Comment: FDA’s Office of Food Additive Safety (OFAS) frequently receives submissions on food-contact substances (FCS) whose technical effect depends on particle size, e.g., latexes or ion exchange resins. This statement helps to ensure that sponsors provide adequate data to demonstrate the effectiveness of particle-based FCSs in their intended food-contact uses.
Change: II.D. Migration Testing & Analytical Methods. Added “If a 100% migration calculation is used for an adjuvant in a polymer system, the sponsor should provide a typical polymer thickness. If none is provided a default assumption of 10 mil (0.01 in) and the surface area of one side will be used in the calculations.”
Comment: Almost invariably, sponsors neglect to provide the thickness of polymer samples used in migration tests or to provide a typical thickness for use in 100% migration calculations. This information is crucial for converting migration test results or adjuvant concentrations in the polymer to adjuvant concentrations in food and then to dietary exposure values. When this information is not provided, OFAS has had to go back to sponsors and ask for it.
It appears that, in the case of 100% migration calculations, OFAS will no longer go back to sponsors for the information but will assume the worst case in terms of polymer thickness and migration from one rather than both sides of the polymer. The thicker the polymer, the higher the amount of adjuvant that will move from 1 in2 into food. Few polymers used in food-contact applications are thicker than 10 mils. Use of one side of a polymer in the migration calculation results in twice the concentration in food of an adjuvant that would be obtained using both sides because the polymer surface area is in the denominator. Also, the vast majority of food contacts only one side of its packaging.
Change: II.D.1.b.2. Sample Thickness & Surface Area. Added “Migration from paper is solubility, rather than diffusion, driven therefore paper used in migration tests is considered to be single sided regardless of thickness.”
Comment: I was responsible for this change. I reviewed many submissions on components of paper and paperboard during my career at FDA and found that far too many sponsors applied the double-sided migration “rule” for thick (> 0.05 cm) polymers to thick paper samples. Generally, migration from polymers follows Fick’s law of diffusion, which is why the double-sided migration “rule” applies to thick polymers. Migration from paper does not follow Fick’s law of diffusion because paper components dissolve into food or food simulants. Therefore, migration from paper, regardless of its thickness, is always single-sided.
Change: II.D.3.d. Example Calculations. Added ‘”The examples should include such information as sample size, concentration/dilution steps, and instrument readings (such as peak area or detector response). Modern data systems typically perform these calculations internally based on a series of standards. The instrument readings should be extracted from the internal data set. Consult the instructions for the instrument/software package used in the analysis for guidance on providing these data.”
Comment: Fewer and fewer sponsors were providing sufficient raw data for the OFAS review chemist to reconstruct and check the concentration calculations. When we asked the sponsors for this information, we found that many analysts were using their computerized instruments as “black boxes” and simply reporting the results as they came out of the machine. The added statement helps to ensure that analysts extract the necessary raw data from their instruments to enable OFAS to complete the review.
Change: II.D.3.e. Validation of Analytical Methods. Added “Additionally, as noted in Section II.D.2, the stability of the analyte(s) in the migration test solution should be demonstrated.”
Comment: Guidance dealing with the stability of FCSs and their impurities was somewhat muted or hidden in the 2002 “Chemistry Recommendations.” This became particularly evident during OFAS’ recent review of FCSs containing perfluorinated polymers because perfluorinated substances such as perfluorooctanoic acid (PFOA) were found to “disappear” if glassware was used in the analytical workup; these substances did not disappear if plastic was used. OFAS added several statements like this one to the 2007 “Recommendations” to highlight the importance of determining the stability of FCSs and their impurities during migration studies as well as under their intended conditions of use.
Change: II.E.1.a. Consumption Factor. Added “A consumption factor may alternatively be calculated using estimated maximum production volume. Should this consumption factor be used in exposure estimates, the FCS will be limited to an annual production volume at or below the maximum that has been specified. If the market volume expands to beyond the stated production volume, a new notification/petition will need to be submitted to account for the increased consumer exposure.”
Comment: Because FCNs are exclusive to the sponsor, consumption factors (CF) can be specifically tailored to the sponsor’s market volume. This was not possible with food additive petitions because, once an indirect food additive was regulated, it was generically approved for manufacture or use by anyone.
Change: Added II.G. Reference Format.
Comment: Apparently, several sponsors referred to literature articles or other references in submissions without providing the reference itself or a useful citation of it so that the chemistry reviewer could obtain a copy. The addition of this section helps to ensure that references are cited appropriately in submissions.
Change: Appendix I. Added 50% isooctane as fatty-food simulant for polyethylene terephthalate (PET).
Comment: Over the years, I received calls from potential sponsors in which they explained that ethanol would degrade or otherwise interfere with analysis of their FCS in migration studies and that it would be impossible to detect their FCS in oily food simulants. The OFAS Laboratory (now in the Office of Scientific Analysis and Support) has long recommended 50% isooctane as an alternative fatty-food simulant for PET, based on the literature and their own experience. It is high time this simulant be listed in the “Recommendations.”
Change: Appendix II.1.A. Migration Testing Protocol for High temperature, heat sterilized or retorted. Changed “above 100° C (212°F)” to “(ca. 121 ° C (250°F))” with clarification “Condition of Use A includes reheating or cooking of foods where the temperature is ca.121 ºC (250 ºF), or heat-sterilized or retorted under transient temperatures >121 ºC (250 ºF).” Eliminated testing conditions 50% ethanol at 71°C (160°F) for two hours.
Comment: The cap on temperature was placed to provide a dividing line between conditions of use A and J (see further discussion below). The past definition of condition of use A, originally given in Title 21 of the Code of Federal Regulations, Section 176.170, was extremely vague in that any temperature above 100o C was included. This made it difficult to establish migration testing criteria for temperatures significantly above 100o C, so OFAS had traditionally assumed a cap of ca. 121o C for condition of use A and provided separate testing guidance for FCSs intended for use at significantly higher temperatures in Appendix II.11. “Special High-Temperature Applications” of the 2002 “Recommendations.”
Use of the testing conditions 50% ethanol at 70o C for two hours was eliminated to resolve confusion with the entry for “50% or 95% ethanol at 121°C (250°F) for two hours.” The latter test conditions supersede the former.
Change: Added Appendix II.I. Irradiation (ionizing radiation). “We do not have protocols for studies on FCSs that are intended to be irradiated with ionizing radiation. Please consult with FDA to discuss recommended protocols for this use.”
Comment: This new condition of use was added in response to several submissions OFAS had received over the past few years having to do with the irradiation of prepackaged beef in order to eliminate E. Coli 0H157 and other pathogens (the sponsors wished to irradiate the beef in the packaging to prevent its recontamination). OFAS realized that the test conditions in the 2002 “Recommendations” did not cover components of packaging irradiated in contact with food.
I spent a lot of time working with the OFAS Laboratory and colleagues in OFAS to develop a set of testing protocols for determining the formation of radiolysis products in irradiated polymers and their migration to food. However, based on the complexity of the analyses involved, it was decided that OFAS would provide advice on testing to potential sponsors in response to individual requests rather than as general guidance.
Change: Added Appendix II.J. Cooking (e.g., baking or browning) at temperatures exceeding 121º C (250º F). “For high-temperature oven use (conventional and microwave*), migration testing should be performed at the maximum intended cooking temperature for the longest intended cooking time, using a food oil, or a fatty-food simulant (such as Miglyol 812). *Test protocols for microwave applications, such as microwave-only containers, dual-ovenable containers and microwave heat-susceptor packaging are specifically discussed in Item 11 below.”
Comment: As was discussed above, this new condition of use was added to emphasize in writing what OFAS had assumed for decades, that condition of use A should have a cap of ca. 121o C and that FCSs that will be heated in contact with food to higher cooking temperatures should be subjected to a separate, more rigorous testing protocol. The primary impetus for this change was a recent revelation that several sponsors had assumed for decades that, if an FCS was approved for condition of use A or H, there was no limit to the temperature to which it could be subjected in contact with food, including microwave heat-susceptor temperatures, which can exceed 500o F.
Change: Appendix II.8. Adhesives (Room temperature or below). Removed discussion of regulatory basis (§175.105) for not requiring migration tests for adhesives separated from food by a functional barrier.
Comment: The removal of the regulatory discussion of functional barriers tightens up the language in this section and focuses the sponsor on the exposure calculation or testing that should be done to support an exposure calculation. The removal also harkens to the OFAS management’s movement to divorce the FCN program from the CFR (see below).
Change: Appendix II.11. Changed title from “Special High-Temperature Applications” to “Special Cooking Applications.”
Comment: With this change, OFAS emphasizes the division between conditions of use A and J and the need for more rigorous testing for cooking applications such as microwave heat-susceptors.
Change: Appendix II.11.A. Changed title from “Microwavable Containers” to “Microwave-Only Containers.” Added “Typical cooking conditions have been generally observed to not exceed 130 ºC (266 ºF). Tests performed for broad coverage in packaging under the protocol for condition of use H (above) will also be adequate to model migration for microwave-only containers. However, for those sponsors that propose use of a food-contact article specifically in microwave containers, migration testing should be performed in a food oil, or fatty-food simulant, at 130 ºC (266 ºF) for 15 minutes and in an aqueous-food simulant at 100 ºC (212 ºF) for 15 minutes.”
Comment: The title was changed because containers that can be microwaved or heated on the stove or in a conventional oven are covered by the testing protocol for condition of use J or by that for dual ovenable trays (Appendix II.11.B).
The long experience OFAS has had in reviewing submissions for microwave-only containers, as well as the extensive experiments the OFAS Laboratory has conducted on them, enabled OFAS to present specific testing protocols rather than the general advice given in the 2002 “Recommendations.”
Change: Appendix II.13. Dry Foods. Replaced “no migration testing is recommended” with “If the FCS is intended for use only with dry foods with surface containing no free fat or oil, a migration of 50 ppb may be assumed. This migration level can then be multiplied by the appropriate food-type distribution factor and consumption factor to obtain an estimated dietary concentration. If the intended use for the FCS includes other food types (e.g., acidic, aqueous, or fatty foods), in addition to dry foods with surface containing no free fat or oil, then the migration studies conducted for those food types will subsume any migration for a dry food with surface containing no free fat or oil. If you desire to conduct migration studies for dry foods containing no free fat or oil, consult with FDA for recommended migration protocols.”
Comment: OFAS has long assumed 50 ppb migration of any FCS to dry food (with surface containing no free fat or oil) and used this value to calculate dietary exposure. Adding this information to the “Recommendations” allows sponsors to do the calculation themselves so they know the dietary exposure of their FCS and its contribution to the cumulative exposure (CEDI). The statement that migration studies conducted for the other food types subsume any migration for a dry food (with surface containing no free fat or oil) has also been in practice in OFAS for many, many years. Presenting this statement in the “Recommendations” informs sponsors that migration testing they conduct for aqueous, acidic, or fatty foods also covers dry foods (containing no free fat or oil). Because there is no such thing as “zero migration,” and because methods are being developed in the European Union and elsewhere for determining migration of FCSs to dry food, OFAS now lists migration testing as an option for determining dietary exposure rather than simply stating that “no migration testing is recommended.”
Change: Added Appendix II.16. Selected Migration Testing Protocols for Degradable Polymers or Reactive FCSs. “The notifier should include detailed information on the intended use and address the stability of the FCS during the intended use conditions. The degradation or reaction mechanism of the FCS should be described thoroughly, and should include structural diagrams of possible degradation products and intermediates. Stability and migration testing of the FCS should be conducted with analysis for TNVs, oligomers, breakdown products, and other impurities. GPC analysis before and after extraction tests is recommended to determine changes, e.g., in the molecular weight distribution or the level of low molecular weight oligomers. For migration studies, the samples should be sufficiently aged under appropriate conditions to account for degradation during storage of the FCS (before use) and the shelf-life (during use) of the food-contact article. The sponsor should address whether accelerated migration studies are appropriate for the reaction mechanism. If the FCS will be stored before use, additional stability testing to analyze the effects of exposure to potentially extreme ambient conditions during storage is recommended.”
Comment: A number of years ago, after reviewing several submissions related to degradable polymers, I worked on developing guidance for sponsors intending to submit FCNs for these substances. However, it was determined later that the difference in testing between typical and degradable polymers was not sufficient to warrant a separate guidance document. The guidance given above is based on my original work and that of a coworker who reviewed more recent submissions on degradable polymers.
Change: Appendix IV. Table 1. Consumption Factors.
Changed CF for retort pouches from 0.05 to 0.0004.
Added CF for “All Polymers” of 0.8 to include polymer-coated metal and paper. The CF of 0.4 for “Polymers” is for polymer-only containers.
Increased CF for polystyrene from 0.1 to 0.14 and eliminated impact and non-impact subcategories.
Added CFs for polyolefin films and several PET subcategories.
Comment: The new CF for retort pouches is based on extensive market research I did on this type of packaging several years ago. Shelf-stable retorted foods never became as popular among the U.S. civilian population as had been projected. As a result, the new CF is primarily based on MREs (meals, ready-to-eat) consumed by the U.S. military.
The new CF for polystyrene is based on market research done recently by two of my coworkers. I do not know why the CFs for the impact and non-impact subcategories were eliminated. Possibly the data supporting the new CF could not be divided between the subcategories.
The remaining CFs are based on new information compiled by OFAS, which is an ongoing operation for all FCSs. I do wish to comment that the CF of 0.05 given for recycled PET actually applies to any recycled polymer (see “Use of Recycled Plastics in Food Packaging: Chemistry Considerations” at http://www.cfsan.fda.gov/~dms/opa2cg3b.html, which I wrote).
Change: Added Appendix V. Food Types and Conditions of Use. Eliminates need to refer to tables in §176.170. Adds conditions of use I (irradiation) and J (cooking at > 121o C).
Comment: Since the creation of the FCN program in 1997, the OFAS management has made a concerted effort to divorce FCNs from the CFR as much as possible, primarily because of the inflexibility of the CFR. Rather than continue to make constant reference to the Food Types and Conditions of Use tables in §176.170, OFAS initially placed these tables on its website and referred to them there (see http://www.cfsan.fda.gov/~rdb/opa-fcn3.html). Now the tables are also listed in the “Recommendations.”
Conditions of use I and J were added to OFAS’ website about two years ago and are now in the “Recommendations.” As was discussed above, condition of use I was added in response to a significant number of submissions we had received regarding the irradiation of prepackaged beef in order to eliminate E. coli 0H157 and other pathogens. Condition of use I was also added to emphasize that separate approval is required for irradiated uses of FCSs even if the FCS is already approved for unirradiated uses. Condition of use J was added to allow OFAS to place a cap on condition of use A and to separate it from high-temperature, cooking uses of FCSs. Although it had been obvious to OFAS for decades that high-temperature, cooking uses should require separate, more rigorous migration testing than that described for condition of use A, it had not been so obvious to sponsors. In fact, OFAS recently discovered that some sponsors had assumed for decades that testing for condition of use A or H covered high-temperature, cooking uses.
OFAS has apparently been correct about divorcing the FCN program from the CFR and its inflexibility. By listing the Food Types and Conditions of Use tables on its website and in the “Recommendations,” which are both considered non-binding guidance, OFAS is free to change them as rapidly as technology and food safety issues change. Industry can comment on this guidance at any time and is not required to follow it, provided that an acceptable alternative is followed in order to meet the safety requirement. If OFAS had had to change these tables via notice, comment, and rulemaking, we might have seen the changes in the CFR in about a decade.
Change: Appendix VI. References and Footnotes. Added footnote 9 regarding chloroform-soluble extractives of the TNE “Chloroform may not be a good solvent for certain polymer/migrant systems. This is most likely due to a large difference in solubility between the polymer/migrants and chloroform. If the Hildebrand solubility parameter difference between the extractives and the solvent falls outside the range of ±3 (SI), one should either use another solvent that is capable of effectively solvating the potential extractives or demonstrate that the intended extractives are soluble in the chosen solvent. Hildebrand solubility parameters for polymer/solvent systems can be found in the Polymer Handbook, 4th Edition, J. Brandrup (Editor), Edmund H. Immergut (Editor), Eric A. Grulke, Akihiro Abe, Daniel R. Bloch, John Wiley & Sons.”
Comment: This footnote reflects OFAS’ latest knowledge on this subject. OFAS has been getting away from including chloroform-soluble extractives (CSE) of the total non-volatile extractives (TNE) in calculating dietary exposure to FCSs. The CSE/TNE method harkens back to the days before modern analytical methods such as gas chromatography were developed. A chloroform extraction was often the only way to reduce the TNE to a “reasonable” value to represent the sum of substances migrating from the FCS to a food simulant (the substances left behind in the aqueous phase were assumed to be inorganic salts with no safety concerns). With modern analytical methods, it is now possible to analyze migration solutions in their entirety. In addition, with the CSE/TNE method, water-soluble migrants of concern such as ethylene glycol and diethylene glycol are ignored because they go into the aqueous phase with the “inorganic salts.”