations." This is an indicator that the guidance document, which is focused in reality on the Food-Contact Notification (FCN) system, is actually a general revision to the Chemistry guidelines. Thus, while certain word changes have been made to reflect this specific focus, it is clear that the document is an updated general set of guidelines. My comments below will not point out the language changes that take into account the FCN focus.

Identity

FDA clarifies the scope of impurities that should be reported for the subject substance - residual starting materials (all reactants, solvents, and catalysts), by products, and degradation products, along with supporting analytical data and calculations relating to these impurities. FDA had not been explicit on these previously.

Migration Testing

FDA has previously indicated that polymers that are used in contact with food at temperatures below their glass transition temperature (Tg) should be tested at 40 C for 30 days instead of at 10 days. The previous guidelines noted polyethylene terephthalate (PET) as the example of polymers that fall into this category. In addition to PET, the new guideline document includes polystyrene as well as PET as examples of this class of polymers. Furthermore, FDA adds the recommendation of 30 days (either testing or extrapolation) for polymers that have a glass transition temperature above 40 C to Appendix II, which describes the testing time and temperature for various conditions of use; this Appendix did not previously note the 30-day preference.

FDA indicates for the first time that it is permissible to use the chloroform-soluble portion of the total nonvolatile extractives (TNE), rather than the TNE per se, obtained from a new polymer to determine migration of the polymer's low molecular weight oligomers.

FDA also notes that it may be necessary to determine the migration of decomposition products of a substance, where the decomposition products arise either as a result of the substance performing its ordinary technical effect or after migration to food (or food simulants). While it has always been FDA's prerogative to request such data, this is the first time that FDA has explicitly noted the possible need for such information. FDA suggests that stability studies could be performed to address this matter.

While FDA had previously noted that the Agency had begun compiling a migration database, the new guidelines indicate that a hardcopy of the database may be obtained through a request under the Freedom of Information Act (FOIA).

FDA notes that mathematical calculations may be performed in lieu of performing migration tests. Specifically, calculations based on an assumption that 100% of the substance migrates to food may be performed. Alternatively, calculations based on the principles of diffusion may be performed; the examples of acceptable diffusion models that are cited are the Limm and Piringer models. FDA points out the appropriate caveats for using diffusion modeling (e.g., uniform distribution of the substance in the polymer). In addition, FDA has added a section to Appendix II setting forth a worst-case calculation that may be used for certain substances used at the wet-end of the manufacture of paper and paperboard.

FDA has added PET to the list of other polymers (rigid polyvinyl chloride and polystyrene) for which 50% ethanol would be a suitable alternative fatty food simulant. Some of you may recall that FDA was considering including PET in this category prior to the issuance of the 1988 "Recommendations."

Exposure

FDA notes that it is, as it has always been, receptive to receiving new information on packaging materials and, consequently, the Agency has updated the default CF values based on information received by FDA since the 1995 "Recommendations" document was issued. The "updated" CFs are set forth in Table I of Appendix IV of the guidelines and are discussed below:

Adhesives: FDA has set forth a default CF of 0.014 (14%) for adhesives. It is important to bear in mind that this value encompasses all types of adhesives used for all types of applications in which adhesives are used. As with all other broad CFs, it potentially could be refined by employing relevant and justifiable industry data, as has been accomplished on several occasions (see examples below).

Retort pouch: FDA has tabulated a value of 0.05 (5%). While appearing in tabular form for the first time, this value was already described in the 1995 "Recommendations."

Microwave susceptor: The value described is 0.01 (1%), even though data have been submitted to the Agency that indicates that the actual value is significantly lower than 1%.

Polyolefins: The Agency has set forth the following CF values for low density polyethylene (LDPE), linear low density polyethylene (LLDPE), high density polyethylene (HDPE), and polypropylene (PP):

LDPE 0.12
LLDPE 0.06
HDPE 0.13
PP 0.04

These values are precisely the refined CF values provided to FDA by SPI's Polyolefin Safety Task Group in May 1995, although the 1995 SPI report contains further refinements for each of these types of polyolefins.

Polystyrene: FDA has divided the polystyrene CF into two subcategories - impact and non-impact - assigning values of 0.04 and 0.06, respectively. These values reflect the refined CF values provided to FDA by SPI's Polystyrene Work Group in April 1993, although the 1993 SPI report contained further refinements for each of these types of polystyrene.

Polyvinyl chloride (PVC): FDA has divided the PVC CF into two subcategories - rigid and plasticized - assigning values of 0.04 and 0.06, respectively. While appearing in tabular form for the first time, this subdivision was already described in the 1995 "Recommendations."

Polyester: FDA has explicitly set forth a CF value of 0.05, which is the value in place prior to the 1995 "Recommendations."

Cellophane: FDA has set forth a CF value of 0.01, which is the value in place prior to the 1988 "Recommendations."

Nylon: The Agency employs a CF value for nylon resins for the first time - 0.02 (2%).

EVA: FDA has described a CF value of 0.02, which is the value in place prior to the 1988 "Recommendations."

History of FDA's Toxicology Guidelines

As noted above, Part 171 of the Food Additive Regulations sets forth the types of data needed in a petition to permit the Agency to establish the safe use of a food additive, but the Sections in Part 171 do not provide practical guidance on the quality and the nature of the toxicology data required for petitions. Although questions began almost immediately regarding the kinds of toxicology data and other information which would satisfy FDA's needs for evaluating food additive petitions, FDA issued its first set of guidelines in 1982 for support of Direct Food Additive Petitions in a document entitled "Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food," usually referred to as the "Redbook." FDA issued a draft revision of this document, having the same title but commonly referred to as "Redbook II," in 1993; FDA has not yet issued a final version of Redbook II. While these documents are useful for guidance in the performance of a given test that is needed, they are not intended to cover food-contact substances, such as indirect food additives, and do not, consequently, provide guidance on which tests are needed to assure the safety of a given substance.

FDA has issued guidance "sheets" over the years that provide a sketch of the dietary exposure "cross-over" points that require more or less rigorous toxicology testing. However, with the issuance of the "Draft Toxicology Information Prepared for the March 12, 1999 Stakeholders Meeting on Premarket Notification for Food-Contact Substances," FDA has for the first time issued its Toxicology guidelines for food-contact substances. The Toxicology guidelines are intended primarily as a guidance document for the system that will permit Premarket Notification for Food-Contact Substances; my objective here is to provide a summary of the general utility of the document.

Utility of the Toxicology Guidelines

FDA has noted specifically the dietary exposure "crossover" points for the toxicology data to support FDA filings; i.e., the level of testing and types of toxicology testing are dependent on a determination of the dietary exposure for a substance. These are summarized below.

Dietary concentration: 0.5 ppb

No toxicity studies are recommended for the substance.

Dietary concentration: >0.5 ppb and 50 ppb

While acute toxicity data, including LD50 values, have long been provided in Indirect Food Additive Petitions for exposure levels below 50 ppb, FDA notes that such studies are rarely used in the overall safety assessment of food-contact substances to which long-term repeated exposure is expected. Instead, FDA now indicates that it intends to require genotoxic testing for substances with an exposure level above 0.5 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 and (2) an in vitro test with cytogenic evaluation of chromosomal damage using mammalian cells or an in vitro mouse lymphoma tk+/- assay. FDA notes that it prefers the mouse lymphoma tk+/- assay for the latter test.

We have reservations about this new baseline requirement conceptually because of the ambiguity in analyzing the results of such tests and because of the possible low levels of correlation of cancer to the testing results. At this point, it is not entirely clear that the substitution of the genotoxic testing for the simple acute testing that has been the rule in low exposure cases is appropriate. In any case, if this requirement is put in place, it is important that the Agency clearly set forth how it will view the data that is submitted.

We understand that there is concern among the toxicologists in the regulated community that the mouse lymphoma assay is not a reliable indicator of carcinogenicity or other toxicological concerns, yielding a high rate of false positives. Hopefully, the Agency will leave the door open for other combinations of genetic toxicity studies that would provide the Agency with the type of data needed and are consistent with the regulatory requirements of other jurisdictions.

In addition, if the Agency decides to require genotoxic testing for substances with an exposure level between 0.5 ppb and 50 ppb, we believe sufficient safety data exist so that FDA can exempt polymers from testing requirements. We believe there is general agreement in the scientific community that polymers, and even oligomers, do not pose significant toxicology concerns if their monomers have been tested satisfactorily.

Dietary concentration: >50 ppb and 1 ppm

In addition to the genetic toxicity tests noted above, FDA indicates that the substance should be evaluated by two subchronic (90-day) oral toxicity tests, one in a rodent species and one in a non-rodent species. Depending on the outcome of these studies, additional studies may be needed, such as metabolism studies, teratogenicity studies, reproductive toxicity studies, neurotoxicity studies, or immunotoxicity studies.

The recommendation for the 90-day studies, supplemented as needed, has long been the data requirement for this range of dietary exposure.

Dietary concentration: >1 ppm

In addition to the data set forth above, FDA recommends that a chronic study be provided in support of a Food Additive Petition. Once again, this has long been the Agency's requirement for this range of exposure.

Concluding Comments

As with the previous guidelines, the Agency makes it clear that the guideline documents may not cover every situation, and that the guidelines that are presented are, in fact, recommendations and not "carved-in-stone" requirements. Where ample justification can be supplied, the Agency continues to accept departures from the specifics described in the document.

We recognize that creating documents such as these guidelines, and managing to place them it into the public arena, is an arduous effort; we commend the individuals responsible, both for their efforts and their generally reasonable guidance based on scientific principles. The guideline documents continue to be indispensable to the industry for instruction in the performance of the necessary testing to establish the regulatory status of a component of food-contact articles.

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