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Center for Food Safety & Applied Nutrition Office of Premarket Approval June 1995 (Effective June 18, 2001, Office of Premarket Approval is now Office of Food Additive Safety. See updated contact information) |
The latest version of this guidance issued on April 10, 2002. Below is an earlier version.
These recommendations were developed to assist petitioners in the preparation of the chemistry portion of petitions for indirect food additives. The law, regulations and specific letters take precedence over these informal recommendations.
This document supersedes the Recommendations dated September, 1988, Version 1.2., March, 1993
II. INDIRECT FOOD ADDITIVE PETITIONS
III. INQUIRIES REGARDING COMPLIANCE WITH FOOD ADDITIVE REGULATIONS
IV. THRESHOLD OF REGULATION POLICY
APPENDIX I - FATTY-FOOD SIMULANTS FOR PARTICULAR POLYMERS
APPENDIX II - SELECTED MIGRATION TESTING PROTOCOLS
APPENDIX III - ILLUSTRATIVE EXAMPLE OF VALIDATION OF ANALYSES
Section 409(a) of the Federal Food, Drug, and Cosmetic Act (the Act) states that use of a food additive shall conform to a regulation prescribing the conditions under which the additive may safely be used. The definition of a food additive (Section 201(s)) includes substances used in the processing, packaging, holding, and transporting of food that have no functional effect in the food but which may reasonably be expected to become components of food. These latter substances are known as indirect food additives. Specific regulations are established to cover the safe use of indirect food additives. These regulations are set forth in Title 21 of the Code of Federal Regulations (21 CFR) parts 175-179. In addition to the specific regulations, 21 CFR 174.5 lays out general safety requirements for all indirect food additives.
Anyone intending to use an additive that does not conform to an existing regulation must file a petition proposing the issuance of a new regulation. Section 409(b)(2) of the Act sets forth the statutory requirements for such a petition. 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, (4) methods for the analysis of the additive, and (5) full reports of investigations made with respect to the safety of the additive. These requirements are described in greater detail in 21 CFR 171.1. That section also specifies the format of the petition. Alternatively, in some cases, an exemption to regulation as a food additive may be pursued (see Section IV).
These recommendations are intended to amplify and explain the statutory chemistry requirements for indirect food additive petitions.(1) Considering that the science and technology of food-packaging and food-contact articles as well as the scientific basis for evaluating exposure to indirect food additives are continually evolving, these recommendations will be periodically updated to address new developments in these areas. For indirect food additive applications not explicitly covered by these recommendations, appropriate information should be developed in collaboration with the Food and Drug Administration (FDA).(2)
II. INDIRECT FOOD ADDITIVE PETITIONS
Provide "the name and all pertinent information concerning such food additive, including, where available, its chemical identity and composition."(3)
Identity information is necessary to specify uniquely the additive for which a regulation is sought and to identify substances that may migrate into food from use of the additive. These substances include not only the petitioned additive itself, but also degradation products and impurities in the additive that may have no functional effect.
Information identifying the food additive should be as complete as possible with respect to the name, composition, and method of manufacture of the additive. Such items include:
In addition, provide the following information:
b. 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 Numbers.
c. Chemical equations for known or likely side reactions occurring during manufacture of the additive. Include catalyst degradation reactions, if known.
d. Concentrations of all major impurities together with supporting analytical data and calculations. In the case of polymers, include concentrations of residual monomers.
e. Data to characterize the additive. 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 as specified in 21 CFR 171.1(h)(2) should be so noted.
Provide "a statement of the conditions of the proposed use of such additive, including all directions, recommendations, and suggestions proposed for the use of such additive...."
Provide "all relevant data bearing on the physical or other technical effect such additive is intended to produce, and the quantity of such additive required to produce such effect."
Present data to show that the additive will achieve the intended technical effect and that the proposed use level is the minimum level required to accomplish the intended technical effect (21 CFR 171.1(c)). For an indirect food additive, "technical effect" refers to the effect on the food package or processing equipment, not on the food. An example would be the effect of an antioxidant on a particular polymer. In the case of a new food-contact polymer, present data that demonstrate the particular properties of the polymer that are useful for food-contact applications. This information is frequently available in product technical bulletins.
In cases where the use level of an additive is self-limiting, provide supporting data.
D. MIGRATION AND ANALYTICAL METHODOLOGY
Provide "a description of practicable methods for determining the quantity of such additive in or on food, and any substance formed in or on food, because of its use."
A petitioner shall provide information sufficient to permit estimation of the daily intake of the additive, i.e., consumer exposure. From analyzed or estimated levels of an additive in food or food-simulating solvents, the Chemistry Review Branch (CRB) calculates the concentration of the additive expected in the daily diet. A more complete discussion of this topic is given in Section E and Appendix IV.
The concentration of an additive in the daily diet or exposure may be calculated from measured levels in food or in food-simulating solvents. Although FDA has always accepted reliable analyses of additives in real foods, in practice many analytes are difficult to measure in food. Alternatively, petitioners may submit migration data obtained with food-simulating solvents, that can reproduce the nature and amount of migration of the additive into food. Because an additive may contact many foods with different processing conditions and shelf lives, the submitted migration data must reflect the most severe temperature/time conditions to which the food-contact article containing the additive will be exposed.
Before undertaking migration studies, the petitioner should carefully consider the potential uses of the additive. 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 because such experiments would lead to elevated levels of the additive in the food simulants and, potentially, to increased toxicity testing requirements. In some cases where the use level of the additive is low, it may be possible to dispense with migration studies altogether by calculating worst-case migration assuming that 100% of the additive migrates to food. The following example illustrates this approach:
Consider an adjuvant added prior to the sheet-forming operation in the manufacture of paper. If it is found by analysis or calculation that the final additive concentration in paper cannot exceed 1 ppm and the basis weight of the finished paper is 50 pounds/3000 ft², or 50 mg/in², then the maximum weight of additive per unit area of paper is 1x10-6 g adjuvant/g paper x 50 mg/in² = 0.000050 mg/in². If all the additive migrates into food and 10 grams of food is in contact with 1 square inch of paper (CRB's usual assumption), the maximum concentration in food would be 5 parts per billion. It may be expected that this low concentration in food would lead to an estimated daily intake of the additive sufficiently low so as to preclude the need for expensive toxicological testing. Therefore, migration studies which could result in further lowering of the estimate of daily intake would be unnecessary.
When migration studies are necessary, standard procedures should be followed to ensure reproducibility, to allow for comparisons with data obtained from different laboratories with different additives and, most importantly, to allow for comparisons with migration studies in the literature that have been carried out using real foods or food simulants.
Additionally, and importantly, the cell is subjected to mild agitation to minimize any localized solubility limitation that might result in mass-transfer resistance in the simulant phase.
For applications in which a two-sided cell design is not suitable, such as laminate constructions, the petitioner may refer to the references in Appendix V for application describing other cell designs. The petitioner may also devise an alternative cell. FDA is willing to comment on any such design.
b. TEST SAMPLE. Some important considerations are the following:
Practically, CRB considers migration to be independent from both sides of the sample if the sample thickness is at least 0.05 cm (20 mil or 0.020 in) and not more than 25 percent of the additive has migrated by the end of the experiment. If neither of these conditions is met, use the surface area of only one side in the calculation. In such a case, the final regulation may have to limit maximum film thickness.
c. VOLUME OF TEST SOLVENT. The 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. In general, other ratios may be acceptable if migration levels do not approach concentrations reflecting the partition limit (i.e., the solubility of the additive in the food-simulating liquid). Precipitation of the additive from solution or a cloudy solution are indications that this limit has been achieved. Always report the volume-to-surface area ratio.
d. FOOD SIMULATING SOLVENTS. The following food-simulating solvents are recommended. Additional discussion on this subject is found in Appendix I.
| Food-Type | Recommended Food-Simulating Solvent |
|---|---|
| Aqueous and Acidic Foods (Food Types I, II, IVB, VIB, and VIIB as defined in 176.170(c) Table 1). | 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, or Miglyol 812TM (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 C10, C12, and C14. Miglyol 812TM is derived from coconut oil (see main text and Appendix I). | |
Previous test protocols (prior to 1988) recommended the use of water and 3% acetic acid as food simulants for aqueous and acidic foods, respectively. However, water and 3% acetic acid have been shown, in a number of instances, to underestimate migration into aqueous foods. Therefore, 10% ethanol is now recommended as an aqueous food simulant.(6) Use this solvent for evaluating migration to aqueous, acidic, and low-alcohol foods, except when the acidity of the food can be expected to lead to significantly higher levels of migration than with 10% ethanol or, in certain instances, if the polymer or adjuvant is acid-sensitive, or if trans-esterification occurs in ethanol solutions. In those instances, separate extractions in water and 3% acetic acid should be conducted.
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 can be used to evaluate exposures and support clearances for 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 at high temperature. Studies by the Chemistry Methods Branch (CMB) have indicated that Miglyol 812TM, a fractionated coconut oil having an estimated boiling point range of 240 to 270°C and composed of saturated C8 (50-65%) and C10 (30-45%) triglycerides, is an acceptable alternative fatty-food simulant for migration testing.(7) HB307, a mixture of synthetic triglycerides, primarily C10, C12, and C14, is also useful as a fatty-food simulant.(8)
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 fatty-food simulants appears in Appendix I. For other polymers, the petitioner should consult with CRB (via the Office of Premarket Approval) concerning use of a fatty-food simulant.
e. TEMPERATURE AND TIME OF TEST. Conduct migration testing under the most severe conditions of temperature and time for which a regulation is requested. If the intended application of the packaging material involves contact with food at temperatures higher than room temperature, conduct tests at the highest use temperature for the maximum 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, the migration protocols call for short-term accelerated testing intended to simulate additive migration that may occur during the entire food-contact scenario. Selected protocols are given in Appendix II; however, depending on the particular food-contact application, a specific protocol may be devised in consultation with CRB.
For room-temperature applications, a test temperature of 49°C (120°F) for 10 days has been previously recommended. This accelerated testing protocol was based on studies showing that migration levels were roughly equivalent to levels after extended time periods (6-12 months) at 20°C (68°F). Recent studies by CMB, 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 hours. Up to 80% of the total migration observed over the 10 day period is usually completed within this two hour period at the higher temperature. Therefore, 40°C is now regarded as acceptable for migration studies for room-temperature applications and for the portion of the migration test for elevated-temperature applications intended to reflect long term ambient storage.(9)
For refrigerated or frozen food applications, the test temperature is 20°C (68°F).
For polymers, such as polyolefins, that are used with food at temperatures above their glass transition temperatures, the highest migration values (typically the ten day values) are used to calculate the concentration of migrants in food.
For polymers, such as polyethylene terephthalate (PET), that are used with food at temperatures below their glass transition temperatures, a change in temperature generally produces a smaller change in migration rate than when they are used above the glass transition temperature. 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 20°C. The petitioner may wish to carry out testing for 30 days to avoid uncertainties in extrapolation. Of course, if a petitioner provides data that demonstrate that a different extrapolation period is more appropriate for a given additive/polymer combination, such information may be used for evaluating additive exposure.
For restricted uses where the maximum shelf life and food-contact temperature of an article are known, it is possible to carry out migration studies for the maximum shelf life under temperature conditions approximating expected use. Petitioners may want to consult CRB before undertaking such tests.
For each migration experiment, analyze portions of the test solutions at several time intervals. Recommended times for a ten-day test are 2, 24, 96, and 240 hours. Analyze a blank using a test cell identical to that used for testing the additive-containing samples.
f. END TESTS. It is important to realize that the appropriate migration test conditions for a new food additive are not those described in 21 CFR 175.300, 21 CFR 176.170 or other sections in 21 CFR. These published "end-test" extractions are quality control test methods that are used to determine whether a particular product is equivalent to the material that served as a basis for the regulation. End tests generally bear no relation to the migration testing required for evaluating probable exposure to a new food additive and cannot be used to support the regulation of a food additive.
Perform migration studies in triplicate and analyze the test solutions for the migrants. If the petition is for a polymer, determine the amount and nature of total extractives. Ordinarily, the total amount is determined by weighing. The nature of the extractives, which may include monomers, oligomers, adjuvants, catalyst residues, etc., is determined by suitable chemical or physical tests, such as NMR, UV-visible, and atomic absorption spectroscopy, and gas or liquid chromatography. Indicate the limit of quantitation and selectivity of the methods used. If quantitation of individual migrants is not possible, at the very least show the distribution of the extractives between organic and inorganic fractions by solvent fractionation (e.g., the fraction of the total extractive residue that is soluble in chloroform).
Analyze test solutions from petitioned polymers for constituent monomers. Alternatively, the known residual level in the polymer may be used to calculate monomer dietary concentrations by assuming that all of the residual monomer migrates into food and that ten grams of food is in contact with one square inch of food-contact article.
If the petition is for a polymer adjuvant, it is normally necessary to analyze the test solutions only for the adjuvant. Occasionally, however, it may be necessary to quantitate, in the test solution, impurities or decomposition products present in the adjuvant in addition to the adjuvant itself. An example would be the presence of carcinogenic impurities in the adjuvant.
Report results in terms of milligrams of substance extracted per square inch (mg/in²) of surface area. Although migration amounts are often expressed in terms of mg/dm², CRB prefers the mixed unit mg/in² to facilitate conversion to concentration in food. If ten grams of food are in contact with one square inch of packaging surface, migration of 0.01 mg/in² corresponds to a concentration in food of 1 ppm. 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, use the lowest ratio from the actual food-contact applications and provide justification for the ratio selected.
Submit the following for each method:
b. STANDARD CURVES. Obtain the standard curve, or calibration curve, by analyzing a prepared medium fortified, i.e., spiked, 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 must bracket the concentration of the migrant in the test solution. An analyte concentration of 1 ppm determined from a standard curve obtained from concentrations of 10, 15 and 20 ppm would be unacceptable.
c. EXAMPLES OF SPECTRA OR CHROMATOGRAMS. Provide sample spectra and chromatograms. Clearly identify and label all major peaks so that ambiguities in interpretation may be avoided.
d. EXAMPLES OF CALCULATIONS RELATING THE DATA OBTAINED FROM INSTRUMENTAL METHODS TO THE REPORTED LEVELS (MILLIGRAMS OF MIGRANTS(s) PER SQUARE INCH OF SAMPLE SURFACE AREA EXTRACTED). Such calculations provide the reviewer with an internal check on the reported method.
e. VALIDATION OF ANALYTICAL METHODS. Validation of a method's intended use, the determination of accuracy and precision, usually involves replicate analyses of appropriate matrices spiked with known amounts of the additive at concentrations similar to those encountered in the migration studies and determination of the percentage recovery of the spiked additive. 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 spiking and recovery measurements. Recovery is defined as the difference between measured analyte levels in the spiked matrix and the unspiked matrix. Percent recovery is the recovery divided by the spiking level times 100, i.e., if "a" is the measured level in the unspiked solution, "b" is the measured level in the spiked solution and "c" is the spiking level, then percent recovery equals (b-a)/c x 100.
Migration test solutions must be spiked before analytical workup but after the prescribed test time, e.g., 240 hours. It is important that the actual test solutions be spiked and not the pure food-simulating solvents. Spiking of pure solvents instead of the test solutions is probably the most common deficiency in the validation section of indirect food additive petitions.
Perform spiking and recovery experiments using three (3) sets of triplicate samples of the test solutions to be spiked with each set spiked at a separate level. The spiking levels should be one-half (1/2) times the analyzed concentration of the additive, one (1) times the concentration, and two (2) times the concentration. In the event that no additive is detected, determine the LOD for the method. For quantifiable levels of the additive, acceptable recoveries should meet the following criteria:
| Levels in food or food-simulating solvents(a) | Acceptable average recovery | Acceptable relative standard deviation |
|---|---|---|
| <0.1 ppm | 60-110% | <20% |
| >0.1 ppm | 80-110% | <10% |
| a- If 0.001 mg of a substance is extracted from one square inch of packaging material into 10 grams of food or food-simulating solvent, the estimated concentration in food is 0.1 ppm. | ||
For purposes of 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 completely 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 atomic absorption spectrometry. In this case, spike the matrix at two separate concentrations (at least) in addition to the unspiked concentration, and verify the linearity of the standard addition curve by calculation of the least squares correlation coefficient.
Submit representative spectra or chromatograms from validation analyses of spiked and blank samples. Spectra or chromatograms of the "blank" are necessary to verify the absence of interferences. An illustrative example appears in Appendix III.
E. CONSUMER EXPOSURE
"In determining .... whether a proposed use of a food
additive is safe, the Secretary shall consider .... the
probable consumption of the additive and of any substance
formed in or on food because of the use of the additive."
Migration data developed following procedures outlined in Section D are intended to provide estimates of the highest level of migration to food that might result from use of the additive. CRB estimates probable exposure to the additive by combining the migration data with information on uses of food-contact articles that may contain the additive, i.e., on the fraction of a person's diet likely to contact packaging materials containing the additive.
From a given concentration of the additive 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 3000 grams per person per day (solids and liquids). A concentration in the daily diet of 1 ppm corresponds to an EDI of 1x10-6 g additive/g food x 3000 g food/person/day or 3 mg/person/day.
Both the concentration in the daily diet and the EDI are used in the safety evaluation of an additive. The concentration in the daily diet is used in determining the types of toxicity studies required to establish the safety of the additive under the proposed conditions of use. The Division of Health Effects Evaluation (DHEE) calculates an acceptable daily intake (ADI) based on the results of the feeding studies. If the EDI is lower than the ADI, use of the additive can be permitted. If this is not the case, the petitioner can sometimes obtain a regulation by limiting the proposed uses, which in turn reduces the EDI.
When CRB computes exposure to an adjuvant, the petitioned adjuvant is assumed to capture the entire market for which it is petitioned. While this approach is conservative, it reflects both uncertainties about likely market penetration as well as limitations in the data surveyed. Thus, if a company petitions for 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 resin category, CRB may employ a CF for the coverage that is sought that is lower than the CF for the whole resin category. 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.
When new products are introduced, they will initially be treated as replacement items for existing technology. Conservative estimates will be based on the assumption that the new product will capture the entire market. For example, the retortable pouch was initially 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 consumption factor was lowered to 0.05. This is the minimum CF used for exposure estimates involving low consumption applications and is intended to compensate for the inherent limitations of any survey of food packaging applications.
b. FOOD-TYPE DISTRIBUTION FACTOR. Before migration levels can be combined with CF values to derive estimates of probable consumption, the nature of the food that will likely contact the packaging material must be known. Migration into a fatty-food simulant, for example, will be of little use in estimating probable exposure if the packaging material is used exclusively to package aqueous food. To account for the variable nature of food contacting each packaging material, "food-type distribution factors" (fTs) have been calculated for each packaging material to reflect the fraction of all food contacting each material that is aqueous, acidic, alcoholic and fatty. Appropriate fT values for both packaging categories and polymer types appear in Table II of Appendix IV.
c. CONCENTRATION IN THE DAILY DIET AND EDI. The concentration of the additive in food contacting the packaging material, <M>, is derived by multiplying the appropriate fT values by the migration values, Mi, 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 packaging material containing the additive.
<M> = faqueous and acidic (M 10% Ethanol)+ falcohol (M 50% Ethanol)+ ffatty(Mfatty)
where Mfatty refers to migration into a food oil or other appropriate fatty-food simulant.
The concentration of the additive in the diet is obtained by multiplying <M> by CF. The estimated probable daily intake (EDI) for the additive 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 3000 g of food (solid and liquid) per day (see Appendix IV for sample calculations):
EDI = 3000 g food/person/day x <M> x CF
If the petitioned polymer or adjuvant is already regulated for other uses, CRB will estimate the cumulative exposure to the additive from the proposed and regulated uses (see the example in Appendix IV).
The approach outlined above is designed to deal with the majority of petitioned uses for adjuvants and polymers in food packaging applications 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 will be based on estimates of the amount of food to be contacted during the service life of the food-contact article (see Appendix II, Section 4).
Exposure estimates will, in general, be made by CRB using the aforementioned procedures. More refined exposure estimates may be possible, however, with additional information provided by the petitioner. For instance, suggestions for 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, cited above, is one example. Another example is the division of polymer coatings for paper into subcategories, such as poly(vinyl acetate) polymer coatings, styrene-butadiene polymer coatings, etc. If a compound 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.
In those cases where the nature of the coverage requested may require more detailed information or where a petitioner believes that exposure will be overstated by simply selecting CF and fT values presented in Appendix IV, data of the following type may be submitted to facilitate calculations of CF and fT values for materials likely to contain the additive:
b. Characterization of the foods that might contact the food package, along with supporting documentation, and the likely fT values.
c. Information that would demonstrate that only a fraction of a resin category would be affected by the coverage sought.
d. Technological limitations that could affect the type of food contacted or the fraction of the diet that might be contacted.
FDA requires that the petitioner submit relevant and reliable migration data for a petitioned additive to estimate potential exposure. In an effort to reduce this burden, CRB is compiling additive migration data from various sources for use in estimating additive migration.
Migration data for specific additive/polymer/food-simulating liquid 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 in certain cases such as high temperature applications may be difficult to perform, may be reduced.
As a simple 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, say 60°C and 80°C, may be extrapolated by means of an Arrhenius plot to predict additive 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 additive/polymer/food simulating liquid can be obtained from a plot of ln D vs 1/T(K). Thus, additive migration for 2 hours at 121°C can be estimated and added to additive 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 migration database is intended as a repository for migration data, including diffusion coefficients and relevant polymer/additive properties. CRB encourages the submission of such information for inclusion in the database as it is expected that the database will be useful in reducing the burden on petitioners in the preparation of food additive petitions. Only migration data that follow Fickian diffusion should be submitted. 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. This additional information may be submitted to FDA (Office of Premarket Approval) in the form of a letter, as part of a petition, or in a Food Additive Master File.
III. INQUIRIES REGARDING COMPLIANCE WITH FOOD ADDITIVE
REGULATIONS
FDA receives numerous letters and inquiries requesting opinions on the compliance with food additive regulations of individual substances or formulations to be used in the preparation of articles intended for producing, manufacturing, packaging, processing, transporting, holding, or cooking food. Often the information submitted is not sufficient to permit a decision on the food additive status of the material in question. The following information is generally pertinent and is recommended for inclusion in the initial letter to minimize delays in response.
Identify the individual substances, or components of a formulation, by their chemical names. Submit their structural formulas and Chemical Abstracts Service Registry Numbers, if available. Food additives are not listed in the regulations under trade names, nor does FDA maintain a list of such names. Therefore, FDA cannot review materials identified only by trade names. Additionally, give the weight percentages of each component of a formulation.
Identify the most severe anticipated conditions of use of food-contact articles manufactured using the additive (i.e., time-temperature conditions, types of foods to be contacted, and whether the article is intended for single or repeated use).
List the specific regulation section numbers, if known, that are believed to authorize the use of the formulation or its components under the desired conditions of use. Because regulations frequently contain limitations on the maximum use level of an additive, maximum temperature of use, and type of food with which it may be used, this information should be provided unless it is known that such information is unnecessary for evaluation. (Some regulations contain no specific limitations.)
In the event that the agency determines that any of the individual substances, or components of a formulation, are not authorized by a regulation for the proposed use, a food additive petition may be filed to propose the issuance of a new regulation. Alternatively, an exemption to regulation as a food additive may be pursued (see Section IV).
IV. THRESHOLD OF REGULATION POLICY
The agency has established a policy, known as the Threshold of Regulation policy,(11) that may be applied to an indirect food additive for which the extent of migration to food results in exposure so trivial (less than or equal to 0.5 ppb of the additive in the daily diet) as not to require the issuance of a regulation. The proposed use must meet the exemption criteria established in 21 CFR 170.39. Under this policy, information about the proposed use of a substance will undergo an abbreviated review by FDA, as opposed to the extensive review and formal issuance of a food additive regulation. Anyone seeking comment on whether the use of a particular substance meets the criteria should contact FDA's Office of Premarket Approval. Following is a list of the chemistry information that FDA will need to determine whether an exemption from regulation is appropriate:
B. Detailed information on the proposed conditions of use of the substance (e.g., temperature, types of food with which the substance will come into contact, the duration of contact, and whether the food-contact article will be for repeated or single use applications).
C. Information that will enable FDA to estimate the daily dietary concentration resulting from the proposed use of the additive. This information may consist of:
In cases where there is no detectable migration into food-simulating solvents or food, or when the substance is not detected in the food-contact article by a suitable analytical method, report the validated LOD or LOQ of the method. In cases where data are provided only in the form of manufacturing use levels or residual levels of the substance in the food contact article, FDA will calculate a worst-case dietary concentration assuming 100% migration of the substance into food.
D. For repeat-use articles, estimate the amount of food contacting a specific unit of surface area over the expected service life of the food-contact article.
* Office of Premarket Approval, Center for Food Safety and Applied Nutrition (HFS-200), US Food and Drug Administration, 200 C St., SW., Washington, DC 20204 (See updated contact information)
June, 1995
premarkt@cfsan.fda.gov
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