Recommendations for Submission
Chemical and Technical Data for
Direct Food Additive and
GRAS Food Ingredient Petitions
U. S. Food and Drug Administration
Center for Food Safety and Applied Nutrition
Office of Premarket Approval
Chemistry Review Branch
This document supersedes the "FDA Guidelines for Chemistry and Technological Data Requirements for Direct Food Additives and GRAS Food Ingredients" dated August, 1983.
TABLE OF CONTENTS
B. Manufacturing Process
C. Specifications for Food-Grade Material
D. Stability of the Added Substance
E. Intended Technical Effect and Use Level
F. Methodology for Analysis of the Added Substance in Food
D. Consumer Exposure
This document describes the types of chemical and technological data that FDA's Office of Premarket Approval in the Center for Food Safety and Applied Nutrition considers necessary for the evaluation of petitions seeking regulation of the safe use of direct food additives or for the affirmation of the use of food ingredients as generally recognized as safe (GRAS).
As prescribed by the Federal Food, Drug, and Cosmetic Act (the Act) and Title 21, Code of Federal Regulations (21 CFR) 170.3(h)(i), food additives must be shown to be safe (i.e., to have a reasonable certainty of no harm) under their intended conditions of use before they can be intentionally added to food. Food additives generally fall into two broad categories: (1) those that are added directly to food, as codified in 21 CFR Part 172, and (2) those that are added indirectly to food through contact of the food with packaging materials, processing equipment, or other food-contact materials, as codified in 21 CFR Parts 174-178. In addition, there is another class of food additives that does not neatly fit into either the direct or indirect food additive categories. These substances are called secondary direct food additives, and are codified in 21 CFR Part 173. These are substances whose functionality is required during the manufacture or processing of food and are ordinarily removed from the final food; although residuals might carry over to the final product, these residuals are not expected to exhibit any technical effect in food. Examples of secondary direct additives include enzyme immobilizing agents, ion exchange resins, boiler water additives and other processing aids.(1)
Section 201(s) of the Act exempts substances that are GRAS from the definition of a food additive. There are two broad categories of GRAS substances codified in 21 CFR: (1) those listed as GRAS in 21 CFR Part 182 during 1958-1962 without having been subjected to a detailed scientific review of all information available on the safety of these substances; and (2) those in Part 184 that have been affirmed as GRAS by the Agency since the Presidential Directive of 1969. This Directive required the Agency to initiate a safety review of the status of all ingredients that were on the GRAS list, with the intention of affirming their use as GRAS, determining that they were subject to prior sanction, or concluding that they should be regulated as food additives. (Substances subject to prior sanction are listed in 21 CFR Part 181.) To affirm the use of a food ingredient as GRAS, the ingredient must be generally recognized among experts qualified by training and experience to evaluate its safety. Safety, under the conditions of intended use, may be shown through (1) scientific procedures or (2) experience based on common use in food prior to January 1, 1958.
Section 409(b)(2) of the Act describes the statutory requirements for food additive petitions. Briefly, these encompass five general areas of information: (1) the identity of the additive; (2) the proposed use of the additive; (3) the intended technical effect of the additive; (4) a method of analysis for the additive in food; and (5) full reports of all safety investigations with respect to the additive. In addition, the petitioner shall furnish, upon request, a complete description of the methods, facilities, and controls used in or for the production of the additive (21 CFR 409(b)(3)) and/or samples of the additive and of food in which the additive will be used (21 CFR 409(b)(4)).
21 CFR 171.1(c) describes in greater detail the data requirements for food additive petitions, including the five basic areas of information and scientific data noted above, as well as other administrative information and environmental assessment requirements. This document addresses chemistry-related issues only.
As described in 21 CFR 171.1(h), certain data and information contained in food additive petitions are available for public disclosure, while other data are not. Questions in this regard should be directed to the Office of Premarket Approval.
B. GRAS Affirmation Petitions
The Act does not provide specific statutory requirements for GRAS affirmation petitions. As noted above, Section 201(s) of the Act exempts GRAS substances from the meaning of the term "food additive" and, therefore, from the statutory requirements for food additive petitions. Section 201(s) also provides that general recognition of safety must be established either through (1) scientific procedures or (2) experience based upon common use in food prior to January 1, 1958. Under 21 CFR 170.35, the Agency has established a voluntary GRAS affirmation petition process in order to minimize controversy over whether the Agency agrees that the use of a substance is GRAS.
The eligibility requirements for classification of a substance as GRAS are described in 21 CFR 170.30. For a substance to be eligible for GRAS affirmation based upon its history of use in food prior to 1958, certain criteria must be met. If the substance was commonly used in food in the United States prior to 1958, then information documenting this use must be generally available (21 CFR 170.30(c)(1)). If the substance was only used in food outside the United States prior to 1958, then published documents, or other information, that shall be corroborated by information from a second, independent source that confirms the history and conditions of use, must be readily available in the country in which the history of use occurred, as well as to experts in the United States (21 CFR 170.30(c)(2)). If the substance did not have a common history of use in food prior to 1958, then the substance can be considered for affirmation as GRAS only based upon scientific procedures, as set forth in 21 CFR 170.30(b).
The regulatory requirements for GRAS affirmation petitions differ from food additive petitions in terms of the format, data requirements, and administrative requirements. In addition, there are distinctions in data requirements for GRAS petitions based upon history of use and those based upon scientific procedures. The data requirements for GRAS affirmation of a substance are set forth in 21 CFR 170.30(b) and (c). GRAS affirmation based upon scientific procedures requires "the same quantity and quality of scientific evidence as is required to obtain approval of a food additive" (21 CFR 170.30(b)); thus, in preparing a petition for GRAS affirmation based upon scientific procedures, consideration shall also be given to the requirements set forth in 21 CFR 171.1(c) for food additive petitions, as well as those in 21 CFR 170.35(c)(1). The data requirements for a petition for GRAS affirmation based upon history of use are set forth in 21 CFR 170.35(c)(1); these petitions do not require the same quantity and quality of scientific evidence that is required for approval of a food additive regulation (21 CFR 170.30(c)(1)).
Under 21 CFR 170.35(c)(3), all GRAS affirmation petitions are placed on view in the office of the Dockets Management Branch, where they are available for public inspection; thus, any trade secret information in a GRAS affirmation petition would not be protected under 21 CFR 20.61. Hence, trade secret information should not be included in GRAS affirmation petitions. Additionally, scientific information essential to a GRAS affirmation petition must be available to the public in the open literature.
The following is intended to explain to prospective petitioners the statutory and regulatory data requirements as they apply to substances added directly to food; differences between requirements for GRAS substances and food additives are noted.
- Formal chemical name. The IUPAC or Chemical Abstracts name is acceptable.
- Common names, synonyms, or trade names.
- Chemical Abstract Service (CAS) Registry Number, where possible. CAS Registry Numbers for new compounds and assistance with nomenclature can be obtained by contacting CAS Client Services, Box 3343, 2540 Olentangy River Road, Columbus, Ohio 43210-0334, U.S.A.
- Empirical and structural formulae, and molecular or formula weights.
- Composition. For mixtures, identify as many of the components as necessary to reasonably define the composition of the mixture. Provide information on the identity for each component in the mixture and a material balance.
- For substances of natural origin, provide information on the source (e.g., genus, species, geographical factors).
- Further characterizing information. Where applicable, submit data
on chemical and physical properties of the substance (e.g., melting
point, boiling point, specific gravity, refractive index, optical
rotation, pH, solubility, reactivity, etc.) and chromatographic,
spectroscopic or spectrometric data (e.g., spectra from nuclear
magnetic resonance, infrared, electronic absorption, or mass
spectra) that can be used as a "fingerprint".
Information on the method of manufacture of an additive or food ingredient is necessary not only for identification of that substance, but also for identification of any impurities in the additive or food ingredient that have no functional effect in food. For substances of natural origin containing known toxicants, the ability of the manufacturing process to reduce toxicants to acceptable levels should be addressed.
A discussion of the manufacturing process should include a list of the reagents, solvents, catalysts, processing aids, purification aids, etc. used, as well as a detailed description of the process itself, including all reaction conditions and production controls. A description of alternative methods of manufacture, if known, should also be included.
Specifications for identity and purity of the petitioned additive or ingredient should be proposed, preferably, in the format of the Food Chemicals Codex, 3rd or current edition.(2) If published specifications for the added substance are available, then these should be cited and appropriately referenced. The petitioner may also recommend changes to specifications in the Food Chemicals Codex monographs (cf. 21 CFR 170.35(c)(1)(i)(f)). Specifications should include the following:
- A description of the substance. For substances derived from natural sources, the sources themselves should be clearly identified.
- Identification tests for the substance.
- An assay for the substance.
- Physico-chemical characteristics of the substance (e.g., ash content, moisture content, melting point, density, refractive index, pH).
- Limits for impurities and contaminants.
i. Specifications for contaminants should include arsenic,
lead, and heavy metals (as lead). In certain cases,
specifications for other heavy metals, such as cadmium and
mercury, might be appropriate.
ii. If the substance is derived from a natural source, the need for limits for any known natural toxicant(s) or for microbial contamination should also be considered.
iii. Specification limits for residual reactants, reaction by-products and residual solvents might also be necessary in certain cases.
In light of the Agency's continuing concern over the level of lead in the food supply, special attention should be paid to the proposed specification for lead. Actual lead levels should be determined and specifications should be proposed accordingly, keeping in mind that the proposed specification should be as low as technically feasible taking into account the source and manufacturing process of the substance, availability of appropriate analytical methodology, and probable human exposure to the substance.
In order to demonstrate conformance with the proposed specifications, at least five batches of the added substance should be analyzed. If the analytical method is a common standard test (e.g., Food Chemicals Codex or Association of Official Analytical Chemists (AOAC) method), only the reference needs to be provided. If the method is not common, if a common method is applied to a new substance, or if a modified standard method is used, a detailed description of the method and validation data for the method should be provided (see Section F for a discussion of analytical data requirements).
Specifications as discussed above serve only as minimal criteria for establishing that a substance intended for use in food is "food-grade". For a substance to be considered food-grade, it shall also have been manufactured, packaged, stored, and transported to the end-user under sanitary conditions that preclude, for example, contamination, formation of undesirable degradation products, and mislabeling. Controls or systems to avoid such problems should be established by manufacturers, processors, packers, and distributors throughout their operations. These practices, combined with adherence to the specifications for identity and purity constitute "good manufacturing practice" or GMP. A further elaboration on GMP can be found in the Food Chemicals Codex.(2) .
Data demonstrating the stability of the additive or food ingredient should be included, particularly if the substance is sensitive to environmental conditions, decomposes with time, or otherwise has a limited useful shelf-life or stability. A description of the methodology and all raw data should be provided.
A number of technical effects for which added substances may be used, such as antimicrobial agents, humectants, flavoring agents, surface-active agents, stabilizers and thickeners, are defined in 21 CFR 170.3(o). A substance added to food might have legitimate technical effects in food other than that intended; however, the quantity of the substance added to food shall not exceed the amount reasonably required to accomplish its intended technical effect(s) in the food (21 CFR 172.5(a)(1), 182.1(b)(1), and 184.1(b)).
A discussion of the intended use and use level of the additive or ingredient should include:
- The type of food to which the substance will be added. The petitioned uses should be as broad as possible, consistent with the petitioner's burden to provide data demonstrating that all requested uses are safe. However, if the petitioner wishes to limit that burden, the intended restrictions on the uses must be as explicit as possible. For example, if the use of the substance is being requested only for certain types of baked goods (e.g., cakes or pies), the type of baked goods should be specified.
- The amount of the substance that will be added to food. Maximum and typical amounts should be provided. The amount of the substance in food should be expressed as a concentration (by weight), e.g., in milligrams or grams per kilogram.
- The technical effect of the substance in food.
- The fate of the substance in food, including the identities and amounts of any degradation products that will be formed.
- Any recommendations, suggestions and directions for use, including specimens of labeling.
Data should be submitted to demonstrate the amount of the additive required to achieve the intended technical effect. To demonstrate the minimum level required to accomplish the intended technical effect, the functionality of the added substance should be evaluated at several levels above and below the proposed use level. Some substances may have a technologically self-limiting use level; that is, the substance has a maximum concentration in food above which the food becomes unpalatable, unappealing, or otherwise unfit for human consumption. In such a case, data should be provided that demonstrate the effect of the substance on the food at several levels above and below the proposed self-limiting level.
The depth and degree of the data required to demonstrate the intended technical effect can vary, depending upon the additive. For example, these data may range from simple organoleptic evaluation to complex chemical analysis. Regardless of the degree of sophistication of the method, the experiments should be carefully designed and all appropriate controls included. For relatively new substances or novel technical effects, samples of food, with or without the added substance, might be requested for analysis; however, such samples should not be provided unless expressly requested during the petition evaluation.
GRAS affirmation petitions based upon common use in food prior to 1958 should contain the following historical information with regard to the use of the substance in food:
- The date when the use of the substance began.
- Information and reports, or other data describing and documenting the past use(s) of the substance in food.
- The foods in which the substance was used, the level(s) of use, and the purpose for which the substance was used.
- For substances that would be affirmed GRAS based on history of use outside the United States, information from two independent sources that is readily available in the country in which the history of use occurred as well as in the United States.
If assurance of safe use depends on a limitation imposed on the amount of a substance (additive, associated impurities, or degradation products) that a food can contain, a method is needed that can quantify the substance in food for the purpose of enforcing the limit. Quantifying the levels of a substance in food requires a practical analytical method that can be readily performed in a properly equipped laboratory by appropriately trained personnel. The method must be specific, precise, accurate and reliable; it must also be able to withstand the scrutiny of courtroom cross-examination, if necessary. However, the method must not be so sophisticated or complicated that it can be carried out only in laboratories with highly specialized equipment or by specially trained personnel.
The following is a suggested general format for such an analytical method.
- Introduction. A brief summary of the method should be provided, including its principle, scope and limitations. This section should describe the types of food to which the method may be applied, the substance(s) that can be detected by the method, and the types of substances that would interfere with the method.
- Materials. A detailed description of the reagents (excepting common laboratory items), equipment, instrumentation, computer software, etc. should be provided. This description should be as detailed as possible, and include grades of reagents, protocols for preparation of any reagents, and model numbers of any apparatus or instrument. Where "similar" or "equivalent" materials or equipment might be suitable, this should be noted.
- Standard or Reference Solutions. Standard solutions, consisting of the additive, ingredient, or any other analyte of interest, in an appropriate solvent, should be prepared at five different concentrations that bracket the use level or expected concentration of the substance in food and analyzed in triplicate. For example, if the use level of the substance in a given food is 1.0 ppm, standard solutions should be prepared at 0.25, 0.5, 1.0, 2.0, and 4.0 ppm. The data obtained from the analysis of these solutions should be used to construct a standard or calibration curve that can be used for quantitation of the substance in the food matrix.
- Sample Preparation. A description of the preparation of
food samples that contain the additive, ingredient, or other
analyte of interest should be provided. It is recommended that
samples from five different production lots or batches be
prepared for analysis in triplicate. Blanks and any appropriate
control samples should also be analyzed in triplicate. The
description of the sample preparation should be provided in a
step-by-step format, and should be as clear and concise as
FDA may require samples of the additive or ingredient for a trial of the method, but these samples should be furnished only upon request. If such samples are requested, instructions will be provided as to the types and amounts of samples required by the analyst.
- Equipment calibration and set-up. Instructions for calibrating equipment, introducing the sample, and performing the analysis should be provided in step-by-step detail; the experimental set-up and analytical parameters should also be included. Any precautions and special instructions necessary to carry out the analysis successfully should also be noted. If applicable, trouble-shooting techniques should be provided.
- Limits of detection and quantitation.(3)
The limit of detection is the lowest concentration of analyte
that the analytical method can reliably detect. It is preferable
that the limit of detection be determined from triplicate
analyses of five blank samples (e.g., food matrix without the
added substance). The blank signal (i.e., the analyte response
for the blank sample or the width of the baseline close to the
actual or expected analyte peak) is measured, and the average
signal and standard deviation for the blank are calculated. The
limit of detection is located three standard deviations above
the average blank signal. For cases in which it is not feasible
to determine the limit of detection using blank samples, the
limit of detection should be determined from the peak-to-peak
noise measured on the baseline close to the actual or expected
The region for quantitation of the analyte should clearly be above the limit of detection. The limit of quantitation is located ten standard deviations above the average blank signal.(3)
- Validation. The usual validation procedure consists of
spiking/recovery studies. The percent recovery is defined as:
((a - b) / c) x 100
where "a" is the level of the analyte analytically determined in the spiked sample, "b" is the "background" level (i.e., the level determined in the appropriate blank sample, typically the food without additive), and "c" is the amount of analyte added to the spiked sample.
Spiking and recovery experiments should be performed using fortified samples, each analyzed in triplicate. These samples should consist of food that contains the additive or ingredient, and is also fortified with a known amount of analyte. Typically, the samples are fortified ("spiked") at levels of one-half of, equal to, and twice the typical additive use level or analyte concentration (or limit of detection, if applicable). The range of spiking levels should be broad enough to encompass or bracket the total range of use levels, as well as any regulatory tolerances. Results of spiking experiments should demonstrate between 80 and 110% recovery for analyte concentrations above 0.1 ppm, and between 60 and 110% for concentrations below 0.1 ppm.
In some cases, it might also be necessary to confirm the identity of the substance being analyzed by an independent analytical technique. This information would be specifically requested in those cases.
- Precision and statistical treatment of data. A discussion of statistical treatment of the data is beyond the scope of this document; therefore, appropriate texts should be consulted in this regard. Nevertheless, a petition should include a discussion of the method used to analyze the data, including special techniques or other pertinent information. Usually, good laboratory precision is indicated by a relative standard deviation of less than 10% for analytical values above 0.1 ppm and less than 20% for analytical values below 0.1 ppm. When analytical values are above the ppm range, precision is generally expected to be better than 10%.
- Reporting of data. A balanced analytical report must be submitted; therefore, both favorable and unfavorable results should be included. The report should include raw data sufficient for an independent evaluation of the data; raw data may include copies of instrument recordings, notebook pages, computer printouts, etc. Sample calculations for the construction of calibration curves and for the determination of the amount of analyte in the food samples based upon the raw analytical data should be provided.
As part of the petition process for regulation of a food additive or ingredient, the consumer exposure to the added substance, or any of its by-products, resulting from ingestion of food containing the substance, must be estimated. This estimate, known as the "estimated daily intake", or EDI, is intended to represent chronic daily intake of the added substance. The EDI is typically calculated for the "average" consumer and the "high" consumer. The Agency considers the "high" consumer as one belonging to that subgroup of the population that consumes, on a regular basis, greater quantities of a particular food than the "average" consumer. For purposes of the estimate, this subgroup is generally represented by the consumers of a given food at the 90th percentile in an "eaters-only" population. The Office of Premarket Approval typically consults several sources for the evaluation of food consumption. These include the USDA/National Food Consumption Survey (NFCS) 1977-1978 and 1987-1988 3-day surveys, the Market Research Corporation of America (MRCA; 1982-1987 Menu Census) 14-day frequency of food consumption survey, and USDA "Situation and Outlook" publications for various food commodities (e.g., "Sugar and Sweeteners"). It should be noted that in the USDA/NFCS 1987-1988 survey, certain sub-populations were under-represented; therefore, this database, in particular, must be used with caution.(4)
Typically, the Office of Premarket Approval will calculate an EDI for the additive based upon the following information provided by the petitioner:
- The specific foods in which the additive is to be used.
- The typical and maximum use levels of the additive.
- The identity of subgroups of the population that might be particularly affected by the use of the additive (e.g., an additive that will be used in infant formula or low-calorie foods).
- Any anticipated increase in consumption from its petitioned use(s), if the petition involves a new use of an additive that is covered by an existing regulation.
- Any anticipated increase in consumption from its petitioned use(s), if the substance is a naturally occurring material. The concentration of the substance occurring naturally in food(s) and an estimate of the level of consumption of the food(s) should be provided.
Although the Agency will determine the EDI for a substance, the petitioner may wish to include their own EDI calculation in the petition. The petitioner may consult the above-mentioned references for food consumption data, or develop alternate sources of food intake data, and, at least, provide a mean EDI (to represent the "average" consumer) and the 90th percentile EDI (to represent the "high" consumer), assuming a typical use level of the added substance. However, it is important to note that the EDI must be based on reasonable consumption scenarios that would be permitted under the petitioned regulation; it cannot be based solely on the petitioner's current marketing plans.
Special cases may arise, particularly in the area of substances that could become macro-ingredients in the diet, for which the food consumption and use level information necessary for the estimation of exposure is inadequate or unavailable. Difficulties can arise in estimating intake when current eating habits cannot be reliably extrapolated to predict the probable intake of the new substance. In these cases, new approaches to the premarket estimate must be derived. The petitioner may wish to consult with the Office of Premarket Approval in agreeing to a suitable approach. The potential for large exposures to new macro-ingredients (e.g., fat replacements) reduces the amount of conservatism that can be included in the exposure estimate.
These recommendations do not address administrative, toxicological, microbiological, nutritional, environmental assessment, or labeling requirements that a petitioner might have to satisfy. Information on these or other requirements, as well as specific inquiries regarding GRAS affirmation or food additive petitions can be obtained by contacting the Office of Premarket Approval, HFS-200, 200 C Street, SW, Washington D.C., 20204.
- The chemical and technological data needs for evaluation of
petitions for secondary direct additives vary according to the
proposed use of the additive. Information regarding submission
of data for enzyme preparations, sanitizers, and indirect food
additives may be requested from the Office of Premarket
Approval, HFS-200, 200 C Street, SW, Washington D.C., 20204.
- Copies are available from the National Academy Press, 2101 Constitution Avenue NW, Washington DC, 20418, or are available for inspection at the Office of the Federal Register, 1100 L St. NW, Washington D.C., 20408.
- Guidelines for Data Acquisition and Data Quality Evaluation in Environmental Chemistry (1980) Anal. Chem. 52:2242-2249 and (1983) Anal. Chem. 55:2210-2218.
- General Accounting Office Report GAO/RCED-91-117, Nutrition Monitoring: Mismanagement of Nutrition Survey has Resulted in Questionable Data.
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