U.S. Food & Drug Administration
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.


Recommendations for Chemistry Data for
Indirect Food Additive Petitions

APPENDICES


APPENDIX I

FATTY-FOOD SIMULANTS FOR PARTICULAR POLYMERS

A food oil is a worst-case fatty food. If contact with fatty foods is anticipated, conduct migration studies using a food oil as the food-simulating liquid. 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 C10, C12, and C14) as a fatty-food simulant has previously been recommended. Recent studies in FDA laboratories have shown that Miglyol 812TM a fractionated coconut oil having a boiling range of 240-270°C and composed of saturated C8 (50-65%) and C10 (30-45%) triglycerides, is also an acceptable alternative. Since use of these oils for additive 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 (see the reference list at the end of this Appendix). For polymers other than those listed below, consult CRB (via the Office of Premarket Approval) before migration experiments are undertaken.

  1. Polyolefins complying with 177.1520 and ethylene-vinyl acetate copolymers complying with 177.1350 . . . . . . . . . . . . . . . . .95% or absolute ethanol
  2. Rigid polyvinyl chloride. . . . . . . . . . . .50% ethanol
  3. Polystyrene and rubber-modified polystyrene . .50% ethanol

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. 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. Therefore, although heptane migration data may continue to be accepted, migration values will not be divided by any factor unless there is adequate justification.

References

Snyder, R.C. and Breder, C.V., 1985, New FDA Migration Cell Used to Study Migration of Styrene from Polystyrene into Various Solvents. J. Assoc. Off. Anal. Chem., 68 (4), 770-775.

National Bureau of Standards, March 1982: Migration of Low Molecular Weight Additives in Polyolefins and Copolymers. Final Project Report, NBSIR 82-2472.

Goydan, R., Schwope, A., Reid, R., and Cramer, G., 1990, High Temperature Migration of Antioxidants from Polyolefins. Food Add. and Contam., 7 (3), 323-337, and references cited therein.


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 additive 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 additive within the foods. Therefore, CRB recommends migration testing with food-simulating solvents at the highest temperatures to be experienced by the package during food contact. In those instances where the expected use conditions are not adequately simulated by these protocols or testing with food-simulating solvents at the highest anticipated food-contact temperature is not practicable, alternative protocols to those presented below should be developed in consultation with CRB.

  1. General Protocols (Single-Use Applications) Corresponding to Condition of Use
  2. 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 with a food or liquid fat preclude sensitive analyses. As noted in Section II.D.1.d, migration to aqueous, acidic, and low-alcoholic foods is evaluated using 10% ethanol and migration to high-alcohol foods is evaluated using 50% ethanol.

  3. Adjuvants for Polyolefins
  4. 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, sufficient to provide coverage for all polyolefins including PP, which may be used for retort applications. In such a case, the consumption factor for all polyolefins (CF = 0.33) will be used instead of the individual consumption factor for LDPE (see Appendix IV, Table I). However, it is usually to the petitioner's advantage when seeking coverage for all polyolefins to perform migration testing on HDPE and PP, complying with 21 CFR 177.1520, as well as LDPE. By doing this, actual migration values for these polyolefins, which will likely be lower that those obtained from LDPE, may be used to calculate the EDI.

  5. Adjuvants for Polymers (other than Polyolefins)
    Adjuvants for More than One Polymer
  6. The migration testing protocols for polymers other than polyolefins are the same as those in Section 1 of this Appendix. Consult Appendix I for the recommended fatty-food simulant.

    If a regulation is sought without limitation to specific polymers, the petitioner may obtain this broad coverage by testing with an unoriented LDPE sample complying with 21 CFR 177.1520(a)(2). The specific 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 consumption factor for all polymers (Appendix IV, Table 1, CF = 0.8) will be used with the migration data to calculate the concentration of the additive 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). Consult with CRB to determine which representative polymers should be tested.

  7. Articles Intended for Repeated Use
  8. Test the article with 10% and 50% ethanol and a food oil (e.g., corn oil) or other fat simulant (e.g., HB307 or Miglyol 812TM) for 240 hours at the highest intended temperature of use. Analyze the test solutions for additive migration after 8, 72, and 240 hours. 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, CRB strongly recommends that the petitioner calculate 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. It may be that this calculated concentration is sufficiently low that migration studies will be unnecessary.

  9. Coatings for Cans (21 CFR 175.300)
  10. 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, consult with CRB 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.

  11. Uncoated & Clay-Coated Papers with Latex Binders
  12. These papers are intended for contact with food at temperatures less than 40°C for short periods of time. The protocol is the following:

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

    When total nonvolatile or chloroform-soluble extractives are determined for a paper coating, do not subtract the corresponding extractives from uncoated paper as a blank correction. In the event that the paper disintegrates in a particular solvent, the above protocol may be modified with CRB approval. For a new adjuvant in paper coatings, analyze the test solutions for the unregulated adjuvant. For a new polymer used in paper coatings, analyze the test solutions for constituent oligomers and monomers.

  13. Specially Treated Papers
  14. This class includes such types as fluoropolymer- and silicone-treated papers that have oil-resisting and heat-resisting properties. The specific protocol depends on the particular uses anticipated. It is recommended that the petitioner either devise a protocol and submit it for comment or request comment about appropriate test conditions.

  15. Adhesives (21 CFR 175.105)
  16. For use at room temperature or below, no migration tests are necessary. High temperature applications are discussed in Section 9.

  17. Laminates & Coextrusions
  18. 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 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-H 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 these Recommendations, however, should be the subject of special protocol development in consultation with CRB.

  19. Boil-In-Bags
  20. The protocol is the same as that employed in Condition of Use C.

  21. Special High-Temperature Applications
  22. 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. Recently, CMB has developed protocols for migration testing of dual-ovenablecontainers and microwave heat susceptor materials. These protocols are outlined below.

  23. Colorants for Plastics (21 CFR 178.3297)
  24. 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. 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 ppb would lead to an exposure no greater than 5 ppb in the diet. A solubility less than 10 ppb would lead to an exposure below 0.5 ppb, i.e., below the proposed "Threshold of Regulation" (Section IV).

  25. Dry Foods with Surface Containing No Free Fat or Oil
  26. (21 CFR 176.170(c), Table 1, Food Type VIII)

    Although studies have shown migration of certain adjuvants into dry foods (e.g., low molecular weight adjuvants in contact with porous or powdered foods), at the present time no migration testing is required.


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. 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 normally carried out with the set of test solutions exhibiting the highest level of additive migration, typically those contacting the food simulant for the longest time period (i.e., 240 hours). To validate the analytical methodology, an additional three sets (in triplicate) using 10% ethanol can be run for 240 hours. Each set of these test solutions can then be spiked with the additive at levels corresponding to one-half (1/2), one (1) and two (2) times, respectively, the average migration value determined for the regular (unspiked) 240 hour test solutions.

Instead, the petitioner decided to carry out one large test using enough film and solvent for twelve analyses (three at each time interval). 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 ppm 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 spiked at concentrations corresponding to 0.00040 mg/in², three were spiked at 0.00080 mg/in² and three were spiked 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 spiked 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 spike.
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 spiking 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 I.D.3.e) for a concentration in food of 0.080 ppm (percent recovery 60-110%, relative standard deviation not exceeding 20%). If the corresponding percentages for the other two spiking 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 data used for evaluating exposure to food packaging components. An example of how these data are used is also 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(a) Package Category CF(a)
A. General
Glass 0.1 Paper- Polymer coated 0.2
Metal- Polymer coated 0.17 Paper- Uncoated 0.1
Metal- Uncoated 0.03 Polymer 0.4
B. Polymer
Polyolefins(b) 0.33 PVC 0.1
Acrylics, phenolics, etc. 0.15 All Others(c) 0.05
Polystyrene 0.1
a- Except for metal- polymer coated, polyolefins, acrylics, and phenolics, these CFs have been rounded to one significant figure from those reported in the 1988 Recommendations.
b- The CF for polyolefins is currently subdivided as follows: LDPE 0.18; HDPE, 0.13; PP, 0.02. If polyolefin coverage only involves PP, a minimum CF of 0.05 is used.
c- 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 (fT)
Package Category Food-Type Distribution (fT)
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 .01b 0.20
Paper- Polymer coated 0.55 0.04 0.01b 0.40
Paper- Uncoated 0.57 0.01b 0.01b 0.41
Polymer 0.49 0.16 0.01b 0.34
B. Polymer
Polyolefins, polystyrene 0.67 0.01b 0.01b 0.31
Acrylics, phenolics, etc. 0.17 0.40 0.31 0.12
PVC 0.01b 0.23 0.27 0.49
Acrylonitrile, ionomers, PVDC 0.01b 0.01b 0.01b 0.97
Polycarbonates 0.97 0.01b 0.01b 0.01b
Polyesters 0.01b 0.97 0.01b 0.01b
EVA 0.30 0.28 0.28 0.14
Wax 0.47 0.01b 0.01b 0.51
Cellophane 0.05 0.01b 0.01b 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 indirect additive in the daily diet (CF x <M>, i.e., the fraction of food in the diet contacting the packaging material times the average concentration of the additive in the food contacted) and its estimated daily intake (EDI).

Example 1

The petitioner is seeking coverage for use of a new antioxidant at a maximum level of 0.25% w/w in polyolefins contacting food at or below room temperature (Sections 1.E-G, Appendix II). Migration values from LDPE reported to FDA for the three food simulating solvents are given below:

Solvent (i) Mi (ppm)
10% aqueous ethanol 0.060
50% aqueous ethanol 0.092
Miglyol 812TM 7.7

The petitioner 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 food-type distribution values (fT) for polyolefins are given in Tables I and II, respectively. The <M> for the antioxidant would be calculated as follows:

<M> = (faqueous+facidic)(M10% Ethanol) +falcohol(M50% Ethanol)+ ffatty(MMiglyol 812TM)

= 0.68(0.060 ppm)+0.01(0.092 ppm)+0.31(7.7 ppm)

= 2.4 ppm

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

CF x <M> = 0.33 x 2.4 ppm

= 0.80 ppm or 0.80 mg/kg

If there were no other regulated or proposed uses, then the EDI would be calculated using the above value:

EDI = 3 kg food/person/day x 0.80 mg antioxidant/kg food

= 2.4 mg/person/day

Example 2

In a subsequent petition, the company sought additional coverage for the same antioxidant in polycarbonate and polystyrene resins. Each polymer would contact food at or below room temperature (Sections 1.E-G, Appendix II). Migration levels are given below:

Solvent Polycarbonate Polystyrene Impact Polystyrene
10% aq. Ethanol 0.020 ppm 0.020 ppm 0.020 ppm
50% aq. Ethanol 0.025 ppm 0.035 ppm 0.22 ppm
Miglyol 812TM 0.033 ppm 0.15 ppm 6.2 ppm

The concentration of the antioxidant in the daily diet resulting from each of the proposed uses is calculated below. For polystyrene, the higher migration levels for impact polystyrene are used in the calculation.

Polycarbonates

CF x <M> = 0.05(0.98(0.020 ppm)+0.01(0.025 ppm)+0.01(0.033 ppm))

= 0.001 ppm or 0.001 mg/kg

Polystyrene

CF x <M> = 0.1(0.68(0.020 ppm)+0.01(0.22 ppm)+0.31(6.2 ppm))

= 0.19 ppm or 0.19 mg/kg

The total concentration of the antioxidant in the daily diet resulting from the additional uses in polycarbonate and polystyrene given in this petition is approximately 0.19 mg/kg.

Their contribution to the EDI is:

EDI = 3 kg food/person/day x 0.19 mg antioxidant/kg g food

= 0.57 mg/person/day

The cumulative exposure from the previously regulated use (Example 1, 2.4 mg/person/day) and the additional proposed uses would be 3.0 mg/person/day.


APPENDIX V

CELLS FOR MIGRATION TESTING

The following is a list of references that contain descriptions, photos, or drawings of migration cells for conducting migration testing.

Conventional Applications

Figge, K. and Koch, J., 1973, Effect of Some Variables on the Migration of Additives from Plastics into Edible Fats. Food Cosmet. Toxicol., 11, 975-988. The cell used was a single-sided cell in contact with food oil at 80°C.

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. IEC Product Research and Development, 21, 106-113. The cells used were glass, single-sided and double-sided (immersion) cells, with water, 3% acetic acid, 95% ethanol, and oil at 40°C.

Snyder, R.C. and Breder, C.V., 1985, New FDA Migration Cell used to Study Migration of Styrene from Polystyrene into Various Solvents. J. Assoc. Off. Anal. Chem., 68 (4), 770-775. 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.

Goydan, R., Schwope, A. D., Reid, R. C., and Cramer, G., 1990, High Temperature Migration of Antioxidants from Polyolefins. Food Add. and Contam., 7 (3), 323-337. The cell used was a double-sided (immersion), stainless steel cell, with water, 95% ethanol, and oil at 130°C.

Arthur D. Little, Inc., August 1990, High Temperature Migration of Indirect Food Additives to Foods. FDA Contract 223-89-2202. The cell used was a single-sided glass cell with water, food oil, and food at 135°C.

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.

Microwave Applications

Begley, T. and Hollifield, H., 1991, Application of a Polytetrafluoroethylene Single-Sided Migration Cell for Measuring Migration through Microwave Susceptor Films. ACS Symposium Series 473, Food Packaging Interactions II, Ch. 5. The cell was used with food oil at temperatures up to 240°C.

ASTM 1991 F1349-91, Standard Test Method for Nonvolatile Ultraviolet (UV) Absorbing Extractables from Microwave Susceptors. American Society for Testing and Materials, Philadelphia, PA.

Rijk, R. and De Kruijf, N., 1993, Migration Testing with Olive Oil in a Microwave Oven. Food Add. and Contam., 10 (6), 631-645.


* Office of Premarket Approval, Center for Food Safety and Applied Nutrition (HFS-200), Food and Drug Administration, 200 C St., SW., Washington, DC 20204 (See updated contact information)

June, 1995


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This document was issued in June 1995.
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The latest version of this guidance issued on April 10, 2002.




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