Docket Number: FDA-2013-S-0610 Issued by: Guidance Issuing Office Center for Food Safety and Applied Nutrition

Office of Food Additive Safety

Food and Drug Administration

5001 Campus Drive

College Park, MD 20740

(Tel) 240-402-1200

(This document also available in Chinese).

This guidance represents the Food and Drug Administration's (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations.

Table of Contents

APPENDIX I. FATTY-FOOD SIMULANTS FOR SPECIFIC POLYMERS

APPENDIX II. SELECTED MIGRATION TESTING PROTOCOLS

APPENDIX III. ILLUSTRATIVE EXAMPLE OF VALIDATION OF ANALYSES

APPENDIX IV. CONSUMPTION FACTORS, FOOD-TYPE DISTRIBUTION FACTORS, AND EXAMPLE OF EXPOSURE ESTIMATE CALCULATIONS

APPENDIX V. FOOD TYPES AND CONDITIONS OF USE

APPENDIX VI. REFERENCES AND FOOTNOTES

I. INTRODUCTION

This guidance document is intended for industry and contains FDA's recommendations pertaining to chemistry information that should be submitted in a food contact notification (FCN) or food additive petition (FAP) for a food-contact substance (FCS). It is an update to the 2002 guidance,“Preparation of Food Contact Notifications and Food Additive Petitions for Food Contact Substances: Chemistry Recommendations”. This updated guidance provides references to assist the reader, sets forth current practice, and clarifies the 2002 guidance based on recent experience with individual sponsors.

A FCS is any substance that is intended for use as a component of materials used in manufacturing, packing, packaging, transporting, or holding food if the use is not intended to have any technical effect in the food (sec 409(h)(6) of the Federal Food, Drug, and Cosmetic Act (the Act)).

A FCS that is a food additive must be regulated for its intended use in 21 CFR Parts 173-178, be exempted from regulation under the agency's Threshold of Regulation Process (21 CFR 170.39), or be the subject of a notification under section 409(h) of the Act that is effective (sec 409(a)(3) of the Act). FCNs and FAPs for FCSs as well as Threshold of Regulation (TOR) Exemption requests must contain sufficient scientific information to demonstrate that the substance that is the subject of the submission is safe under the intended conditions of use (secs 409(h)(1) and 409(b) of the Act). Because the safety standard is the same for all food additives, whether subject to the petition process, the FCN process or the TOR exemption process, the data and information that should be included in all submissions are comparable. Data requirements for TOR Exemption requests are defined in 21 CFR 170.39 and are not dealt with in more detail here.

Section 409(b) of the Act sets forth the statutory requirements for data in an FAP to establish the safety of a food additive. These requirements include descriptions of the following: (1) the identity of the additive, (2) proposed conditions of use of the additive, (3) technical effect data, and (4) methods for the analysis of the additive.

FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidance means that something is suggested or recommended, but not required.

Throughout the document, the term “sponsor” is used to denote a notifier or petitioner.

II. CHEMISTRY INFORMATION FOR FCNS AND FAPS

A clear and concise presentation of the information in the format described below will facilitate review of the submission. For notifications, references to the corresponding section(s) in FDA Form 3480 ( PDF format | Word Template ), "Notification for New Use of a Food Contact Substance," are shown in italics.

For those uses resulting in dietary concentrations at or below 0.5 ppb, the data requirements for FCNs or FAPs will be similar to those required for requests submitted under 21 CFR 170.39 (Threshold of Regulation) for substances used in food-contact articles. Specifically, the chemistry information requirements will be similar to those cited in 21 CFR 170.39 (c)(1) and (2). As indicated in 21 CFR 170.39(c)(1), the submission will need to include a description of the chemical composition of the FCS. This would include identity information on the FCS as well as the identities and composition by weight of all likely impurities (i.e., residual starting materials, catalysts, adjuvants, production aids, by-products and breakdown products). Detailed information may be needed where there are specific safety concerns. Providing additional manufacturing information may be the easiest way to address such concerns. For example, manufacturing information may be used to support the conclusion that a volatile chemical is unlikely to remain with the finished FCS because of the high temperatures encountered during the manufacturing process. Similarly, information on the types of solvents used in the manufacturing process along with solubility data of likely impurities may be used to justify a conclusion that an impurity is not likely to be found in the finished FCS. As indicated in 21 CFR 170.39(c)(2), the submission will need to include detailed information on the conditions of use of the substance. This would include a statement describing the technical effect of the substance. FDA has not ordinarily needed data to demonstrate the technical effect for uses that meet the threshold of regulation criteria under 21 CFR 170.39.

A. Identity

(see FDA Form 3480 ( PDF format | Word Template )- Part II, Sections A through C)

Identity information is used to describe the FCS that is the subject of a submission and to identify substances that may migrate into food from use of the FCS. Migrating substances may include not only the FCS itself, but also degradation products and impurities in the FCS.

Information identifying the FCS should be as complete as possible with respect to its name, composition, and method of manufacture. These items include:

Chemical Name. The Chemical Abstracts or IUPAC name is acceptable. Common or Trade Names. These should not be the only means of identification. FDA does not maintain a compilation of common or trade names. Chemical Abstracts Service (CAS) Registry Number. [2] Composition. A full description of the composition of the FCS is used to compile a list of potential migrants to food. This should include chemical formulae, structures, and molecular or formula weights for single compounds or components of commercial mixtures. For polymers, sponsors should submit the weight average (M w ) and number average (M n ) molecular weight, the molecular weight distribution, and the methods used for their determination. If the molecular weight is not readily obtainable, a sponsor should furnish other properties of the polymer that are functions of the molecular weight, such as intrinsic or relative viscosity or melt flow index.

In addition, sponsors should provide the following information:

A complete description of the manufacturing process, including purification procedures, and the chemical equations for all steps of the synthesis. A list of reagents, solvents, catalysts, purification aids, etc., used in the manufacturing process, the amounts or concentrations used, their specifications, and their CAS Registry Nos. Chemical equations for known or likely side reactions occurring during manufacture of the FCS, including catalyst degradation reactions. Concentrations of all major impurities (e.g., residual starting materials, including all reactants, solvents, and catalysts, in addition to byproducts and degradation products) together with supporting analytical data and calculations. In the case of polymers, concentrations of residual monomers should be included. Spectroscopic data to characterize the FCS. In some cases an infrared (IR) spectrum is sufficient, but occasionally other information, such as visible and ultraviolet absorption spectra or nuclear magnetic resonance (NMR) spectra, are more useful.

Those data and information not intended for public disclosure, such as trade secret or confidential commercial information, should be so identified.

Physical/Chemical Specifications. Sponsors should submit the physical and chemical specifications of the FCS (e.g., melting point, impurity specifications) as well as properties that can affect migration potential, such as solubility in food simulants. In cases where particle size is important to achieving the technical effect or may relate to toxicity, sponsors should describe particle size, size distribution, and morphology, as well as any size-dependent properties. In the case of new polymers, sponsors should provide glass transition temperatures, ranges for densities and melt flow indices, and information on morphology (e.g., degree of crystallinity) and stereochemistry. For new adjuvants in regulated polymers, sponsors should submit information on the properties of the polymer (e.g., T g ) used in migration testing (see Appendix II. Section 2. for further discussion). Analyses. If the FCS is intended for use as a component of an otherwise regulated material (e.g., an antioxidant in a regulated polymer), sponsors should provide analytical methods for determining the concentration of the FCS in the material. Supporting analytical data should be submitted (refer to Section D.3.).

B. Use

(See FDA Form 3480 ( PDF format | Word Template )- Part II, Sections D.1, D.2, and E)

Sponsors should examine general use limitations in effective notifications and regulations for similar FCSs and should include a comprehensive set of limitations on the intended use. Certain of these limitations may be the basis for assumptions made in deriving exposure estimates for the FCS. For an FCN, any applicable limitations can be included in the description of the notified use by way of a draft acknowledgement letter. For an FAP, any applicable limitations should be included in draft language for the applicable regulation. In the absence of appropriate limitations, FDA may be required to use assumptions in estimating exposure that would result in more conservative values for certain classes of FCSs.

Sponsors should provide the maximum use level of the FCS and the types of food-contact articles in which it may be used. "Use level" refers to the concentration of a substance in the food-contact article, not in the food. Sponsors should state the range of possible uses, such as films, molded articles, coatings, etc., and report the anticipated maximum thickness and/or weight per unit area of these articles.

Sponsors should state whether the intended use for the FCS is in single-use or repeat-use food-contact articles. Sponsors should also identify the types of food (with examples) expected to be used in contact with the FCS and the maximum temperature and time conditions of food contact[3]. Classifications for food-types and conditions of use that may be helpful are given in Appendix V.

Sponsors should address the stability of the FCS under the proposed conditions of use.

C. Intended Technical Effect

(See FDA Form 3480 ( PDF format | Word Template )- Part II, Section D.3)

Sponsors should present data to show that the FCS will achieve the intended technical effect and that the proposed use level is the minimum level required to accomplish the intended technical effect. "Technical effect" refers to the effect on the food-contact article, not on the food. An example would be the effect of an antioxidant in preventing oxidative degradation of a particular polymer. In the case of a new polymer, sponsors should present data that demonstrate the specific properties of the polymer that make it useful for food-contact applications. If technical effect is dependent on particle size, sponsors should present data that demonstrate the specific properties of the particles that make them useful for food-contact applications. Technical effect information need not be exhaustive and is frequently available in product technical bulletins.

In cases where the use level of an FCS is self-limiting, sponsors should provide supporting information or data.

D. Migration Testing & Analytical Methods

(See FDA Form 3480 ( PDF format | Word Template )- Part II, Section F)

Sponsors should provide information sufficient to permit estimation of the daily dietary concentration of the FCS, i.e., consumer exposure. FDA will calculate the concentration of the FCS or other components that might migrate to food expected in the daily diet based on analyzed or estimated levels in food or food simulants. A more complete discussion of this topic is given in Section II.E. and Appendix IV.

The concentration of an FCS in the daily diet may be determined from measured levels in food or in food simulants. It may also be estimated using information on formulation or residual levels of the FCS in the food-contact article and the assumption of 100% migration of the FCS to food. Although FDA always has accepted reliable analyses of FCS in real foods, in practice, many analytes are difficult to measure in food. As an alternative, sponsors may submit migration data obtained with food simulants that can reproduce the nature and amount of migration of the FCS into food. Because an FCS may be used in contact with many foods with different processing conditions and shelf lives, the submitted migration data should reflect the most severe temperature/time conditions to which the food-contact article containing the FCS will be exposed.

Before undertaking migration studies a sponsor should consider carefully the potential uses of the FCS. If, for example, use at temperatures no higher than room temperature is anticipated, it makes little sense to conduct migration experiments that simulate high temperature food contact. Such experiments would lead to elevated levels of the FCS in the food simulants that might, in turn, require a more extensive toxicological data package to support the exaggerated exposure estimate. In some cases where the use level of the FCS is low, it may be possible to dispense with migration studies altogether by assuming 100% migration of the FCS to food. The following example illustrates this approach:

Consider an adjuvant added prior to the sheet-forming operation in the manufacture of paper. If analysis or calculation shows that the final adjuvant concentration in paper cannot exceed 1 mg/kg and the basis weight of the finished paper is 50 pounds/3000 ft2, or 50 mg/in2, then the maximum weight of adjuvant per unit area of paper is 1 x 10-6 g adjuvant/g paper x 50 mg/in2 = 0.000050 mg/in2[4]. If all the adjuvant migrates into food and 10 grams of food contacts 1 square inch of paper (FDA's default assumption), the maximum concentration in food would be 5 µg/kg. It may be expected that this low concentration in food would lead to a commensurately low dietary concentration for the FCS. Therefore, although migration studies might result in further lowering of the estimate of daily intake, such studies might be unnecessary.

Levels in food should be based on the results of migration testing or other applicable methods in order to reflect as closely as possible the actual use conditions of the food-contact article containing the FCS. In general, migration values determined using the assumption of 100% migration to food should be avoided to reduce conservatisms to the greatest extent possible. 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 are of one side will be used in the calculations.

Design of the Migration Experiment (See FDA Form 3480 ( PDF format | Word Template )- Part II, Section F, item 1) MIGRATION CELL. When use of an FCS is anticipated with one particular type of food-contact article, such as a beverage bottle, the article may be filled with a food simulant and tested. For more general uses or when the surface area of the food-contact article does not produce sufficient extractives for adequate characterization, a migration cell should be used in which a specimen of known surface area is extracted by a known volume of simulant. The two-sided migration cell described by Snyder and Breder (Snyder and Breder, 1985) is recommended. Although this specific cell may not be universally applicable, FDA recommends that two of its essential features be incorporated in modified designs. These are: Polymer plaques of known surface area and thickness (see Section II.D.1.b. for further discussion) are separated by inert spacers (such as glass beads) so that simulant flows freely around each plaque. Migration from the plaque is considered to be two-sided. The headspace is minimized, and gas-tight and liquid-tight seals are maintained. (Minimum headspace and gas tightness are of lesser importance if the migrant of interest is non-volatile.) Importantly, the cell should be subjected to mild agitation to minimize any localized solubility limitation that might result in mass-transfer resistance in the food simulant. For applications in which a two-sided cell design is not suitable, such as laminate constructions, sponsors may refer to the references in Appendix VI for applications describing other cell designs. Sponsors also may devise an alternative cell. FDA is willing to comment on any such design prior to its application for a migration experiment. TEST SAMPLE. Some important considerations are the following: Formulation: Sponsors should use the highest proposed concentration of the FCS in the food-contact article in preparing samples for migration testing. Sponsors should provide information that characterizes resin samples used in testing, including the concentrations and identities of other components that may be present, the chemical composition of the resin (including co-monomer content where appropriate), molecular weight range, density, and melt flow index. If the formulation is plasticized, the most highly plasticized formulation should be used for testing. Sample Thickness & Surface Area: Sponsors should report both the thickness of the test plaque and its total surface area. If a plaque is tested by immersion and is of sufficient thickness to ensure that the initial FCS concentration at its center is unaltered by migration that occurs from both sides during the test period, the surface area of both sides may be used to calculate migration (units of mg/in2). Migration may be considered to occur independently from both sides of a sample plaque if its thickness is at least 0.05 cm (20 mil or 0.020 in) and not more than 25 percent of the FCS has migrated by the end of the experiment. If these conditions are not met, the surface area of only one side should be used in the calculation and consideration should be given to proposing a limitation on film thickness. Migration from paper is solubility, rather than diffusion, driven therefore paper used in migration tests is considered to be single sided regardless of thickness. Polymer properties: If the FCS is a polymer adjuvant, sponsors should perform migration testing on the polymer with the lowest average molecular weight which complies with the specifications set in 21 CFR 177 (see Appendix II. Section 2. for further discussion). If the FCS is a new polymer, the polymer that would be expected to give the highest levels of extractives, i.e., the polymer with the lowest average molecular weight, percent crystallinity, and degree of cross-linking should be tested. FOOD SIMULANTS. The following food simulants are recommended. Additional discussion on this subject is found in Appendix I. Food-Type as defined in 21 CFR 176.170(c) Table 1 Recommended Simulant Aqueous & Acidic Foods (Food Types I, II, IVB, VIB, and VIIB) 10% Ethanol(a) Low- and High-alcoholic Foods (Food Types VIA, VIC) 10 or 50% Ethanol(b) Fatty Foods (Food Types III, IVA, V, VIIA, IX). Food oil (e.g., corn oil), HB307, Miglyol 812, or others(c) a for exceptions, see main text.

b actual ethanol concentration may be substituted (see main text and Appendix II.).

c HB307 is a mixture of synthetic triglycerides, primarily C 10 , C 12 , and C 14 . Miglyol 812 is derived from coconut oil (see main text and Appendix I.).



When food acidity is expected to lead to significantly higher levels of migration than with 10% ethanol, or if the polymer or adjuvant is acid-sensitive, or if trans-esterification occurs in ethanol solutions, separate extractions in water and 3% acetic acid in lieu of 10% ethanol should be conducted. [5] 10% Ethanol is intermediate in alcohol concentration between wine and beer. Migration levels to wine and beer are not expected to be very different from 10% ethanol values. Therefore, test results developed with 10% ethanol may generally be used to evaluate exposures and support clearances for contact with alcoholic beverages with up to 15 volume % ethanol. Unsaturated food oils (like corn and olive oils) can at times be difficult matrices for the analysis of a migrant because these oils are susceptible to oxidation, especially at high temperature. Miglyol 812, a fractionated coconut oil having a boiling point range of 240° to 270°C and composed of saturated C 8 (50-65%) and C 10 (30-45%) triglycerides, is an acceptable alternative fatty-food simulant for migration testing.[6] HB 307, a mixture of synthetic triglycerides, primarily C 10 , C 12 , and C 14 , also is useful as a fatty-food simulant.[7] In some cases, analysis of a migrant in a food oil will not be practical and a simple solvent must be used. There does not appear to be one solvent that will effectively simulate a food oil for all polymers. A list of various polymers and their recommended fatty-food simulants appears in Appendix I. For other polymers, sponsors should consult with FDA concerning use of an appropriate fatty-food simulant before performing migration experiments. The simulant volume should ideally reflect the volume-to-specimen surface-area ratio expected to be encountered in actual food packaging. A ratio of 10 mL/in2 is acceptable. Other ratios may be acceptable if migration levels do not approach concentrations reflecting the partition limit (i.e., the solubility of the FCS in the food simulant). Precipitation of the FCS from solution or a cloudy solution is an indication that this limit has been reached. The volume-to-surface-area ratio should be reported. TEMPERATURE AND TIME OF TEST. Sponsors should conduct migration testing under the most severe conditions of temperature and time anticipated for the proposed use. If the intended use of the FCS involves contact with food at temperatures higher than room temperature, tests should be conducted at the highest use temperature for the maximum expected time period. In many instances, short time periods of elevated temperature-food contact are immediately followed by extended periods of storage at ambient temperatures. For such applications, FDA's recommended migration protocols call for short-term accelerated testing designed to simulate FCS migration that may occur during the entire food-contact period. Recommended protocols for selected situations are given in Appendix II.; however, depending on the particular food-contact application, a specific protocol may be devised. For room-temperature applications, a test temperature of 40°C (104°F) for 10 days is recommended. This accelerated testing protocol is based on studies showing that experimental migration levels are roughly equivalent to levels obtained after extended storage (6-12 months) at 20°C (68°F) [8]. For refrigerated or frozen food applications, the recommended test temperature is 20°C (68°F). For polymers, such as polyolefins, that are used with food at temperatures above their glass transition temperatures (i.e., the polymer is in the rubbery state), the highest migration values (typically, but not always, the ten day values) are generally used by FDA to calculate the concentration of migrants in food. Polymers such as polyethylene terephthalate (PET) and polystyrene (PS), however, are used with food at temperatures below their glass transition temperatures (i.e., the polymer is in the glassy state). At a fixed temperature, the rate of diffusion of migrants through a polymer in the glassy state is lower than if the polymer were in the rubbery state. For this reason, accelerated testing for 10 days at 40°C might underestimate migration that would occur during the entire food-contact scenario. Therefore, migration data obtained over ten days at 40°C should be extrapolated to 30 days in order to better approximate migration levels expected after extended time periods at ambient conditions. The sponsor may carry out testing for 30 days to avoid uncertainties in extrapolation. If data are provided that demonstrate that a different extrapolation period is more appropriate for a given adjuvant/polymer combination, such information would be used for evaluating exposure. For restricted uses where the maximum shelf life and food-contact temperature of an article are known, sponsors are encouraged to carry out migration studies for the maximum shelf life under temperature conditions approximating expected use. Sponsors may want to consult FDA before undertaking such tests. For each migration experiment, FDA recommends that portions of the test solutions should be analyzed during at least four time intervals. Recommended sampling times for a ten-day test are 2, 24, 96, and 240 hours. FDA recommends analysis of a blank or control using a test cell identical to that used for the test article. END TESTS (Compliance Tests). It is important to realize that the appropriate migration test conditions for a new FCS are not those described in 21 CFR 175.300, 21 CFR 176.170 or other sections in 21 CFR. These published "end-test" or compliance test extractions are quality control test methods for verifying whether a particular product is equivalent to the material that served as the basis for the regulation. End tests bear no relation to the migration testing recommended for evaluating probable exposure to a new FCS. Characterization of Test Solutions & Data Reporting (See FDA Form 3480 ( PDF format | Word Template )- Part II, Section F, item 1) Sponsors should perform migration studies in triplicate and analyze the test solutions for the migrants. If the submission is for a polymer, sponsors should determine the amount and nature of total nonvolatile extractives (TNEs). Ordinarily, the TNEs are determined gravimetrically. The nature of the extractives, which may include monomers, oligomers, adjuvants, and catalyst residues, should be determined by suitable chemical or physical tests, such as NMR, ultraviolet (UV)-visible, and atomic absorption spectroscopy (AAS), mass spectrometry (MS), and gas or liquid chromatography (GC or LC). The limit of quantitation (LOQ) and selectivity of the methods should be indicated in the submission. If quantitation of individual migrants is not possible, sponsors should determine the distribution of the extractives between organic and inorganic fractions by solvent fractionation (i.e., the fraction of the TNE residue that is soluble in chloroform or other suitable solvent[9]). This serves, as a first step, to focus on the migrants of interest (e.g., organic components) in determining exposure estimates. In these instances, FDA generally will estimate exposure to TNEs from the use of the FCS assuming that the TNEs (or solvent soluble TNEs) consist solely of low molecular weight oligomers that are chemically equivalent. Because the degree of toxicological testing depends on the magnitude of the exposure estimate, it should be to the sponsor’s advantage to quantitate the components in the TNEs that are not chemically equivalent (e.g., differentiate between low molecular weight oligomers and polymer adjuvants). Test solutions from polymers that are the subject of a submission also should be analyzed for constituent monomers. Alternatively, the known residual monomer level in the polymer may be used to calculate monomer dietary concentrations by using the density of the polymer, the maximum anticipated thickness of the food-contact article, and by assuming that all of the residual monomer migrates into food and that ten grams of food contact one square inch of food-contact article. If the submission is for a polymer adjuvant, the test solutions are generally analyzed only for the adjuvant. Occasionally, however, it may be appropriate to quantitate, in the test solutions, impurities or decomposition products present in the adjuvant if they might be expected to become components of the daily diet in toxicologically significant quantities. A common example would be the presence of carcinogenic impurities in the adjuvant. It also may be appropriate to quantitate, in the test solutions, decomposition products produced either as a result of the FCS exhibiting its intended technical effect in the food-contact article or in the test solutions after migration of the FCS. An example would be the use of a new antioxidant for polyolefins. Polymer antioxidants, by their nature, would be expected to partially decompose during thermal processing of the resin or food-contact article to which they have been added. Frequently, decomposition will occur after migration of the FCS into the food or food simulant, where temperatures may reach 120°C with fatty-food simulants. Information on decomposition in food simulants may be obtained by conducting stability studies on the FCS in parallel with the migration studies. Sponsors should report results in terms of milligrams of substance extracted per square inch (mg/in2) of surface area. Although migration levels often are expressed in terms of mg/dm2, the mixed unit mg/in2 is preferred to facilitate conversion to concentration in food. If ten grams of food are in contact with one square inch of food-contact article surface, a migration of 0.01 mg/in2corresponds to a concentration in food of 1 mg/kg. For specialized food-contact applications where an assumed ratio of 10 g food per in2 is not appropriate, such as in dual-ovenable trays and microwave heat-susceptor applications, sponsors should use the lowest ratio from the actual food-contact applications and should provide justification for the ratio selected. Analytical Methods (See FDA Form 3480 ( PDF format | Word Template )- Part II, Section F, item 1) Sponsors should submit the following for each method: DESCRIPTION OF THE METHOD. The description should include discussions on the method's accuracy, precision, selectivity, limit of quantitation (LOQ), and limit of detection (LOD). [10] Sufficient detail should be provided so that it can be followed by an experienced analytical chemist. If a literature reference is available, a copy should be included in the submission. STANDARD CURVES. Standard curves or calibration curves obtained by analyzing a prepared medium fortified with several known amounts of analyte to obtain concentrations both greater than and less than the concentration of migrant in the test solutions. The prepared medium may be the pure solvent, a solution of known ionic strength, etc. The data points from which the standard curve is derived should bracket the concentration of the migrant in the test solution. An analyte concentration of 1 mg/kg determined from a standard curve obtained from concentrations of 10, 15 and 20 mg/kg would be unacceptable. The correlation coefficient and standard errors of the Y intercept and the slope should be reported with the standard curve. EXAMPLES OF SPECTRA OR CHROMATOGRAMS. Sponsors should submit sample spectra and chromatograms, clearly identifying and labeling all major peaks to avoid ambiguities in interpretation. EXAMPLE CALCULATIONS. Sponsors should submit example calculations relating the data obtained from instrumental methods to the reported levels (preferably in milligrams migrants per square inch of sample surface area). 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. The examples allow the reviewer to perform a rapid internal check on the reported method. VALIDATION OF ANAYLTICAL METHODS. Sponsors should properly validate all analytical methods. Validation of a method's intended use and the determination of accuracy and precision usually involves: 1) replicate analyses of appropriate matrices fortified with known amounts of the analyte at concentrations similar to those encountered in the migration studies, and 2) determination of the percent recovery of the fortified analyte. In cases where a polymer adjuvant is the subject of interest, test solutions of the polymer formulated without the adjuvant may serve as the matrix for fortification and recovery measurements. Recovery is defined as the difference between measured analyte levels in the fortified and unfortified matrices. Percent recovery is the recovery divided by the fortified level times 100, i.e., if "a" is the measured level in the unfortified solution, "b" is the measured level in the fortified solution and "c" is the fortification level, then percent recovery equals (b-a)/c x 100. If migration test solutions are fortified, they should be fortified before analytical workup but after the prescribed test time, e.g., 240 hours. The actual test solutions must be fortified and not the pure food simulants. Fortification of pure simulants instead of the test simulants is probably the most common deficiency in the validation section of an analytical method. Additionally, as noted in Section II.D.2, the stability of the analyte(s) in the migration test solution should be demonstrated. Sponsors should perform fortification and recovery experiments using three (3) sets of triplicate samples of the test simulants with each set fortified at a separate level. The fortification levels should be one-half (½), one (1), and two (2) times the measured concentration of the analyte in the food simulant. In the event that the FCS is not detected, sponsors should determine the LOD for the method. For quantifiable levels of the analyte, acceptable recoveries should meet the following criteria: Levels in food or food simulants(a) Acceptable average recovery Acceptable relative standard deviation <0.1> 60-110% <> >0.1 mg/kg 80-110% <> (a)If 0.001 mg of a substance is extracted from one square inch of packaging material into 10 grams of food or food simulant, the estimated concentration in food is 0.1 mg/kg. In evaluating the precision of the analytical method, the variability arising from analyses of individual samples can be eliminated by performing triplicate analyses on a homogeneous composite (a blend of the triplicate samples) where practicable. Other validation procedures may be appropriate depending on the particular analysis. For example, analysis of the same test solution by two independent analytical methods would be acceptable validation. Similarly, the method of standard additions is an acceptable alternative in certain cases, such as metal analysis by AAS. In this case, fortify the matrix at two separate concentrations (at least) in addition to the unfortified concentration, and verify the linearity of the standard addition curve by calculation of the least squares correlation coefficient (r should be >0.995). Sponsors should submit representative spectra or chromatograms from validation analyses of fortified and blank samples. Spectra or chromatograms of the "blank" will facilitate the verification of the absence of interferences. An illustrative example appears in Appendix III. Migration Database (See FDA Form 3480 ( PDF format | Word Template )- Part II, Section F, item 2) Migration data for specific migrant/polymer/food simulant systems at given temperatures that exhibit a predictable migration-time behavior (e.g., Fickian diffusion) may be used to predict migration at other temperatures. Thus, the need for migration studies for new applications, which may be difficult to perform in certain cases (e.g., high temperature applications), may be reduced. For example, migration data obtained over 10 days (240 h) at 40°C that exhibits Fickian behavior, in combination with migration data obtained at other temperatures (e.g., 60°C and 80°C), may be extrapolated by means of an Arrhenius plot to predict migration under retort conditions (121°C/2 h and 40°C/238 h), if no apparent change in polymer morphology, such as glass transition or polymer melting, is expected between 30°C and 130°C. Apparent diffusion coefficients, D, at 121°C for each migrant/polymer/food simulant can be obtained from a plot of ln D vs 1/T(K). Thus, migration for 2 hours at 121°C can be estimated and added to migration after 238 hours at 40°C to obtain total migration expected for retort and ambient storage conditions. The density and thickness of the polymer sample and initial concentration of the migrant in the polymer are also necessary for the calculations. The FDA migration database is intended as a resource for migration data, including diffusion coefficients and relevant polymer/additive properties. FDA continues to compile migration data from various sources for use in estimating migration levels for FCSs. Reliable migration data, e.g., data that follow Fickian diffusion, provided in support of a premarket submission for a food contact substance would be added to the database. In addition, only migration levels that have been measured at three or more time intervals for a given temperature will be considered for inclusion in the migration database. Sponsors may submit suitable data for inclusion into the database in the form of a letter, as part of a notification or petition, or in a Food Additive Master File (FMF). The FDA migration database is available upon request from the Division of Food Contact Notifications, premarkt@fda.hhs.gov. Migration Modeling (See FDA Form 3480 ( PDF format | Word Template )- Part II, Section F, item 2) As discussed above, migration levels in food are typically estimated based on the results of migration testing under the anticipated conditions of use or under the assumption of 100% migration of the FCS to food. These two approaches are adequate in most instances. A third alternative involves migration modeling. One simple approach to modeling migration for specific migrant/polymer/food simulant systems, based on select experimental data, was discussed above in Section II.D.4. If this approach is taken, the source of any material constants used in the migration modeling should be referenced, whether the source is the FDA migration database or the open literature. Recently, semi-empirical methods have been developed to determine migration levels using limited or no migration data (see, e.g., (Limm and Hollifield, 1996) and (Baner, et al., 1996)). These diffusion models rely on estimation of diffusion coefficients based on the nature of the migrant and the physical properties of the polymer. These models may be useful substitutes for, or additions to, experimental data under limited circumstances. Several caveats should be considered in the application of these diffusion models. First, distribution of the migrant in the polymer is considered isotropic. Non-isotropic distribution, whether intentional or unintentional, would be expected to result in non-Fickian migration. Second, other aspects of migration, such as partitioning, mass transfer, polymer morphology, shape/polarity of the migrant, and plasticization of the polymer are not considered in these models. These factors should be considered carefully when deriving migration levels to food using modeling techniques.

E. CONSUMER EXPOSURE

(See FDA Form 3480 ( PDF format | Word Template )- Part II, Section G)

Migration data developed using the procedures outlined in Section II.D. are intended to provide estimates of the highest level of migration to food that might result from the anticipated use of the FCS. FDA estimates probable exposure to the FCS by combining the migration data with information on uses of food-contact articles that may contain the FCS (i.e., on the fraction of a person's diet likely to contact food-contact articles containing the FCS).

From a given concentration of the FCS in the daily diet, the estimated daily intake (EDI) is calculated as the product of that concentration and the total food intake, assumed to be 3 kilograms per person per day (kg/p/d, solids and liquids). A concentration in the daily diet of 1 ppm corresponds to an EDI of 1 mg FCS/kg food x 3 kg food/p/d, or 3 mg FCS/p/d.

The concentration in the daily diet and the EDI from the subject submission, along with the cumulative EDI (CEDI) from all authorized uses (from FAPs, FCNs and TORs), are used by FDA for the safety evaluation of an FCS. The CEDI of the FCS is used to determine the types of toxicity studies necessary to establish safety under the proposed conditions of use. Toxicological data recommendations for several tiers of CEDIs resulting from all proposed and permitted uses of the FCS, including regulated uses, uses that were the subject of previous FCNs, and the use in the subject FCN, are described in the document entitled "Preparation of Food Contact Notifications for Food Contact Substances: Toxicology Recommendations" available on the Internet at http://www.cfsan.fda.gov/guidance.htm.

The approach outlined below is designed to deal with the majority of FCSs intended for single-use. For estimating dietary exposures to components of repeat-use items and articles used in or with food processing equipment, exposure estimates also will consider the amount of food to be contacted during the service life of the food-contact article (see Appendix II. Section 4.).

Calculation of Exposure CONSUMPTION FACTOR. The term "Consumption Factor" (CF) describes the fraction of the daily diet expected to contact specific packaging materials. The CF represents the ratio of the weight of all food contacting a specific packaging material to the weight of all food packaged. CF values for both packaging categories (e.g., metal, glass, polymer and paper) and specific food-contact polymers are summarized in Table I of Appendix IV. These values were derived using information on the types of food consumed, the types of food contacting each packaging surface, the number of food packaging units in each food packaging category, the distribution of container sizes, and the ratio of the weight of food packaged to the weight of the package. These values, however, may be modified as new information is received. When FDA computes exposure to an FCS, it assumes that the FCS will capture the entire market for which it is intended for use. This approach reflects both uncertainties about likely market penetration as well as limitations in the data surveyed. Thus, if a company proposes the use of an antioxidant in polystyrene, it is assumed that the antioxidant will be used in all polystyrene manufactured for food contact. In certain cases where an adjuvant is intended for use in only a part of a packaging or resin category, a lower CF representing the coverage that is sought may be used. For example, if a stabilizer is intended for use only in rigid and semirigid poly(vinyl chloride) (PVC), a CF of 0.05 rather than 0.1 could be used in estimating exposure since only about 50% of all food-contact PVC could contain the stabilizer. Another example is the division of polystyrene into impact and non-impact categories (see Table I, Appendix IV.). To reduce conservatisms, FDA recommends that sponsors submit as detailed information as possible on the anticipated resin or packaging market(s) that may be captured by articles manufactured from the FCS. 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. When new products are introduced, they will initially be treated as replacement items for existing technology. As noted, FDA generally makes estimates based on the assumption that a new product will capture the entire market. For example, the retortable pouch initially was treated as a replacement for coated metal cans and was assigned a CF of 0.17. As additional information on actual use of the retortable pouch became available, the CF was lowered to 0.0004. In certain cases, the submission of resin or packaging market data may lead to the use of a lower CF. FOOD-TYPE DISTRIBUTION FACTOR. Before migration levels can be combined with CF values to derive estimates of probable exposure, the nature of the food that will likely contact the food-contact article containing the FCS must be known. Migration into a fatty-food simulant, for example, will be of little use in estimating probable exposure if the FCS is used exclusively in or for articles in contact with aqueous food. To account for the variable nature of food contacting each food-contact article, FDA has calculated "food-type distribution factors" (f T ) for each packaging material to reflect the fraction of all food contacting each material that is aqueous, acidic, alcoholic and fatty. Appropriate f T values for both packaging categories and polymer types appear in Table II of Appendix IV. CONCENTRATION IN THE DAILY DIET AND EDI. FDA uses the following approach for calculating the concentration of the FCS in the daily diet. The concentration of the FCS in food contacting the food-contact article, , is derived by multiplying the appropriate f T values by the migration values, M i , for simulants representing the four food types. This, in effect, scales the migration value from each simulant according to the actual fraction of food of each type that will contact the food-contact article. = f aqueous and acidic (M 10% ethanol )+f alcohol (M 50% ethanol )+f fatty (M fatty ) where M fatty refers to migration into a food oil or other appropriate fatty-food simulant. The concentration of the FCS in the diet is obtained by multiplying by CF. The EDI is then determined by multiplying the dietary concentration by the total weight of food consumed by an individual per day. FDA assumes that an individual consumes 3 kg of food (solid and liquid) per day (see Appendix IV. for sample calculations): EDI = 3 kg food/person/day x x CF CUMULATIVE EXPOSURE (CEDI). If the FCS already is regulated for other uses in 21 CFR 170-199, has been exempted from the need for a regulation under the Threshold of Regulation (21 CFR 170.39), or has been the subject of previous effective FCNs, the sponsor should estimate the cumulative exposure to the FCS from the proposed and permitted uses (see the example in Appendix IV.). Information on the regulatory status of an FCS may be obtained by inspection of 21 CFR 170-199, searching the CFR on the Government Printing Office (GPO) World Wide Website at http://www.access.gpo.gov/nara/cfr/index.html, or contacting FDA directly. Information on effective FCNs or Threshold of Regulation exemptions for an FCS may be obtained through the FDA website or by contacting FDA directly. An estimate of cumulative exposure for the regulated, notified and exempted uses of an FCS can be obtained by contacting FDA. FDA also maintains a database of CEDIs for FCSs on the Agency's internet site (http://www.cfsan.fda.gov). Exposure Refinement Exposure estimates, in general, will be made using the aforementioned procedures. More refined estimates may be possible, however, with additional information provided in a submission. For instance, subdividing packaging or resin categories could reduce the calculated exposure by lowering the CF for the category. The division of PVC into rigid and plasticized categories and PS into impact and non-impact categories are two examples. Another example is the division of polymer coatings for paper into subcategories, such as poly(vinyl acetate) coatings, styrene-butadiene coatings, etc. If an FCS is to be used solely in styrene-butadiene coatings for paper, use of the CF for polymer-coated paper (0.2, Appendix IV. Table 1) would be a gross exaggeration. As noted above, FDA encourages the submission of information that may be used to subdivide the market(s) anticipated for articles manufactured from the FCS. In those cases where the nature of the coverage requested may necessitate more detailed information or where a sponsor believes that exposure will be overstated by selecting CF and f T values from Appendix IV., data of the following type may be submitted to facilitate calculations of CF and f T for materials likely to contain the FCS: Estimates of the total amount of food in contact with the packaging material determined using either: package unit data (number of units and their size distribution), or total weight of packaging material produced for food contact, container size distribution, and ratios of weight of food packaged to weight of package. Characterization of the foods that might contact the food-contact article, along with supporting documentation, and the likely f T values. Information that would demonstrate that only a fraction of a packaging or resin category would be affected by the coverage sought. Technological limitations that could affect the type of food contacted or the fraction of the diet that might be contacted.

F. LIST OF ACRONYMS AND ABBREVIATIONS

AAS Atomic Absorption Spectroscopy CAS Chemical Abstracts Service CEDI Cumulative Estimated Daily Intake CF Consumption Factor CFSAN Center for Food Safety and Applied Nutrition CFR Code of Federal Regulations D Diffusion coefficient DC Dietary Concentration DFCN Division of Food Contact Notifications EDI Estimated Daily Intake FAP Food Additive Petition FCN Food Contact Notification FCS Food Contact Substance FDA Food and Drug Administration FDAMA Food and Drug Administration Modernization Act FMF Food Additive Master File FOIA Freedom of Information Act f T Food-type Distribution Factor EVA Ethylene Vinyl Acetate GC Gas Chromatography GPC Gel Permeation Chromatography HDPE High-Density Polyethylene IR Infrared LC Liquid Chromatography LDPE Low-Density Polyethylene LLDPE Linear Low-Density Polyethylene LOD Limit of Detection LOQ Limit of Quantitation the concentration of the FCS in food contacting the food-contact article MS Mass Spectrometry M n number average Molecular Weight M w weight average Molecular Weight NMR Nuclear Magnetic Resonance OFAS Office of Food Additive Safety OMB Office of Management and Budget PET Polyethylene Terephthalate PP Polypropylene ppb parts per billion (ng/g or μg/kg) ppm parts per million (μg/g or mg/kg) PS Polystyrene PVC Poly(vinyl chloride) PVDC Poly(vinylidene chloride) T g Glass Transition Temperature TNE Total Non-volatile Extractive TOR Threshold of Regulation UV Ultra-Violet

G. REFERENCE FORMAT

All published and unpublished studies and information presented in a FCN or petition should be referenced appropriately in the text by citing the author(s) and year of publication. Each published reference should include the names of all authors, the year of publication, the full title of the article, pages cited, and name of publication. For a book, the reference also should include the title of the book, the edition, the editor(s) or authors(s), and the publisher. Reference to unpublished studies should identify all authors, the sponsor of the study, the laboratory conducting the study, the final report date, the full title of the final report, the report identification number, and inclusive page numbers. References to government publications should include the department, bureau or office, title, location of publisher, publisher, year, pages cited, publication series, and report number or monograph number.

APPENDIX I. FATTY-FOOD SIMULANTS FOR SPECIFIC POLYMERS

A food oil is the most extreme example of a fatty food. If contact with fatty foods is anticipated, FDA recommends conducting migration studies using a food oil as the food simulant. In addition to food oils, such as corn and olive oil for which extensive migration data already exist, the use of HB307 (a mixture of synthetic triglycerides, primarily C 10 ,C 12 , and C 14 ) as a fatty-food simulant has been recommended. Studies in FDA laboratories have shown that Miglyol 812, a fractionated coconut oil having a boiling range of 240-270°C and composed of saturated C 8 (50-65%) and C 10 (30-45%) triglycerides, is also an acceptable alternative. Since use of these oils for FCS migration may not always be practicable, the use of aqueous-based solvents that simulate the action of these liquid fats is sometimes necessary. While it seems unlikely that one solvent will be found that simulates the action of a food oil for all food-contact polymers, the following list presents polymers for which adequate data exist to support the use of aqueous-based solvents as fatty-food simulants. The recommendation of these solvents is based upon studies done at FDA, at the National Institute of Standards and Technology (formerly The National Bureau of Standards), and by Arthur D. Little, Inc. under contract to FDA (a list of general references pertaining to these studies is shown in Appendix VI). For polymers other than those listed below, sponsors should consult FDA before undertaking any migration experiments.

1. Polyolefins complying with 21 CFR 177.1520 and ethylene - vinyl acetate copolymers complying with 21 CFR 177.1350 95% or absolute ethanol 2. Rigid poly(vinyl chloride) 50% ethanol 3. Polystyrene and rubber-modified polystyrene 50% ethanol 4. Poly(ethylene terephthalate) 50% ethanol or isooctane

Absolute or 95% ethanol has been found to be an effective fatty-food simulant for polyolefins; however, it appears to exaggerate migration for other food-contact polymers.

Previous test protocols (prior to 1988) recommended the use of heptane as a fatty-food simulant. To account for the aggressive nature of heptane relative to a food oil, division of migration values by a factor of five was permitted. Studies have shown, however, that the exaggerative effect of heptane relative to a food oil varies over orders of magnitude depending on the polymer extracted. Thus, heptane is no longer recommended as a fatty-food simulant. However, FDA recognizes that in cases where very low migration is anticipated, such as for inorganic adjuvants or certain highly cross-linked polymers, heptane can be useful due to the ease of analytical workup. Because of the known variance in the exaggerative effect of heptane relative to food oil, if heptane is used, migration values will generally not be divided by any factor unless there is adequate justification.

APPENDIX II. SELECTED MIGRATION TESTING PROTOCOLS

The following migration testing protocols are intended to simulate most anticipated end-use conditions of food-contact articles. These protocols are based on the premise that migration to aqueous- and fatty-based foods is typically diffusion-controlled within the polymer, strongly affected by the temperatures encountered during food contact, and further modified by the solubility of the FCS in the foods. Therefore, migration testing with food simulants at the highest temperatures to be experienced by the food-contact article during food contact is recommended. Testing with actual fatty foods is also an option, although determination of the analytes of interest is often very difficult. In those instances where the expected use conditions are not adequately simulated by these protocols or testing with food simulants at the highest anticipated food-contact temperature is not practical, alternatives to those protocols presented below should be developed in consultation with FDA.

1. General Protocols (Single-Use Applications) Corresponding to Condition of Use

As noted in Appendix I., migration to fatty foods is evaluated using a fatty food, a pure liquid fat, or, alternatively, aqueous ethanol solutions when analytical limitations preclude sensitive analyses. As noted in Section II.D.1.c., migration to aqueous, acidic, and low-alcoholic foods is generally evaluated using 10% ethanol and migration to high-alcohol foods is generally evaluated using 50% ethanol.

The recommended migration protocols given below are intended to model thermal treatment and extended storage conditions for polymers, such as polyolefins, used with food at temperatures above their glass transition temperatures. The extended storage period generally involves testing at 40°C for 240 hours (10 days). As discussed in Section II.D.1.d., migration data obtained at 10 days for polymers used below their glass transition temperature should be extrapolated to 30 days to better approximate migration levels expected after extended storage at ambient conditions.

High temperature, heat sterilized or retorted (ca. 121 ° C (250°F))* 10% Ethanol(a) 121°C (250°F) for two hours Food Oil (e.g., corn oil) or HB307 or Miglyol 812 121°C (250°F) for two hours 50% or 95% Ethanol(a),(b) 121°C (250°F) for two hours (a)Requires a pressure cell or autoclave, see Appendix VI. Appropriate safety precautions should be exercised when using equipment generating pressures above 1 atmosphere.

(b)Depends on food-contact layer, see Appendix I. After two hours at elevated temperatures, the tests should be continued at 40°C (104°F) for 238 hours to a total of 240 hours (10 days). The test solutions should be analyzed at the end of the initial two hour period, and after 24, 96 and 240 hours. *Conditions of Use A includes reheating or cooking of foods where the temperature is £121 ºC (250 ºF), or heat-sterilized or retorted under transient temperatures >121 ºC (250 ºF). Boiling water sterilized. The same protocol as for Condition of Use A should be used except that the highest test temperature is 100°C (212°F). Hot filled or pasteurized above 66°C (150°F). Solvents should be added to the test samples at 100°C (212°F), held for 30 minutes, and then allowed to cool to 40°C (104°F). The test cells should be maintained at 40°C (104°F) for ten days with samples taken for analysis after the intervals indicated for the previous protocols. If the maximum hot fill temperature will be lower than 100°C (212°F), test solvents may be added at this lower temperature. Alternatively, migration studies should be performed for 2 hours at 66°C (150°F) followed by 238 hours at 40°C (104°F). For the alternative method, the longer time at the lower temperature (2 hours at 66°C vs 30 minutes at 100°C) compensates for the shorter time at 100°C. Note: migration studies conducted according to condition of use C are only adequate to support conditions of use C through G (not condition of use H). Hot filled or pasteurized below 66°C (150°F). The recommended protocol is analogous to that for C except that all test solvents are added to the test samples at 66°C (150°F) and held for 30 minutes before cooling to 40°C (104°F). Room temperature filled and stored (no thermal treatment in the container). The sponsor should conduct migration studies for 240 hours at 40°C (104°F). The test solutions should be analyzed after 24, 48, 120 and 240 hours. Refrigerated storage (no thermal treatment in the container). The recommended protocol is identical to that for E except that the test temperature is 20°C (68°F). Frozen storage (no thermal treatment in the container). The recommended protocol is identical to F except that the test time is five (5) days. Frozen or refrigerated storage; ready-prepared foods intended to be reheated in container at time of use. 10% Ethanol(a) 100°C (212°F) for two hours Food Oil (e.g., corn oil) or HB307 or Miglyol 812 100°C (212°F) for two hours 50% or 95% Ethanol(a),(b) 100°C (212°F) for two hours (a)Requires a pressure cell or autoclave, see Appendix VI.

(b)Depends on food-contact layer, see Appendix 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. Cooking (e.g., baking or browning) at temperatures exceeding 121 ºC (250 ºF). 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.

2. Adjuvants for Polyolefins

In general, under identical testing conditions, levels of migrants from low-density polyethylene (LDPE) are higher than from high-density polyethylene (HDPE) or polypropylene (PP). Migration studies done solely on LDPE (complying with 21 CFR 177.1520(a)(2)) at 100°C (approximately the highest temperature at which LDPE remains functional) are, therefore, generally sufficient to provide coverage for all polyolefins including PP, which may be used for retort applications. In such a case, the CF for all polyolefins (CF = 0.35) generally will be used instead of the individual CF for LDPE (0.12, see Appendix IV. Table I).

Nevertheless, when seeking coverage for use with all polyolefins, it is usually advantageous to perform migration testing on HDPE, PP and linear LDPE (LLDPE), complying with 21 CFR 177.1520, as well as LDPE. By doing this, actual migration values for these polyolefins, which will likely be lower than those obtained from LDPE, may be used to calculate the EDI.

The specific polymer test sample used in the migration testing should be one that has a morphology typically used in food packaging applications. The test material must comply with specifications set out in 21 CFR 177.1520. In addition to noting which specifications listed in 21 CFR 177.1520 apply, information characterizing the polymer resin, such as molecular weight distribution, melt flow index, and degree of crystallinity should be provided.

The catalyst technology for the manufacture of polyolefins is continually being improved. The choice of a particular catalyst technology for the synthesis of polyolefins such as LLDPE, HDPE, and PP determines their unique physical properties, such as molecular weight and melt flow index. These factors should be taken into account when selecting the appropriate test polymer for the adjuvant. In addition, an increase in the comonomer content of a copolymer generally results in a lower melt range, lower density, and lower crystallinity in comparison to the homopolymers. Therefore, for the broadest possible coverage of an adjuvant, migration testing should be conducted on LLDPE, HDPE or PP copolymers (not homopolymers) incorporating the highest comonomer level.

3. Adjuvants for Polymers (other than Polyolefins)

Adjuvants for More than One Polymer

The recommended migration testing protocols for polymers other than polyolefins are the same as those in Section 1. of this Appendix. Appendix I. should be consulted for the recommended fatty-food simulant.

If use of an FCS is sought without limitation to specific polymers, sponsors should test with an unoriented LDPE sample complying with 21 CFR 177.1520(a)(2). The test protocol depends on the anticipated conditions of use (refer to Section 1. of this Appendix). If the most rigorous applications correspond to Condition of Use A (Section 1.A.), the test temperature should be the highest temperature at which the polymer remains functional (ca.100°C for LDPE). The CF for all polymers (Appendix IV. Table 1, CF = 0.8) should be used with the migration data to calculate the concentration of the FCS in the daily diet. In general, a lower calculated concentration in the daily diet will result if a series of representative polymers are separately tested and individual consumption factors are applied (refer to the examples in Appendix IV.). Sponsors should consult with FDA to determine which representative polymers should be tested.

4. Articles Intended for Repeated Use

The article should be tested with 10% and 50% ethanol and a food oil (e.g., corn oil) or other fatty-food simulant (e.g., HB307 or Miglyol 812) for 240 hours at the highest intended temperature of use. The test solutions should be analyzed for migration of the FCS after 8, 72, and 240 hours. Sponsors should provide estimates of the weight of food contacting a known area of repeat-use article in a given time period as well as an estimate of the average lifetime of the article. Together with the migration data, this will allow calculation of migration to all the food processed over the service life of the article.

In the case of an adjuvant in a repeat-use article, FDA strongly recommends an initial calculation of a "worst-case" level in food by assuming 100% migration of the adjuvant over the service life of the article and dividing that value by the quantity of food processed. If this calculated concentration is sufficiently low, migration studies will be unnecessary.

5. Coatings for Cans

The migration testing protocol is usually that outlined in Section 1.A. of this Appendix for high temperature, heat sterilized or retorted products. If broad coverage is sought for all types of coatings, sponsors should consult with FDA to determine which coatings should be tested. For use conditions less severe than retort sterilization at 121°C, follow the migration test protocols outlined in Sections 1.B.-G. of this Appendix which most closely approximate the most severe expected use conditions.

6. Uncoated & Clay-Coated Papers with Latex Binders

These papers are intended for contact with food at temperatures less than 40°C for short periods of time. The recommended protocol is the following:

10% Ethanol 40°C (104°F) for 24 hours 50% Ethanol 40°C (104°F) for 24 hours Food Oil (e.g., corn oil) or HB307 or Miglyol 812 40°C (104°F) for 24 hours

Migration studies conducted on uncoated or clay-coated papers typically result in a high level of extractives due to the large number of low-molecular weight, soluble components in both paper and paper coatings. Therefore, when total nonvolatile extractives or solvent-soluble8 total nonvolatile extractives are determined for a paper coating, do not subtract the corresponding extractives from uncoated paper as a blank correction. Rather than using paper as a support for the coating, it is often useful to apply the coating to a suitable inert substrate, such as glass or metal, for use in migration testing. For a new adjuvant in paper coatings, the test solutions should be analyzed for the unregulated adjuvant. For a new polymer used in paper coatings, the test solutions should be analyzed for constituent oligomers and monomers.

7. Specially Treated Papers

This class includes such types as fluoropolymer- and silicone-treated papers that have oil- and/or heat-resistant properties. The specific protocol depends on the particular uses anticipated. It is recommended that the sponsor either devise a protocol and submit it to FDA for comment or request comment from FDA about appropriate test conditions.

8. Adhesives (Room temperature or below)

If the adhesive is either separated from food by a functional barrier, or the quantity of adhesive that contacts aqueous and fatty food is limited to the trace amount at seams and edges, then migration levels for the substances generally will be assumed to be no greater than 50 ppb. Applying a CF of 0.14 for adhesives gives a dietary concentration of 7 ppb. If these assumptions cannot be supported, data or calculations should be submitted to model the intended use of any adhesive component. If a sponsor wishes to perform migration testing, multilaminate samples should be fabricated with the maximum anticipated amount of the adhesive component and with the minimum thickness of the food-contact layer. The migration protocol corresponds to condition of use E. Alternatively, migration levels in food can be estimated based on migration modeling (see Section II.D.5.).

9. Laminates & Coextrusions

Components of multilayer structures used above room temperature are the subject of two regulations. One covers laminates used in the temperature range 120°F (49°C)-250°F (121°C) (21 CFR 177.1395) and the other covers laminate structures used at temperatures of 250°F (121°C) and above (21 CFR 177.1390). Layers not separated from food by barriers preventing migration during expected use must be listed in these regulations, or be the subject of an effective FCN, unless they are authorized elsewhere for the intended use conditions as specified in 21 CFR 177.1395(b)(2) and 21 CFR 177.1390(c)(1). Test protocols presented in Sections 1.A.-J. may be appropriate for evaluating the level of migration from non-food-contact layers of some laminate structures. End uses that differ considerably from those considered in this guidance, however, should be the subject of special protocol development in consultation with FDA.

10. Boil-In-Bags

Use of the protocol for Condition of Use C is recommended.

11. Special Cooking Applications

Advances in packaging technology have led to the development of food packaging materials that can withstand temperatures substantially exceeding 121°C (250°F) for short periods of time for the purposes of heating and cooking of ready-prepared food. FDA recommends use of the following protocols for migration testing of microwave-only containers, dual-ovenable containers, and microwave heat susceptor materials.

MICROWAVE-ONLY CONTAINERS The temperature ultimately experienced by a food-contact material when cooking foods in a microwave oven is dependent on many factors. Some of these are food composition, heating time, mass and shape of the food, and shape of the container. For example, food with mass in excess of 5 g/in2 container surface area and having a thick shape will require longer cooking times to achieve the desired degree of interior cooking than if it had a lower mass-to-surface area ratio and were thinner. Typical cooking conditions have been generally observed to not exceed 130 ºC (266 ºF). Test 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. DUAL-OVENABLE TRAYS For high-temperature oven use, migration testing should be performed at the maximum intended conventional oven cooking temperature for the longest intended cooking time, using a food oil, or fatty-food simulant (such as Miglyol 812). MICROWAVE HEAT-SUSCEPTOR PACKAGING The high temperatures attained by packaging using susceptor technology may result in (a) the formation of significant numbers of volatile chemicals from the susceptor components and (b) loss of barrier properties of food-contact materials leading to rapid transfer of nonvolatile adjuvants to foods. Studies by FDA, with hot vegetable oil in contact with a susceptor, have shown that the susceptor materials liberate volatile chemicals that may be retained in the oil at parts-per-billion (ppb) levels. FDA recommends the use of the protocol outlined in an article by McNeal and Hollifield (McNeal and Hollifield, 1993) for the identification and quantification of volatiles from susceptors. To isolate and identify the total available nonvolatile extractives, sponsors should perform Soxhlet extractions on finely shredded portions of laminated susceptor materials using polar and nonpolar solvents as outlined in Appendix X1 of ASTM method F1349-91. Migration protocols for UV-absorbing nonvolatiles also are outlined in ASTM method F1349-91 and in an article by Begley and Hollifield (Begley and Hollifield, 1991). The ASTM method relies on the determination of a time-temperature profile based on cooking a food product according to label directions, for the maximum cooking time. The temperature reached by a microwave heat-susceptor, however, is dependent on the amount and characteristics of the food product. Testing methods should involve a standard set of conditions that represent the maximum anticipated use conditions. Therefore, FDA recommends that migration studies be conducted in a manner similar to that outlined in the article by Begley and Hollifield. The recommended standard test conditions are as follows: use laminated susceptor stock representative of the proposed application(s); use a microwave oven with an output wattage of at least 700 watts; use a maximum microwave time of 5 minutes; use an oil mass-to-susceptor surface area on the order of 5 g/in2; and use a water load on the order of 5 g/in2. Exposure estimates may be based, in the absence of validated migration studies, on the assumption of 100% migration of the total nonvolatile extractives to food, as determined by Soxhlet extractions. Validated migration protocols for the direct determination of aliphatic migrants are not available at this time. However, the amount of aliphatic migrants may be estimated by subtracting the UV-absorbing nonvolatiles and inert materials from the total nonvolatiles obtained by Soxhlet extraction (see Appendix X1 in ASTM method F1349-91). Exposure estimates for aliphatic migrants should be based on the assumption of 100% migration to food.

12. Colorants for Plastics

Some colorants, pigments in particular, may be quite insoluble in the food simulants 10%- and 95%-ethanol. In such cases, solubility information may provide a basis for an alternative to migration testing for evaluating worst-case exposure since migration levels would not be expected to exceed the limits of solubility of the colorant at the proposed use temperature. If the colorant is to be used in all plastic packaging, for which a CF = 0.05 would be used, a solubility below ca. 100 µg/kg at 40°C would lead to a dietary concentration no greater than 5 ppb under conditions as severe as condition of use E (40 ºC for 240 hours). A solubility less than 10 µg/kg would lead to an exposure below the threshold level of 0.5 ppb dietary concentration (see 21 CFR 170.39).

13. Dry Foods with Surface Containing No Free Fat or Oil

(21 CFR 176.170(c), Table 1, Food Type VIII)

Dry foods with the surface containing no free fat or oil typically exhibit little to no migration, although some studies have shown migration of certain adjuvants into dry foods (e.g., volatile or low molecular weight adjuvants in contact with porous or powdered foods). 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.

14. Wet-End Additives used in the Manufacture of Paper and Paperboard

Paper additives used in the wet-end of papermaking include those designed to improve the papermaking process, such as processing aids, and those designed to modify the properties of the paper, such as functional aids. Functional aids, mostly organic resins or inorganic fillers, are designed to bond to the paper fibers and, thus, are substantive to paper. For those FCSs that are substantive to paper, migration studies should be conducted and the test solutions analyzed for constituents of the substance. For example, in the case of a polymeric retention aid, the test solutions should be analyzed for constituent oligomers and monomers. On the other hand, processing aids are intended to remain with the process water slurry and, thus, are generally not substantive to paper. Exposure estimates for non-substantive additives may be based on migration studies, or alternatively, on scenarios involving partitioning of the additive between paper fibers and slurry water. The following example illustrates this approach:

Consider an adjuvant added prior to the sheet-forming operation in the manufacture of paper. The intended use level is reported to be 10 mg/kg in the slurry. Since the additive is not substantive to paper, the mass of water (containing the additive) in contact with the pulp at the point in the papermaking process where the slurry enters the drier determines the level of the adjuvant retained in paper. Prior to entering the driers, the slurry is mechanically concentrated to contain approximately 33% pulp and 67% water. This corresponds to an adjuvant level of 20 mg/kg relative to the pulp. Assuming that finished paper contains 92% pulp, a paper basis weight of 50 mg/in2, 100% migration of the adjuvant to food, and that 10 g of food contacts 1 in2 paper, this results in an adjuvant concentration in food of 0.09 mg/kg, or 90 µg/kg. Applying a CF of 0.1 for uncoated and clay-coated paper gives a dietary concentration of 9 ppb.

15. Materials for use during the Irradiation of Prepackaged Food

We do not currently have protocols for studies on FCSs that are intended to be irradiated. Please consult with FDA to discuss recommended protocols for this use.

16. 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.

APPENDIX III. ILLUSTRATIVE EXAMPLE OF VALIDATION OF ANALYSES

Polyethylene film containing a new antioxidant was subjected to migration testing with 10% ethanol. The test solutions were analyzed for antioxidant migration. Tests were carried out in separate cells each containing 100 in2 of film. Four sets of test solutions (in triplicate) were analyzed at 2, 24, 96 and 240 hours for a total of 12 test solutions. After each time interval, each solution from one set was evaporated to dryness, the residue dissolved in an appropriate organic solvent, and a known aliquot injected into a gas chromatograph.

Validation experiments are carried out with the set of test simulants exhibiting the highest level of antioxidant migration. To validate the analytical method, an additional three sets (in triplicate) using 10% ethanol can be run for 240 hours. Each set of these test solutions then can be fortified with the antioxidant at levels corresponding to one-half (1/2), one (1) and two (2) times, respectively, the average migration value determined for the regular (unfortified) 240 hour test solutions.

Instead, the sponsor decided to carry out one large test using enough film and solvent for twelve analyses (three at each of the four time intervals). After 240 hours, the test solution was divided into twelve (12) equal solutions (i.e., four sets of triplicate samples). One set (three solutions) was found to contain antioxidant at an average level of 0.00080 mg/in2. This value corresponds to 0.080 mg/kg in food if it is assumed that 10 grams of food contacts 1 in2 of film. Of the remaining nine solutions (three sets), three solutions were fortified at concentrations corresponding to 0.00040 mg/in2, three were fortified at 0.00080 mg/in2, and three were fortified at 0.00160 mg/in2. Each solution was worked up and analyzed as described above. To illustrate the recovery calculations, the results for the set of three solutions fortified at one-half times the average migration (0.00040 mg/in2) are summarized in the following table:

Measured Level in each Sample (mg/in2)(a) Recovery (mg/in2)(b) Percent Recovery (%)(c) 0.00110 0.00030 75.0 0.00105 0.00025 62.5 0.00112 0.00032 85.0 (a)includes 0.00040 mg/in2 fortification.

(b)calculated by subtracting the average level (0.00080 mg/in2) from the measured levels in each sample.

(c)calculated by dividing the recovery by the fortification level (0.00040 mg/in2), and multiplying by 100 (see Section II.D.3.e.).

The average percent recovery is 74.2%, and the relative standard deviation is 15.2%. These are within the limits specified (see Section II.D.3.e.) for a concentration in food of 0.080 mg/kg (percent recovery 60-110%, relative standard deviation not exceeding 20%). If the corresponding percentages for the other two fortification levels are also within these limits, the validation for the 10% ethanol migration studies would be acceptable. The actual validation procedure used will, of course, depend on the particular type of analysis.

APPENDIX IV. CONSUMPTION FACTORS, FOOD-TYPE DISTRIBUTION FACTORS, AND EXAMPLE OF EXPOSURE ESTIMATE CALCULATIONS

This appendix summarizes packaging data recommended by FDA for evaluating exposure to FCS. An example of how these data are combined with levels of an FCS in food also is presented. A more complete discussion of the source of these data and their use in exposure calculations is presented in Section II.E.

TABLE I - CONSUMPTION FACTORS (CF) Package Category CF Package Category CF A. General Glass 0.1 Adhesives 0.14 Metal- Polymer coated 0.17 Retort pouch 0.0004 Metal- Uncoated 0.03 Microwave susceptor 0.001 Paper- Polymer coated 0.2 All Polymers(a) 0.8 Paper- Uncoated and clay-coated 0.1 Polymer 0.4 B. Polymer Polyolefins 0.35(b) PVC 0.1 -LDPE 0.12 -rigid/semirigid 0.05 -LLDPE 0.06 -plasticized 0.05 -HDPE 0.13 PET(c,d) 0.16 -PP 0.04 Other Polyesters 0.05 Polystyrene 0.14 Nylon 0.02 EVA 0.02 Acrylics, phenolics, etc. 0.15 Cellophane 0.01 All Others(e) 0.05 (a)Originates from adding CFs for metal-polymer coated, paper-polymer coated, and polymer (0.17 + 0.2 + 0.4 = 0.8).

(b)Polyolefin films, 0.17 (HDPE films, 0.006; LDPE films, 0.065; LLDPE films, 0.060; and PP films, 0.037).

(c)PET-coated board, 0.013; thermoformed PET, 0.0071; PET carbonated soft drink bottles, 0.082; custom PET, 0.056; crystalline PET, 0.0023; PET films, 0.03.

(d)A CF of 0.05 is used for recycled PET applications (see the document entitled "Points to Consider for the Use of Recycled Plastics in Food Packaging: Chemistry Considerations").

(e)As discussed in the text, a minimum CF of 0.05 will be used initially for all exposure estimates.

TABLE II - FOOD-TYPE DISTRIBUTION FACTORS (f T ) Package Category Food-Type Distribution (f T ) Aqueous(a) Acidic(a) Alcoholic Fatty A. General Glass 0.08 0.36 0.47 0.09 Metal- Polymer coated 0.16 0.35 0.40 0.09 Metal- Uncoated 0.54 0.25 0.01(b) 0.20 Paper- Polymer coated 0.55 0.04 0.01(b) 0.40 Paper- Uncoated and clay-coated 0.57 0.01(b) 0.01(b) 0.41 Polymer 0.49 0.16 0.01(b) 0.34 B. Polymer Polyolefins 0.67 0.01(b) 0.01b 0.31 Polystyrene 0.67 0.01(b) 0.01(b) 0.31 -impact 0.85 0.01(b) 0.04 0.10 -nonimpact 0.51 0.01 0.01 0.47 Acrylics, phenolics, etc. 0.17 0.40 0.31 0.12 PVC 0.01(b) 0.23 0.27 0.49 Polyacrylonitrile, ionomers, PVDC 0.01(b) 0.01(b) 0.01(b) 0.97 Polycarbonates 0.97 0.01(b) 0.01(b) 0.01(b) Polyesters 0.01(b) 0.97 0.01(b) 0.01(b) Polyamides (nylons) 0.10 0.10 0.05 0.75 EVA 0.30 0.28 0.28 0.14 Wax 0.47 0.01(b) 0.01(b) 0.51 Cellophane 0.05 0.01(b) 0.01(b) 0.93 (a)For 10% ethanol as the food simulant for aqueous and acidic foods, the food-type distribution factors should be summed.

(b)1% or less

Examples of Exposure Estimate Calculations

The following hypothetical examples are intended to illustrate the calculation of the concentration of an FCS in the daily diet (CF x , i.e., the fraction of food in the diet contacting the food-contact article times the average concentration of the FCS in food) and its EDI and CEDI.

Example 1

An FCN is received that describes the use of a new antioxidant at a maximum level of 0.25% w/w in polyolefins contacting food at or below room temperature (see Appendix II. Sections 1.E. through 1.G.). Migration values from LDPE reported to FDA for the three food simulants are given below:

Solvent (i) M i (mg/kg) 10% aqueous ethanol 0.060 50% aqueous ethanol 0.092 Miglyol 812 7.7

The notifier used a solvent volume-to-exposed surface area ratio of 10 mL/in2. Therefore, solution concentrations are essentially equivalent to food concentrations (under the assumption that 10 g food contacts 1 in2 of surface area). The CF and f T s for polyolefins are given in Tables I and II, respectively. The for the antioxidant would be calculated as follows:

= (f aqueous +f acidic )(M 10% ethanol ) + f alcohol (M 50% ethanol ) + f fatty (M Miglyol 812 ) = (0.68)(0.060 mg/kg )+0.01(0.092 mg/kg)+0.31(7.7 mg/kg) = 2.4 mg/kg

The concentration of the antioxidant in the daily diet resulting from the proposed use would be:

CF x = 0.35 x 2.4 mg/kg = 0.84 mg/kg

If there were no other permitted uses, then the CEDI would be calculated using the above value:

CEDI = 3 kg food/person/day x 0.84 mg antioxidant/kg food = 2.5 mg/person/day

Example 2

In a subsequent notification, expanded use of the same antioxidant in polycarbonate and polystyrene food-contact articles is described. Each polymer would contact food at or below room temperature. Migration levels are given below:

Solvent Migration to Food (mg/kg) Polycarbonate Polystyrene Impact Polystyrene 10% aq. Ethanol 0.020 0.020 0.020 50% aq. Ethanol 0.025 0.035 0.22 Miglyol 812 0.033 0.15 6.2

The concentration of the antioxidant in the daily diet resulting from each of the proposed uses is calculated below. A CF of 0.04 for impact polystyrene and a CF of 0.06 for all other polystyrenes was used in the calculation.

Polycarbonates

CF x = 0.05(0.98(0.020 mg/kg) +0.01(0.025 mg/kg)+0.01(0.033 mg/kg)) = 0.001 mg/kg

Polystyrene

CF x = 0.06(0.52(0.020 mg/kg) +0.01(0.035 mg/kg)+0.47(0.15 mg/kg)) = 0.0049 mg/kg

Impact Polystyrene

CF x = 0.04(0.86(0.020 mg/kg) +0.04(0.22 mg/kg)+0.10(6.2 mg/kg)) = 0.026 mg/kg

The total concentration of the antioxidant in the daily diet resulting from the additional uses in polycarbonate and polystyrene is approximately 0.032 mg/kg.

The contribution to the EDI is:

EDI = 3 kg food/person/day x 0.032 mg antioxidant/kg food = 0.096 mg/person/day

The CEDI for the previously permitted use (Example 1, EDI of 2.5 mg/person/day) and the additional proposed uses (EDI of 0.1 mg/person/day) would be 2.6 mg/person/day.

APPENDIX V. FOOD TYPES AND CONDITIONS OF USE

TABLE 1. TYPES OF RAW AND PROCESSED FOODS I. Nonacid, aqueous products; may contain salt or sugar or both (pH above 5.0) II. Acid, aqueous products; may contain salt or sugar or both, and including oil-in-water emulsions of low- or high-fat content. III. Aqueous, acid or nonacid products containing free oil or fat; may contain salt, and including water-in-oil emulsions of low- or high-fat content. IV. Dairy products and modifications: Water-in-oil emuslsions, high- or low-fat Oil-in-water emulsions, high- or low-fat V. Low-moisture fats and oils VI. Beverages: Containing up to 8 percent of alcohol. Nonalcoholic. Containing more than 8 percent alcohol. VII. Bakery products other than those included under Types VIII or IX of this table: Moist bakery products with surface containing free fat or oil. Moist bakery products with surface containing no free fat or oil. VIII. Dry solids with the surface containing no free fat or oil (no end test required). IX. Dry solids with the surface containing free fat or oil.

TABLE 2. CONDITIONS OF USE A. High temperature, heat sterilized or retorted (ca. 121 ºC (250 ºF)). B. Boiling water sterilized. C. Hot filled or pasteurized above 66 ºC (150 ºF). D. Hot filled or pasteurized below 66 ºC (150 ºF). E. Room temperature filled and stored (no thermal treatment in the container). F. Refrigerated storage (no thermal treatment in the container). G. Frozen storage (no thermal treatment in the container). H. Frozen or refrigerated storage; ready prepared foods intended to be reheated in container at time of use. I. Irradiation (ionizing radiation). J. Cooking at temperatures exceeding 121 ºC (250 ºF).

APPENDIX VI. REFERENCES AND FOOTNOTES

1. REFERENCES

a. General References

American Society for Testing and Materials (ASTM), E 1303-95, Standard Practices for Refractive Index Detectors used in Liquid Chromatography. ASTM, West Conshohocken, PA 19428-2959.

Arthur D. Little, Inc., July 1983: A Study of Indirect Food Additive Migration. Final Summary Report. 223-77-2360.

Arthur D. Little, Inc., September 30, 1988: High Temperature Migration Testing of Indirect Food Additives. Final Report. FDA Contact No. 223-87-2162.

Arthur D. Little, Inc., August 1990: High Temperature Migration Testing of Indirect Food Additives to Food. Final Report. FDA Contract No. 223-89-2202.

ASTM E 1511-95, Standard Practice for Testing Conductivity Detectors Used in Liquid or Ion Chromatography. ASTM, West Conshohocken, PA 19428-2959.

Baner, A., Brandsch, J., Franz, R. and Piringer, O., 1996, The Application of a predictive migration model for evaluating the compliance of plastic materials with European food regulations. Food Additives and Contaminants, 13 (5), 587-601.

Begley, T. H. and Hollifield, H. C., 1991, Application of a polytetrafluoroethylene single-sided migration cell for measuring migration through microwave susceptor films. American Chemical Society Symposium Series 473: Food and Packaging Interactions II, Chapter 5, 53-66.

Chang, S., 1984, Migration of low molecular weight components from polymers: 1. Methodology and diffusion of straight-chain octadecane in polyolefins. Polymer, 25, 209-217.

Currie, L. A., 1968, Limit of qualitative detection and quantitative determination, application to radiochemistry. Analytical Chemistry, 40 (3), 586-593.

Goydan, R., Schwope, A., Reid, R., and Cramer, G., 1990, High temperature migration of antioxidants from polyolefins. Food Additives and Contaminants, 7 (3), 323-337.

Helmroth, E., Rijk, R., Dekker, M., Jongen, W., 2002, Predictive modeling of migration from packaging materials into food products for regulatory purposes. Food Science and Technology, 13, 102-109.

Katan, L.L., 1996, Migration from Food Contact Materials, Blackie Academic & Professional.

Keith, L. H., Crummett, W., Deegan, Jr., J., Libby, R. A., Taylor, J. K., and Wentler, G., 1980, Principles of environmental analysis. Analytical Chemistry, 55, 2210-2218.

Limm, W. and Hollifield, H. C., 1995, Effects of temperature and mixing on polymer adjuvant migration to corn oil and water. Food Additives and Contaminants, 12 (4), 609-624.

Limm, W. and Hollifield, H.,1996, Modeling additive diffusion in polyolefins. Food Additives and Contaminants, 13 (8), 949-967.

McNeal, T. P. and Hollifield, H. C., 1993, Determination of volatile chemicals released from microwave-heat-susceptor food packaging. J. AOAC International, 76 (6), 1268-1275.

National Bureau of Standards, March 1982: Migration of Low Molecular Weight Additives in Polyolefins and Copolymers. Final Project Report, NBSIR 82-2472. NTIS PB 82-196403, National Technical Information Services, Springfield, VA.

Piringer, O.G. and Baner, A.L., 2000, Plastic Packaging Materials for Food, Wiley-VCH.

Schwope, A. D. and Reid, R. C., 1988, Migration to dry foods. Food Additives and Contaminants, 5 (Suppl. 1), 445-454.

Schwope, A. D., Till, D. E., Ehntholt, D. J., Sidman, K. R., Whelan, R. H., Schwartz, P. S., and Reid, R. C., 1986, Migration of an organo-tin stabilizer from polyvinyl chloride film to food and food simulating liquids. Deutsche Lebensmittel Rundschau, 82 (9), 277-282.

Schwope, A. D., Till, D. E., Ehntholt, D. J., Sidman, K. R., Whelan, R. H., Schwartz, P. S., and Reid, R. C., 1987, Migration of Irganox 1010 from ethylene-vinyl acetate films to foods and food-simulating liquids. Food and Chemical Toxicology, 25 (4), 327-330.

Schwope, A. D., Till, D. E., Ehntholt, D. J., Sidman, K. R., Whelan, R. H., Schwartz, P. S., and Reid, R. C., 1987, Migration of BHT and Irganox 1010 from low-density polyethylene (LDPE) to foods and food-simulating liquids. Food and Chemical Toxicology, 25 (4), 317-326.

Snyder, R.C. and Breder, C.V., 1985, New FDA migration cell used to study migration of styrene from polystyrene into various solvents. Journal of Association Official Analytical Chemist, 68 (4), 770-775.

Till, D., Schwope A. D., Ehntholt, D. J., Sidman, K. R., Whelan, R. H., Schwartz, P. S., and Reid R. C., 1987, Indirect food additive migration from polymeric food packaging materials. CRC Critical Reviews in Toxicology, 18 (3), 215-243.

Till, D. E., Ehntholt, D. J., Reid, R. C., Schwartz, P. S., Sidman, K. R., Schwope, A. D., and Whelan, R. H., 1982, Migration of BHT antioxidant from high density polyethylene to foods and food simulants. Industrial & Engineering Chemistry, Product Research and Development, 21 (1), 106-113.

Till, D. E., Ehntholt, D. J., Reid, R. C., Schwartz, P. S., Schwope, A. D.; Sidman, K. R., and Whelan, R. H., 1982, Migration of styrene monomer from crystal polystyrene to foods and food simulating liquids. Industrial & Engineering Chemistry, Fundamentals, 21 (2), 161-168.

Till, D. E., Reid, R. C., Schwartz, P. S., Sidman, K. R., Valentine, J. R., and Whelan, R. H., 1982, Plasticizer migration from polyvinyl chloride film to solvents and foods. Food and Chemical Toxicology, 20 (1), 95-104.

The following are lists of references that contain descriptions, photos, or drawings of migration cells for conducting migration testing for different packaging applications.

b. Cells for Migration Testing

Conventional Applications

ASTM F34-98, Standard Practice for Construction of Test Cell for Liquid Extraction of Barrier Materials. ASTM, West Conshohocken, PA 19428-2959.

Dow Chemical, Inc., A single-sided migration cell, known as the Dow cell, has been used with food oil at 175°C. The cell is available from: Kayeness, Inc., 115 Thousand Oaks Blvd., Suite 101, P.O. Box 709, Morgantown, PA 19543 (610-286-7555). Model no. D9030.

Figge, K. and Koch, J., 1973, Effect of some variables on the migration of additives from plastics into edible fats. Food Cosmetics Toxicology, 11, 975-988. The cell used was a single-sided cell in contact with food oil at 80°C.

Goydan, R., Schwope, A. D., Reid, R. C., and Cramer, G., 1990. The cell used was a double-sided (immersion), stainless steel cell, with water, 95% ethanol, and oil at 130°C.

Limm, W. and Hollifield, H., 1995. The cell used was a single-sided glass cell with water, food oil, and food at 135°C.

Snyder, R.C. and Breder, C.V., 1985. The cell used was a double-sided (immersion) glass cell with water, 3% acetic acid, 95% ethanol, and oil at 40°C and 50% aqueous ethanol at 70°C. This cell is also specified in ASTM D4754-87 "Standard Test Method for the Two-Sided Liquid Extraction of Plastic Materials Using FDA Migration Cell." ASTM, West Conshohocken, PA 19428-2959.

Till, D.E., Ehntholt, D. J., Reid, R. C., Schwartz, P. S., Sidman, K. R., Schwope, A. D., and Whelan, R. H., 1982. The cells used were glass, single-sided and double-sided (immersion) cells, with water, 3% acetic acid, 95% ethanol, and oil at 40°C.

Microwave Applications

ASTM F1349-91, Standard Test Method for Nonvolatile Ultraviolet (UV) Absorbing Extractables from Microwave Susceptors. ASTM, West Conshohocken, PA 19428-2959.

Begley, T. and Hollifield, H., 1991. The cell was used with food oil at temperatures up to 240°C.

Rijk, R. and De Kruijf, N., 1993, Migration testing with olive oil in a microwave oven. Food Additives and Contaminants, 10 (6), 631-645.

2. FOOTNOTES

[1]This guidance has been prepared by the Office of Food Additive Safety in the Center for Food Safety and Applied Nutrition at the U.S. Food and Drug Administration.

[2] CAS Registry Numbers for new compounds and assistance with nomenclature can be obtained by writing to Chemical Abstracts Service (CAS) Client Services, 2540 Olentangy River Road, P.O. Box 3343, Columbus, OH 43210, or by visiting their website at http://www.cas.org/.

[3] Migration into food depends on the chemical structure of the FCS, the nature of the food matrix contacting the FCS, the type of food with which it is in contact, and the temperature and duration of food contact. Prior to the submission of an FCN or FAP, a potential submitter may wish to meet or correspond with FDA to discuss appropriate migration testing protocols (see Appendix II.).

[4] Migration values often are expressed in units of mg/dm2. The mixed unit, mg/in2, is preferred, however, to facilitate conversion to concentrations in food. If 10 g of food are in contact with 1 square inch of food-contact surface, a migration of 0.010 mg/in2 corresponds to a concentration in food of 1 mg/kg.

[5] In the past, FDA recommended 8% ethanol as an aqueous food simulant. Increasing the ethanol concentration from 8% to 10% will have a minimal impact on migration studies conducted on adjuvant/polymer systems. This change also harmonizes more closely FDA's migration protocols with those of other nations. See the reference list at the end of Appendix II. relating to FDA's development of the use of food simulants.

[6] Miglyol 812, a product of SASOL, GMbH, Witten, Germany.

[7] HB307 is available from NATEC, Behringstrasse 154, Postfach 501568, 2000 Hamburg 50, Germany.

[8] Previous test protocols (prior to 1995) recommended a test temperature of 49°C for 10 days. Recent studies by FDA, however, have shown little difference in migration levels at 49°C and 40°C (104°F). Furthermore, the differences in migration levels between 49°C and 40°C are of even less significance for migration studies requiring elevated temperatures (e.g., 100°C or 121°C) for the first two hour