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Center for Food Safety & Applied Nutrition Office of Premarket Approval September 1999 (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.
Guidance for Industry
Preparation of Premarket
Notifications for Food Contact Substances: Toxicology Recommendations
Additional copies are available from:
Office of Food Additve Safety (OFAS), HFS-200
Center for Food Safety & Applied Nutrition (CFSAN)
Food and Drug Administration (FDA)
5100 Paint Branch Parkway
College Park, MD 20740
(Tel) 301-436-1200
Contact information updated since original publication.
(See
additional contact information.)
U. S. Department of Health and Human Services
Food and Drug Administration
Center for Food Safety and Applied Nutrition (CFSAN)
September, 1999
HIGHLIGHTS OF THE 1999 GUIDANCE FOR INDUSTRY "PREPARATION OF PREMARKET NOTIFICATIONS FOR FOOD CONTACT SUBSTANCES: TOXICOLOGY RECOMMENDATIONS"
Safety Narrative (SN) and Comprehensive Toxicological Profile (CTP). The toxicology data package for a premarket notification should contain both a safety narrative and comprehensive toxicological profile of the food contact substance that is the subject of the notification. The SN should provide the basis for the notifier's determination that the intended use of the food contact substance is safe. The CTP should provide summaries and critical evaluations of all of the available toxicological information pertinent to the safety evaluation of the food contact substance. In some cases, notifications may need to include CTPs for toxicologically relevant constituents of the food contact substance. If a constituent of a food contact substance is carcinogenic, the notification should include a quantitative risk assessment.
Toxicity Testing Recommendations for Food Contact Substances and Their Constituents. This document recommends toxicity testing to assess the potential carcinogenicity and subchronic toxicity of food contact substances that are the subject of premarket notifications and their constituents. The recommendations describe the minimum level of toxicity testing generally considered appropriate at various cumulative estimated daily intakes (CEDIs) (1). At CEDIs of the food contact substance <0.5 ppb, no toxicity tests are recommended (2). FDA intends to require, under the authority of 21 U.S.C. 348(h)(B)(3), at CEDIs > 1 part per million (ppm), that, ordinarily, a food additive petition be submitted for the use of a food contact substance. In some cases, toxicity testing may need to be approached on a case-by-case basis if indicated by the intended use or potential toxicity of a food contact substance.
Evaluation of Structural Similarities to Known Toxicants. To the extent feasible, knowledge in predicting potential toxicity based on structure/activity relationships may be incorporated into the safety assessment of food contact substances that are the subject of premarket notifications. Such information may be used as part of an overall strategy for assessing the safety of a food contact substance or to help interpret toxicity test results.
FDA Form No. 3480. FDA Form No. 3480 "Notification for New Use of a Food Contact Substance" is attached.
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TABLE OF CONTENTS
Section 309 of the Food and Drug Administration Modernization Act of 1997 (FDAMA), amended Section 409 of the Federal Food, Drug, and Cosmetic Act (FFDCA) (21 U.S.C. 348) to establish a premarket notification (PMN) procedure as the primary method by which the Food and Drug Administration (FDA) regulates food additives that are food contact substances. Food contact substances include all substances that are intended for use as components of materials used in manufacturing, packing, packaging, transporting, or holding food if the use is not intended to have any technical effect in the food.
Notifications for food contact substances must contain sufficient scientific information to demonstrate that the substance that is the subject of the notification is safe for the intended use (21 U.S.C 348(h)(1)). Because the safety standard is the same for all food additives whether subject to the petition process or the PMN process, information in a PMN should be comparable to that required in a food additive petition.
This guidance has been prepared by the Office of Premarket Approval of the Center for Food Safety and Applied Nutrition (CFSAN) at the Food and Drug Administration in accordance with FDA's "Good Guidance Practices" (62 FR 8961; Feb. 27, 1997). The purpose of this document is to provide general guidance for the toxicology information that should be included in a PMN for an FCS. This guidance represents FDA's current thinking on the toxicology information for a PMN. It does not create or confer any rights for or on any person and does not operate to bind the Agency or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute and regulations. For situations not addressed in the guidance, notifiers are advised to consult FDA. Periodically, FDA will update this guidance in light of new information.
The level of toxicology testing that is recommended to support a premarket notification for a food contact substance is largely determined by the CEDI of (alternatively, "the exposure to") the food contact substance. The CEDI is the sum of the EDIs to the food contact substance that may result from the application of the substance described in the notification and any other food uses of the substance. For information on estimating human dietary exposures, refer to the document entitled Guidance for Industry: Preparation of Premarket Notifications for Food Contact Substances: Chemistry Recommendations (1999).
In some cases, limitations in the submitted chemistry information could affect the magnitude of the exposure estimate, and thereby affect the toxicological testing recommendations. Therefore, FDA recommends that notifiers provide adequate information on the level of the food contact substance expected in foods in order for an estimate of the CEDI to reflect probable consumer exposure to the food contact substance and to ensure that the appropriate level of toxicity testing is conducted.
The Agency generally recommends that the test substance for toxicity studies be identical to the substance that is expected to migrate to food. Ordinarily, the appropriate test substance is the food contact substance itself. In some cases, however, appropriate test substances may include various constituents of the food contact substance, such as minor components, materials used in manufacturing, or decomposition products, if these constituents are expected to migrate to food. For example, for a food contact substance that is a polymer, low-molecular weight oligomers (but not the polymer itself) may be expected to migrate to food from the food contact substance. In this case, FDA recommends that low-molecular weight oligomers be used as the test substances for toxicity studies.
Some food contact substances decompose to other substances that exert technical effects during the manufacture of the food contact substance (e.g., slimicides) or in the food contact substance itself (e.g., phosphorus-based antioxidants in which phosphorus oxidizes to phosphates and phosphites). Other food contact substances, such as antioxidants in polymers, are known to decompose during processing, in storage, and in food or food-simulating solvents. In such cases, decomposition products of the food contact substances may be appropriate test substances for toxicity studies.
Test and control substances should be characterized and handled in accordance with the Good Laboratory Practice regulations for non-clinical laboratory studies (21 CFR Part 58, Subpart F - Test and Control Articles). In all cases, the composition of the test substance used in toxicity studies should be known. Notifiers should provide the names, structural formulae, and quantities of major components and other constituents of the test substance, and the approximate total quantity of unidentified material. Common names and trade names should be provided, if available. A single batch of a test substance should be used for a toxicity study, if possible. If more than one batch is used, however, the strength, composition, purity, and other characteristics of each batch should be approximately the same.
Additional information is contained in the document Guidance for Industry: Preparation of Premarket Notifications for Food Contact Substances: Chemistry Recommendations (1999) For guidance on toxicity studies for specific test substances, notifiers are advised to contact the Agency.
The information provided in this document is intended to help ensure that sufficient toxicology information is available on a food contact substance and its constituent(s) (e.g., manufacturing materials and decomposition products) to determine whether the substance is safe under its intended conditions of use. Although the information contained in this document represents the Agency's current thinking on the toxicology information needed to establish the safety of food contact substances and their constituents, an alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations.
Information on the appropriate format and organization of toxicology information in the toxicology data package is provided (see VI.).
Each notification should contain a concise safety narrative (SN). The SN should summarize the information that the notifier believes justifies a conclusion that the intended use of a food contact substance is safe. Ordinarily, the SN should reference the estimated human exposure and potential toxicity of the food contact substance and its constituent(s) (e.g., manufacturing materials and decomposition products), and should be based on chemistry and toxicology information and analyses described in detail in other sections of the notification. The SN should include conclusions regarding the mutagenic and carcinogenic potential of the food contact substance, and any toxicologically relevant constituents, as appropriate. In the SN, the notifier should be explicit in reporting all effects of a food contact substance, including those considered adverse or physiologic. If an Acceptable Daily Intake (ADI) for the food contact substance is determined, it should be justified in terms of the end-point chosen, the animal species selected, and the safety (or uncertainty) factor applied. Generally, an ADI for a food contact substance used below 50 ppb is not available because chronic or subchronic studies are not usually recommended below 50 ppb. In cases where such studies are available, an ADI may be calculated. If a previously established ADI supports the new intended use of a food contact substance, this justification should be discussed.
Each notification should include a comprehensive toxicological profile (CTP) for the food contact substance that is the subject of the notification. If there are constituent(s) of the food contact substance (e.g., manufacturing materials and decomposition products) that are expected to migrate to food and be present in the human diet, then CTPs for constituents of potential toxicological concern should also be provided in the notification.
CTPs should summarize and evaluate all toxicology studies and related information available on a particular substance. Studies or information recommended below (see IV.C) that identify adverse effects of the substance, or that bear significantly on the determination of an acceptable daily intake (ADI) for the substance, should be described in detail (see VI.).
Toxicological data obtained via the oral route are considered most relevant to the safety assessment of substances in food. The data collected from studies using other routes of administration may be of value when systemic effects at distal sites are observed. Generally, information and data related to local effects in animals or humans, such as skin and eye irritation, are of limited value in assessing the safety of food contact substances. Studies and information that are determined to be of limited value should be described briefly.
CTPs should contain a no-observed-effect level (NOEL) for each non-neoplastic adverse effect of the substance; NOELs should be based on the study, species, strain and sex that appear to be most sensitive to an identified adverse effect, unless there is a scientific rationale that justifies an alternative approach. The NOEL for each identified adverse effect should be multiplied by the appropriate safety factor. FDA recommends that the lowest value calculated among the set of identified adverse effects be considered the acceptable daily intake (ADI), unless there is scientific rationale that justifies an alternative approach for determining acceptable intake. In general, FDA recommends that a safety factor of 1/1000 should be used for NOELs derived from subchronic studies (i.e., 90-days to one year in duration) and a safety factor of 1/100 should be used for NOELs derived from chronic studies (i.e., one year or longer in duration). For reproduction and developmental endpoints, FDA recommends that a safety factor of 1/1000 should be used if the observed effects are severe or irreversible (e.g., a missing limb or decrease in the number of pups born live); otherwise, FDA recommends a safety factor of 1/100 be used.
The NOELs used to calculate ADIs should be expressed as mg per kg body weight of the test animal. If the levels of the food contact substance or constituents given to test animals in a study are expressed as percent or parts per million in the diet, the notifier should report the NOEL using these units and also calculate intake as mg per kg body weight. The notifier should clearly indicate if actual food consumption data were used in such calculations.
FDA believes that information on the genetic toxicity and carcinogenicity of a substance is important to the safety assessment of such substance, even when the substance is expected to be present in the diet only at a very low level. Thus, information on the genetic toxicity and potential carcinogenicity of the food contact substance and its constituents should be described in detail in the CTPs. Factors to consider in determining whether results of genetic toxicity studies indicate a potential carcinogenic concern for the substance include: (1) other available safety data; (2) the array of positive and negative genetic toxicity test results; (3) the estimated CEDI of the substance; and, (4) the chemical structure of the substance (see IV.E.).
In preparing a toxicological profile, the available information should be well organized. For example, the toxicological studies should be grouped according to the duration of exposure (i.e., acute, subacute, subchronic, and chronic). Studies in genetic toxicity, reproduction/teratology, and other specialized areas including pharmacokinetic, immunological, neurotoxicological, clinical, and epidemiological studies, if any, should be grouped separately. When appropriate, data should be presented in tabular form to facilitate their appraisal (e.g., to summarize the results of multiple short-term studies with related endpoints). A list of references should be part of the toxicological profile. Additional recommendations on the format and organization of the CTP are provided below (see VI.A.).
The Agency recommends toxicology studies to assess the safety of a food contact substance, and its constituents if appropriate, on the basis of CEDIs. In general, if the EDI for a new use represents a small fraction of the CEDI, and the CEDI is less than an applicable ADI, the notifier may not need to submit any new toxicity data. These recommendations are consistent with the general principle that the potential risk of a substance is likely to increase as exposure increases.
For a food contact substance with a CEDI greater than 0.5 ppb, FDA recommends that genetic toxicity testing be done. This is because carcinogenicity is a health concern at low levels of exposure and genetic toxicity testing is the most reliable experimental indicator of potential carcinogenicity, with the exception of full-scale chronic animal carcinogenicity studies. The genetic toxicity tests that are recommended are derived from the report of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) . In the judgement of the Agency, these tests are generally appropriate for the evaluation of food contact substances. In some cases, genetic toxicity testing may not be useful or the recommendations that are provided below may need to be modified. For example, the Agency believes that genetic toxicity testing of polymers is unnecessary and that testing of oligomers and other constituents that can migrate into foods is more appropriate. Another example is the case of a biocidal substance where a microbial assay would be inappropriate.
This guidance permits notifiers to exercise their own judgement in selecting toxicity tests, including genetic toxicity tests, to be performed for food contact substances. The level of testing and types of toxicology information needed for determining the safety of a particular food contact substance or its constituent(s) should be evaluated on a case-by-case basis, with reference to the intended use (i.e., biocides), potential acute and chronic toxicity (e.g., signs/symptoms of neurotoxicity and hyperplasia, respectively), and structural alerts.
The Agency recommends that the following toxicology studies be performed to assess the
safety of a food contact substance (and its constituents if appropriate) with the indicated
CEDIs:
When the estimated CEDI of a food contact substance or a constituent is expected to be greater than 1 ppm, the Agency expects to require that a food additive petition be submitted for the food contact substance. (see VII.).
The so-called Delaney clause of the Act’s food additive provisions (sec. 409(c)(3)(A)) prohibits the approval of carcinogenic food additives including food contact substances. Importantly, however, the Delaney clause applies to the additive itself and not to constituent chemicals in the additive. Therefore, if a food additive, including a food contact substance, has not been shown to cause cancer but contains an unintended carcinogenic constituent, FDA evaluates the constituent under the general safety standard using quantitative risk assessment procedures. Notifiers should include risk assessments for such constituents, as appropriate, in their notifications. If the calculated upper bound, lifetime risk of a constituent is less than10-8, the risk associated with the constituent will generally be considered insignificant.
If the results of epidemiology studies or rodent carcinogenicity studies on the constituent are either positive or equivocal, the notifier ordinarily should calculate an extreme-case, upper-bound, lifetime risk to humans from exposure to the constituent. In the absence of convincing scientific evidence that justifies other approaches to estimating risk, the notifier should: (1) use the tumor data from the most sensitive species, strain, sex, and study; (2) assume that tumors arising at multiple sites are independent of each other and add their risks; and (3) calculate the extreme-case, upper-bound, lifetime risk by multiplying the unit cancer risk by the estimated human exposure to the constituent based on the use that is the subject of the notification. The unit cancer risk is defined as the slope of a straight line drawn from the lowest apparent effect dose to zero. Unit risks for some constituents of food contact substances have been calculated by the Agency; these are available upon request.
General information on the Agency's approach to risk assessment is contained in publications by Kokoski et al. (1990) and Lorentzen (1984). For more specific information on the Center for Food Safety and Applied Nutrition's quantitative risk assessment procedures, notifiers should contact the Agency.
It is reasonable to expect that the chemical structure and physicochemical properties of a food contact substance are potential determinants of toxicity. To the extent feasible, knowledge in predicting toxicity based on structure/activity relationships may be incorporated into the safety assessment of food contact substances. When appropriate, expert analysis, decision-tree procedures (Cramer et al., 1978), or computer-assisted quantitative structure/activity techniques may be used to relate the chemical structure of a food contact substance with a toxicological endpoint of interest. Such information should not be considered as a substitute for actual data, but may be useful in developing an overall strategy for assessing the safety of a food contact substance and interpreting the results of carcinogenicity and other types of toxicology studies.
A notifier may request a pre-submission meeting regarding a notification for a food contact substance. Many notifications will not require pre-submission interactions (i.e., a routine pre-submission period) between the Agency and the notifier. Such interactions will occur at the discretion of the notifier and are intended to facilitate the submission of successful notifications since notifications without adequate scientific support will be rejected. The Agency considers all pre-submission meetings consultative in nature; such meetings should not be considered determinative with respect to an Agency decision to accept or object to a notification submitted to the Agency subsequent to a pre-submission meeting.
One example of when a pre-submission meeting might be helpful is when the ADI/CEDI ratio is less than five. In such cases, the notifier may wish to request a pre-submission meeting to discuss possible interpretive differences in establishing a NOEL to calculate an ADI. Because dosing levels in toxicology studies are often spaced by a factor of three and the determination of the NOEL would seldom be expected to differ by more than a single dose, FDA believes that this factor of five is an appropriate rule-of-thumb for notifier’s to use in determining if a pre-submission meeting is warranted.
Pre-submission meetings may also be helpful when there are questions regarding the
carcinogenicity of a food contact substance, significant risk potentially associated with a
carcinogenic constituent, or when there are equivocal mutagenicity data.
FDA's Redbook (Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food, 1982) provides general guidance on the conduct of standard toxicity tests, other than genetic toxicology tests, and is relevant to toxicity testing of food contact substances and their constituents. Additional information may also be found in the 1993 draft of Redbook II.
For guidelines on the conduct of genetic toxicity tests, notifiers should consult the upcoming draft of the Redbook to be available in FDA's website. For guidelines for genetic toxicity tests not yet found at this website, FDA recommends that notifiers consult the testing guidelines published by the Organization for Economic Co-operation and Development or the guidelines of the United States Environmental Protection Agency and the genotoxicity guidelines of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use are attached.
Alternative procedures for conducting toxicity tests may be used. In such cases, the Agency recommends that notifiers consult with scientists at the Agency on proposed deviations from recommended toxicity test protocols before the tests are conducted.
All toxicity tests should be conducted according to the good laboratory practice (GLP) regulations of the Food and Drug Administration, or the GLP guidelines of the United States Environmental Protection Agency or the Organization for Economic Co-operation and Development. A statement that the study has been, or will be, conducted in compliance with the good laboratory practice regulations set forth in 21 CFR Chapter 1, Title 21, Part 58 and a quality assurance statement should be part of each nonclinical study submitted in a notice. If a study was not conducted in compliance with the regulations, a brief statement of the reason for noncompliance should be given. For a toxicology study conducted after 1978 that is noncompliant with the GLP regulations, FDA expects to require that notifiers include a report of a data audit by an independent third party auditor if the study is essential to assessing the safety of the food contact substance.
This section contains FDA's recommendations on the general organization of information and data contained in the toxicological data package (see A.) and on the preparation of study summaries (see B.). Some discussion of how the data obtained from various types of toxicological studies affect the overall safety assessment of a food contact substance is also provided.
The toxicology data package should be organized as follows:
Section B. below discusses study summaries in detail. Information on the Safety Narrative and Comprehensive Toxicological Profile are discussed in sections IV.A. and IV.B.; data submission and the reference list are discussed in sections C. and D.
Individual summaries of unpublished study reports and published articles that bear significantly on the safety assessment of a food contact substance should be prepared and properly referenced. Study reports and published articles of the same study type (i.e., subchronic, chronic, reproductive, etc.) should be grouped first by species (e.g., mouse, rat, dog, etc.), then summarized in chronological order within each grouping. Each summary should include the following minimum information:
If the test substance in a specific study differs from the food contact substance that is the subject of the notification, its relationship to the food contact substance should be clearly indicated. For example, the test substance should be identified as a component of the substance, monomer, oligomer, decomposition product, side reaction product or impurity, as appropriate. Other information regarding the test substance is contained in Section III., above.
A summary table of the effects observed, if any, should be prepared for each study type (i.e., subchronic, chronic, reproductive, etc.) to facilitate the evaluation and determination of no-effect levels for all of the substance-related effects.
FDA's views of the relevance of various types of toxicological studies to the safety assessment of a food contact substance are discussed below by study type.
Acute Toxicity Studies
Acute toxicity data, including LD50 values, are rarely used in the overall safety assessment of food contact substances to which long-term repeated exposure of consumers is expected. It is not necessary to discuss individual acute studies. Instead, the results of acute toxicity studies may be presented in a table.
Genetic Toxicity Studies
The potential for genetic toxicity is an important consideration in the safety evaluation of food contact substances with projected levels of dietary exposure above 0.5 ppb. In evaluating the safety of the food contact substance, and related substances if appropriate, notifiers should consider all published and unpublished genetic toxicity data. In summarizing the data, the notifier should:
Group the available data by the test system (e.g., gene mutations in bacteria, gene mutations in cultured mammalian cells, chromosome aberrations in vitro, chromosome aberrations in vivo, etc.). Individual studies within the same test system should be presented in chronological order;
Prepare a table of the genetic toxicity data for the food contact substance, and related substances if appropriate; and,
Formulate and justify an overall conclusion regarding the genotoxic potential of the food contact substance.
Short-term Toxicity Studies
Short-term toxicity studies in animals are usually only 7-28 days in duration. They should not be used to establish an ADI for a food contact substance. Individual summaries of short-term studies should be included in the CTP, but such studies should not be discussed in detail. For these studies, endpoints or target organs potentially associated with toxicity and dose levels appropriate for longer-term toxicity tests should be emphasized, as appropriate.
Subchronic Toxicity Studies
NOELs from subchronic toxicity studies often are the basis for determining ADIs for food contact substances. In such cases, it is important to provide complete summaries of subchronic studies, including detailed discussions of the study results. However, if the primary objective of a subchronic study is to identify the target organ or select doses for a longer study, it may be appropriate to limit the discussion as for short-term toxicity studies.
Reproductive and Developmental Toxicity Studies
NOELs from reproductive and developmental toxicity studies may be the basis for determining ADIs for food contact substances. Therefore, a summary and detailed discussion of the results of each study should be provided. For both parental animals and their offspring in each generation, no-effect levels should be identified for all substance-related changes. The summaries should state whether the effects used to derive NOELs are considered to be severe or irreversible and discuss the relevance of such severity or reversibility to the selection of the appropriate safety factor for determining an ADI. The toxicological relevance of any reported changes should be evaluated and, if observed, the impact of concurrent maternal toxicity on the results of the study should be addressed.
Chronic Toxicity Studies
The results of chronic rodent or non-rodent studies should be summarized and discussed in detail. Due to the increased duration of these studies (i.e., at least a year), toxic effects may be identified that would not be detected in shorter studies. Consequently, if chronic toxicity studies are available, these studies will ordinarily supersede subchronic studies for the purpose of establishing an ADI for a food contact substance, or related substances.
Carcinogenicity Studies
All neoplastic and non-neoplastic study observations should be discussed. Summary tables of statistically significant and biologically significant neoplastic and non-neoplastic lesions at any organ/tissue site should be prepared. The incidence of test animals with benign and malignant tumors at a specific organ site, both separately and combined, should be provided as appropriate (McConnell et al., 1986 ; NTP Guidelines). If available, a detailed morphological description of any significant lesions should be included. Statistical trend tests should be performed in addition to tests of significance between dose and control groups. In addition, all effects observed should be evaluated for potential biological relevance. Related histopathological information, such as time to tumor formation and historical tumor data, should be discussed. Reports prepared by the National Toxicology Program provide good examples of how to present the histopathological data requested above. The CTP should state clearly whether the food contact substance was associated with neoplastic or pre-neoplastic changes and discuss whether the incidence, location and type of tumors observed in this study demonstrate any carcinogenic effects attributable to the food contact substance or related substances, as appropriate. Note that the detailed information described above is particularly needed to support a conclusion that no carcinogenic effects were observed in a study.
Special Studies
This subheading includes metabolism and pharmacokinetic studies, studies designed to test specific toxic effects (e.g. neurotoxicity, immunotoxicity), and observations in humans. Ordinarily, these studies are not a necessary part of the testing paradigm for food contact substances. However, if these studies are available, individual study summaries should be provided. If the results significantly affect the ADI determination for a food contact substance, special studies should be discussed in detail.
Full study reports, including the primary data (i.e., individual animal data, plate counts, etc.), should ordinarily be submitted for all recommended toxicology studies on the food contact substance, or other substances as appropriate, whether conducted by the notifier or by a third party. It is particularly important that notifiers submit full study reports of studies and related information that are used quantitatively, (e.g., to conduct risk assessments or set no-observed-effect levels). For clarification or to determine if the full study report for a specific toxicology study should be included in a premarket notification, notifiers are advised to contact the Agency after reviewing the information provided in B. above. It is not necessary for notifications to include full study reports of all of the data summarized and discussed in the CTP(s) (e.g., ocular irritation studies and skin sensitization studies).
All published and unpublished studies and information presented in the toxicological data package should be appropriately referenced in the text by citing the author(s) publication name, and year of publication. All references should be listed alphabetically. Each published reference should include the names of all authors, the year of publication, the full title of the article, and pages cited. For a reference from a book, also include the title of the book, the editor(s), and the publisher. Reference to unpublished studies should identify all authors, the sponsor of the study, the laboratory conducting the study, the final report date, the full title of the final report, the report identification number, and inclusive page numbers. References to government publications should include the department, bureau or office, title, location of publisher, publisher, year, pages cited, and publication series, and report number or monograph number.
The search parameters that were used for all literature searches conducted should be provided. The parameters of interest including the names of databases searched, the period of years searched, and the specific search terms used.
FDA believes that premarket review and approval of a food additive petition for the use of a food contact substance should be required only in those cases where it is necessary for adequate assurance of safety. FDA expects to propose regulations identifying the circumstances in which a food additive petition would be required for the use of a food contact substance. Such regulations would also permit FDA to accept a notification if the Agency determines that submission and review of a petition are not necessary for adequate assurance of safety.
FDA currently believes that there are two sets of circumstances in which premarket review and approval of a food additive petition for the use of a food contact substance through the petition process are necessary for adequate assurance of safety. These circumstances are:
uses of a food contact substance that increase the CEDI of the substance from food uses to greater than 1 part per million (ppm) or, in the case of biocides, to greater than 200 parts per billion (ppb); or
when there are one or more carcinogenicity studies on the FCS that have not been previously reviewed by the Agency and which are not clearly negative for carcinogenicity.
These two sets of circumstances are discussed in more detail below.
FDA expects to propose regulations requiring a food additive petition for uses of a food contact substance that increase the CEDI of the substance from food uses to greater than 1 ppm or, in the case of biocides, to greater than 200 ppb. Historically, FDA has based its recommendations for toxicity data to support the safe use of food additives on the estimated intake of the food additives. As a general rule, higher estimated intakes of substances in the diet pose both an increased risk of toxicity and a wider range of potential toxic effects. The maximum levels of CEDI identified above are levels at which the agency has historically requested more comprehensive toxicity testing in order to address a substance’s potential to induce diverse toxic effects. To address the risk of these effects, FDA has asked for longer term toxicity studies and toxicity studies that measure a wider variety of toxic endpoints. The agency believes that this approach has proved to be sound in that it has ensured the safety of additives permitted in the food supply. Thus, FDA continues to believe that uses of food contact substances that have the potential for inducing diverse toxic effects of consequence to human health generally require longer term and more specialized toxicity testing to support their safe use. Where such toxicity testing is needed, the agency believes that submission, review, and approval of a food additive petition is appropriate because the petition process will afford FDA the time necessary to review the more extensive toxicity data package.
FDA has tentatively concluded that a lower dietary concentration cutoff for PMNs for biocides is appropriate for substances that are toxic by design. Biocides are a class of food contact substances that are expected to be more toxic because their intended technical effect is microbial toxicity. Consistent with FDA’s testing recommendations, FDA intends that this lower cut-off level would apply to substances used as food contact substances primarily for their antimicrobial or fungicidal effects.
The use of carcinogens as food additives is prohibited by the food additives anti-cancer clause in section 409(c)(3)(A) of the act (the so-called Delaney clause). FDA believes that, if data exist that may demonstrate that a food contact substance is carcinogenic, a thorough review of such data is appropriate and necessary to adequately assure safety and properly administer the statute. The determination of carcinogenic potential is a critical aspect of the safety evaluation that may be too complicated for the Agency to complete within the 120-day time frame allotted for review of food contact substance notifications. Therefore, the Agency expects to propose regulations to require a food additive petition when there are carcinogenicity studies of the food contact substance that have not previously been reviewed by FDA and that are not clearly negative for carcinogenicity.
FDA's experience in evaluating the safety of food contact substances and their constituents indicates that situations may arise in which a premarket notification will be appropriate for the use of a food contact substance even if the CEDI for the food contact substance or its constituents are equal to or greater than 1 ppm, or 200 ppb in the case of biocides. Examples of such cases are provided below.
A premarket notification may be appropriate for a food contact substance, even if the estimated CEDI is >1 ppm, or 200 ppb for biocides, when:
There is an existing ADI for the food contact substance and its constituent(s) . In such a case, the notifier should contact the Agency to determine the applicability of the ADI for the food contact substance, before submitting a premarket notification.
A large database is available on a close structural analog of the food contact substance and its constituent(s), which analog has been approved by the Agency. In such cases, the following toxicological tests are recommended to demonstrate the degree of toxicological and metabolic similarity between the FDA-regulated analog and the food contact substance and its constituent(s): (a) a subchronic oral toxicity study in a rodent or non-rodent species and, (b) comparative absorption, distribution, metabolism, and elimination studies.
The food contact substance undergoes chemical or metabolic transformation solely to products known to be of little toxicological concern at the estimated level of CEDI. Such assertions should be supported by relevant in vivo or in vitro data.
Cramer, G.M., Ford, R.A., and Hall, R.L. 1978. Estimation of toxic hazard - A decision tree approach. Food Cosmet. Toxicol. 16:255-276.
Code of Federal Regulations, Chapter 1, Title 21, Part 58 - Good Laboratory Practice for Non-Clinical Laboratory Studies. Final Rule for Good Laboratory Practice Regulation under the Federal Food, Drug, and Cosmetic Act. Federal Register 43:59986-60025, Dec. 22, 1978.
Kokoski, C.J., Henry, S.H., Lin, C.S., and Ekelman, K.B. Methods used in safety evaluation. In: Food Additives, edited by Branen, A.L., Davidson, P.M., and Salminen, S., Marcel Dekker, Inc., New York, p. 579-616, 1990.
Lorentzen, R. 1984. FDA Procedures for carcinogenic risk assessment. Food Technology 38(10):108-111.
McConnel E.E., Solleveld, H.A., Swenberg, J.A., and Boorman, G.A. 1986. Guidelines for combining neoplasms for evaluation of rodent carcinogenesis studies. J. Natl. Canc. Inst. 76:283-289.
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1. FDA recognizes that this guidance's use of cumulative estimated daily intake (CEDI) appears to differ from the approach of FDA's threshold of regulation (TOR) process, 21 CFR 170.39. The two approachs are, in fact, consistent. Under TOR, indirect food additive uses that result in incremental exposures of less than 0.5 ppb in the diet are eligible for exemption from the food additive petition requirement. At the time the TOR program was established, FDA determined that, because of the conservative assumptions ordinarily applied in estimating exposure, the cumulative exposure from a limited number of trivial food additive uses is not likely to be more than negligible. Accordingly, in the case of the TOR exposure levels, it was not necessary to utilize cumulative exposure levels. FDA believes that the determination made in TOR is still sound. .
2. However, if multiple trivial uses of a food contact substance result in a significant increase in the CEDI, this will be considered by FDA in determining whether additional toxicity testing is necessary.
The latest version of
this guidance issued on April 10, 2002.
This document was issued in September 1999.
For more recent information on Guidance and Reference Documents for
Petitions and Notifications
see
http://www.cfsan.fda.gov/~dms/opa-guid.html
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