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CFSAN/Office of Food Additive Safety
March 2006
Comments and suggestions regarding this document may be submitted at any time. Submit comments to Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
For questions regarding this document, please contact Diana Doell at the Center for Food Safety and Applied Nutrition (CFSAN) at 301-436-1276, e-mail address diana.doell@fda.hhs.gov.
Additional copies are available from:
Office of Food Additive Safety, HFS-200
Center for Food Safety and Applied Nutrition
Food and Drug Administration, 5100 Paint Branch Parkway
College Park, MD 20740
301-436-1276
http://www.cfsan.fda.gov/guidance.html
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Food Safety and Applied Nutrition (CFSAN)
March 2006
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.
This document describes the types of chemical and technological data that FDA's Office of Food Additive Safety (OFAS) in the Center for Food Safety and Applied Nutrition (CFSAN) considers necessary for the evaluation of petitions seeking regulation for the safe use of direct food additives.
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 are currently categorized as direct additives, secondary direct additives,2 indirect additives,3 and sources of ionizing radiation.4 Section 201(s) of the Act exempts the use(s) of a substance that is generally recognized as safe (GRAS)5 from the definition of a food additive. The CFR contains regulations for food ingredients that are listed or affirmed as GRAS. This document is guidance for submitting a petition for a direct food additive (i.e., a substance added directly to food, as codified in 21 CFR Part 172). Color additives, as codified in 21 CFR Parts 73 and 74, are not discussed in this document.6
This document is a revision of, and supercedes, the "FDA Guidelines for Chemistry and Technological Data Requirements for Direct Food Additives and GRAS Food Ingredients" dated May 1993. This guidance focuses only on direct food additives and the discussion of GRAS Petitions has been removed.
This guidance is
intended to address needs for most petitions, but some recommendations may not
be applicable in all cases. If a recommendation does not appear to apply to
the petitioned additive and use, the petitioner should explain briefly why the
data recommended here are not needed to evaluate the safety or promulgate a
regulation for the petitioned request.
FDA's guidance documents, including this guidance, do not
establish legally enforceable responsibilities. Instead, guidances describe
the Agency's current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory or statutory requirements are
cited. The use of the word should in Agency guidances means that something
is suggested or recommended, but not necessarily required.
Section 409(b)(2) [§409(b)(2)] of the Act describes the statutory requirements for food additive petitions. Briefly, these encompass five general areas of information:
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 [§409(b)(3)] and/or samples of the additive and of food in which the additive will be used [§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, an environmental assessment, and specimens of proposed labeling. This guidance document addresses only chemistry-related issues.
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 OFAS.7
Information allowing the unequivocal identification and characterization of the food additive should be provided. Such items include:
In accordance with 21 CFR 171.1(c)A, where such information is not available, a statement as to the reasons why it is not available should be submitted.
Information on the method of manufacture of a food additive is necessary for identification and characterization of both the intended component(s) and any likely impurities (e.g., residual starting materials, products of side reactions, and decomposition products of reactants or of the additive) in the additive. For food additives of natural origin that might contain known toxicants, the petitioner should address the ability of the manufacturing process to control, reduce, or concentrate toxicant levels.
A discussion of the manufacturing process should include a list of the reagents, solvents, catalysts, processing aids, purification aids, specialized equipment, etc. used, as well as a detailed description of the process itself, including all reaction conditions (e.g., time, temperature, and pH) and production controls (including steps taken to limit the presence of reaction by-products and other impurities). The petitioner should also identify any alternative method(s) of manufacture of the additive, if known, and provide as full a description as possible for the method. In all cases, the manufacture of the additive should be consistent with good manufacturing practice (GMP; discussed below in Section C).
Specifications for identity and purity of the petitioned food additive should be proposed.8 If published specifications for the food additive are available, for example in the Food Chemicals Codex (FCC), 5th (2003) or current edition,9 then these should be cited and appropriately referenced. The data provided in this section of a food additive petition should represent a complete compositional analysis of the food additive. Proposed specifications should include:
In light of 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 proposed accordingly. Keep in mind that the proposed specification should be as low as technically feasible taking into account the source and manufacturing process of the food additive, availability of appropriate analytical methodology, and probable human exposure to the food additive.
In order to demonstrate conformance with the proposed specifications, at least five batches of the food additive should be analyzed. If the analytical method is a common standard test (e.g., FCC 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 food additive, 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).
Data demonstrating the stability of the additive should be included, particularly if the additive is sensitive to environmental conditions, such as moisture, air, or temperature, or otherwise has a limited stability. Stability testing should be conducted under the intended conditions of use of the food additive over its anticipated lifetime.
A description of the stability tests should be straightforward and sufficiently detailed for understanding. All raw data, including copies of instrument recordings, a data summary, and analytical methods should be provided.
Food additives are used to accomplish a variety of technical effects. For example, an additive may be classified as an antimicrobial agent, humectant, flavoring agent, surface-active agent, stabilizer or thickener. These terms, as defined in 21 CFR 170.3(o), describe physical or technical functional effects for which food additives are intentionally added to foods. The quantity of the additive shall not exceed the amount reasonably required to accomplish its intended technical effect(s) in the food [21 CFR 172.5(a)(1)].
A discussion of the intended use and use level of the additive should include:
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 food additive should be evaluated at several levels above and below the proposed use level (e.g., at levels of ½, 1, and 2 times the intended use level). Some food additives may have a technologically self-limiting use level; that is, the food additive 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 additive 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, data can range from a simple organoleptic evaluation to a complex chemical analysis. Regardless of the degree of sophistication of the method, the experiments should be carefully designed, taking into account the need for controls. For relatively new substances or novel technical effects, samples of food, with or without the added substance, might be requested for analysis; however, the petitioner should not provide such samples unless expressly requested by FDA during the petition evaluation.
If assurance of safe use of an additive depends on a limitation imposed on the amount of a substance (the additive, its associated impurities, or its degradation products) that a food can contain, a method that can quantify the substance in food for the purpose of enforcing this limit should be provided. Quantifying the levels of a substance in food requires a practical analytical method that can be readily performed by appropriately trained personnel in a properly equipped laboratory. The method must be specific, accurate, precise, and reliable. 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. If analytical testing has been contracted out, the raw data from the contract laboratory should be provided in the petition, as well as the contract laboratory methods and relating validation data. If the analytical method will be incorporated by reference in the regulation, 1 CFR 51.9(b)(2) states that the regulation must identify the title, date, edition, author, publisher, and identification number of the analytical method incorporated by reference.
The following is a suggested general format for an acceptable analytical method.
{[a - b] / c} x 100%
As part of the petition process for regulation of a food additive, the consumer intake of the additive, and its by-products, resulting from ingestion of food containing the additive, must be estimated. This estimate, known as the estimated daily intake (EDI), is intended to represent chronic intake (i.e., average daily intake over a lifetime) of the food additive. 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, the "high" consumer subpopulation is generally represented by the consumers of a given food at the 90th percentile.
OFAS will calculate an EDI for the food additive based upon the following information provided by the petitioner:
Typically, OFAS makes some basic assumptions in calculating an intake estimate for a food additive. These assumptions generally lead to a conservative estimate of the intake. First, OFAS assumes that the additive is used at the maximum petitioned level. Second, OFAS assumes that the additive is used in all foods intended to be formulated with the additive.
However, depending on the data available and the intended use of the food additive, OFAS may consider alternative approaches in calculating an EDI, e.g., use of the typical use level of the additive, or consideration of market share of the food formulated with the additive. If the petitioner wishes to use an alternative approach in calculating an EDI, the basis for applying this approach must be fully described, with supporting documentation, in the petition.
A more thorough discussion of OFAS' approaches to estimating consumer intake may be found elsewhere.11
Although OFAS will determine the EDI for a food additive, petitioners are encouraged to provide their own EDI calculation in the petition. If the petitioner chooses to calculate an EDI, the petitioner should consult the above-referenced document11 for information on food consumption data. The petitioner should provide, at minimum, a mean EDI (to represent the "average" consumer) and the EDI at the 90th percentile (to represent the "high" consumer), assuming a maximum use level of the food additive in all foods intended to be formulated with the additive. Alternative approaches to calculating the EDI may also be appropriate. However, the EDI must be based on reasonable consumption scenarios that would be permitted under the petitioned regulation; it should not be based solely on the petitioner's current marketing plans.
In certain cases, the food consumption and use level information necessary for the estimation of intake 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 intake estimate might need to be derived, for example, in the area of food additives that could become macro-ingredients (e.g., fat replacements) in the diet. The petitioner may wish to review other guidance11 and consult with OFAS in agreeing to a suitable approach.
These recommendations do not address administrative, toxicological, microbiological, nutritional, environmental assessment, or labeling requirements that a petitioner should satisfy. Information on these or other requirements, as well as specific inquiries regarding food additive petitions, can be obtained by contacting the Office of Food Additive Safety, 5100 Paint Branch Parkway, College Park, MD 20740-3835, or at http://www.cfsan.fda.gov/~dms/guidance.html (Food and Cosmetic Guidance Documents).
1 This guidance has been prepared by the Division of Petition Review in the Office of Food Additive Safety Center for Food Safety and Applied Nutrition (CFSAN) at the U.S. Food and Drug Administration.
2 A class of food additives that does not neatly fit into either the direct or indirect food additive categories, the so-called secondary direct food additives, are codified in 21 CFR Part 173. These are food additives whose functionality is required during the manufacture or processing of food and are ordinarily not expected to be present in the final product; 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, and other processing aids. 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 secondary direct additives may be requested from the Office of Food Additive Safety, 5100 Paint Branch Parkway, College Park, MD 20740-3835.
3 Articles used in contact with food and substances used to manufacture them, including processing equipment, are indirect food additives (food-contact substances (FCSs)) if they or their components inadvertently become a component of the food through direct contact. Indirect additives are codified in 21 CFR Parts 174-178. Section 309 of the Food and Drug Administration Modernization Act of 1997 (FDAMA) amended section 409 of the Act to establish a food contact notification (FCN) as the primary means by which FDA evaluates food additives that are FCSs. More information on the FCN process can be found at the following websites: http://www.cfsan.fda.gov/~dms/opa2pmna.html (Preparation of Food Contact Notifications: Administrative) and http://www.cfsan.fda.gov/~dms/opa2pmnc.html (Preparation of Food Contact Notifications and Food Additive Petitions for Food Contact Substances: Chemistry Recommendations). The development of the notification program does not preclude submission of an indirect food additive petition. Situations in which a food additive petition is required for a FCS are outlined in OFAS's administrative guidance for the preparation of food contact notifications, which can be found at: http://www.cfsan.fda.gov/~dms/opa2pmna.html (Preparation of Food Contact Notifications: Administrative).
4 See 21 CFR Part 179.
5 The CFR contains two sections of regulations of substances that are GRAS. The first section, 21 CFR Part 182, lists substances that were in common use prior to the 1958 amendment to the Federal Food, Drug, and Cosmetic Act. The second section, 21 CFR Part 184, contains those substances 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.
Since 1997, FDA has had in place a GRAS Notification program (Proposed rule: 62 FR 18937), which is a voluntary process that allows a notifier to inform FDA of its determination that a particular use of a substance is GRAS. The program permits notifiers to submit a summary of their basis for the GRAS determination and, at the same time, gives FDA the opportunity to raise questions or concerns regarding the basis for that determination. Additional information on the GRAS notification program can be found at: http://www.cfsan.fda.gov/~dms/opa-noti.html (GRAS Notification Program). The agency is developing the final rule for Substances Generally Recognized as Safe (Docket Number 97N-0103).
6 Guidance for the submission of chemical and technological data on color additives for food, drugs, or cosmetics can be found at: http://www.cfsan.fda.gov/~dms/opa-col1.html.
7 Guidance for requesting information and/or records from FDA through the Freedom of Information Act (FOIA) can be found at http://www.fda.gov/opacom/backgrounders/foiahand.html (A Handbook for Requesting Information and Records from FDA).
8 Specifications serve only as minimal criteria for establishing that a substance intended for use in food is "food-grade." For a food additive to be considered food-grade, it shall also have been manufactured, packaged, stored, and transported 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 operation. These practices, combined with adherence to the specifications for identity and purity constitute "good manufacturing practice" or GMP. Further elaboration on GMP can be found in the Food Chemicals Codex (FCC).
9 Copies of the FCC are available from the National Academy Press, 2101 Constitution Avenue NW, Washington DC, 20418.
10 Guidelines for Data Acquisition and Data Quality Evaluation in Environmental Chemistry (1980) Anal. Chem. 52:2242-2249 and (1983) Anal. Chem. 55:2210-2218.
11 A discussion of some of the approaches FDA could possibly use to estimate intake of a food additive can be found in the document titled "Estimating Exposure to Direct Food Additives and Chemical Contaminants in the Diet," which can be found at http://www.cfsan.fda.gov/~dms/opa-cg8.html. [August 2006: See updated information "Guidance for Industry - Estimating Dietary Intake of Substances in Food".]
This document supercedes Recommendations for Submission of Chemical and Technological Data for Direct Food Additives and GRAS Food Ingredients (May 1993)