Categories and Subcategories of Substances Added to Food
The Food Additives Amendment of 1958 amended the Federal Food Drug and Cosmetic Act of 1938 (FFDCA) to establish the U.S. food additive regulatory program (Public Law 85-929, 72 Stat. 1784, 21 USC 348). Central to the program was the definition of “food additives” as described in Section “Defining Food and Food Additives.” The definition excluded substances specified in the professional parlance as “GRAS substances.” It also excluded pesticide chemicals or residues used in, on, or in association with raw agricultural commodities and substances whose use was previously sanctioned or approved pursuant to the FFDCA, the Poultry Products Inspection Act or the Meat Inspection Act (21 USC 321(s)). Overall, with the 1958 legislation, the U.S. Congress recognized 4 distinct categories of substances added to food and established requirements for each:
- • Food additives
- • GRAS substances
- • Pesticide chemicals or residues; and
- • Prior-sanctioned substances.
After 1958, the U.S. Congress adopted 3 laws that made significant changes to the statutory definition of food additives:
- • The Color Additive Amendments of 1960 created a new regulatory program for FDA to manage “color additives” whether in food, drugs, or cosmetics and exempted them from the definition of food additives (Public Law 86-618, 74 Stat. 397).
- • The Animal Drug Amendments of 1968 exempted drugs in animal feed approved after 1938 from the definition of food additives (Public Law 90-399, 82 Stat. 342).
- • The Dietary Supplement Health and Education Act of 1994 created a new FDA-based regulatory program to manage “dietary supplements” and exempted these from the definition of food additives (Public Law 103-417, 108 Stat. 4325). Generally, these substances are items not intended to be “conventional food” or intended as the sole item of a meal.
As a result of these laws, by 1994, the U.S. Congress had established 7 distinct categories of substances added to food. If a manufacturer intends to use any substance, directly or indirectly, in food it must fall into one of these categories; otherwise, it must not be used or even marketed as it would be considered a contaminant or unapproved food (or color) additive and, therefore, the food would be adulterated. FDA has broad authority to protect Americans from adulterated food (21 USC 331, 321, 342, and 348 and 21 CFR 181.5).
FDA's and EPA's implementation of these laws (and additional changes to the laws) generated subcategories within these categories. Table 1 provides a current listing of the 7 categories with the key subcategories used in this article. Each is described in more detail below.
Table 1–. Categories and subcategories of substances added to food
|1. Food additives|
| A. Direct food additives|
| B. Indirect food additives (few additions after 1997)|
| C. Substances covered by FCS notifications (began in 1997)|
| D. FCSs below threshold of regulation (began in 1995)|
| E. Radiation sources|
|2. GRAS substances|
| A. Common food ingredients in use before 1958|
| B. Manufacturer self-determined|
| C. Association expert panel-determined|
| D. FDA-listed (ended in 1973)|
| E. FDA-affirmed (began in 1973 and effectively replaced after 1997)|
| F. Substances covered by FDA-reviewed GRAS notification (began in 1997)|
|3. Prior-sanctioned substances (federally sanctioned before 1958)|
|4. Color additives (began in 1960)|
|5. Pesticide chemicals or residues (modified in 1996)|
|6. Drugs in animal feed (modified in 1968)|
|7. Dietary supplements (began in 1994)|
To help make sense of these categories and subcategories, refer again to the microwave-ready, frozen children's dinner meal described in the introduction. At the end of each category or subcategory, the authors explain what additives may be in the sample frozen meal described in the introduction section. Table 2 summarizes those explanations.
Table 2–. Categorization of substances potentially associated with sample frozen, microwave-ready children's meal
|Food additives|| |
| Direct food additives||Carrageenan, butylated hydroxytoluene, modified food starch, and possibly some of the natural flavor|
| Indirect food additives||Polyethylene terephthalate. Other unknown but likely to include additives in or on packaging and equipment used to make the food, such as paperboard, inks, adhesives, glues, coatings, and antimicrobials|
| Substances covered by food contact substance (FCS) notifications||Unknown but may include additives in or on packaging and equipment used to make the food that are not in other categories or subcategories|
| FCSs below threshold of regulation||Unknown but may include additives in or on packaging and equipment used to make the food that are not in other categories or subcategories|
| Radiation sources||Final product not treated with ionizing radiation; however, it may have been used on packaging or individual ingredients or additives. Unknown whether other forms of radiation were used on the food|
|“Generally recognized as safe” (GRAS) substances|| |
| Common food ingredients in use before 1958||34 ingredients including chicken breast, water, bleached wheat flour, whole wheat flour, salt, spices, soybean oil, whey protein, and yeast|
| Manufacturer self-determined||Unknown but most likely microcrystalline and carboxymethyl cellulose, soy protein concentrate, and soy protein isolate|
| Association expert panel-determined||Extractives of turmeric and paprika, carboxymethyl cellulose, and some flavoring|
| FDA-listed||Disodium phosphate, monocalcium phosphate, sodium acid pyrophosphate, sodium caseinate, sodium phosphate, cellulose gum, and, possibly, some of the spices and natural flavor|
| FDA-affirmed||Citric acid, garlic powder, guar gum, gum arabic, lactic acid, maltodextrin, potassium chloride, sodium bicarbonate, whey protein concentrate, yeast extract, soy lecithin, beta carotene, dextrose, dried sweet whey, acetic acid esters of mono- and diglycerides with maltodextrin, and, possibly, some of the natural flavor|
| Substances covered by FDA-reviewed GRAS notifications||Unknown but may include additives used to make the food that are not in other categories or subcategories|
|Prior-sanctioned substances||Unknown, possibly some used in manufacture of paper and paperboard|
|Color additives||Annatto, beta carotene, turmeric and red cabbage extract|
|Pesticide chemicals or residues||Unknown but may include residues of pesticides used in or on raw agricultural commodities in the meal, such as the corn, wheat, sugar, spices, and soybean|
|Drugs in animal feed||Unknown but chicken feed may have contained antibiotics and arsenic-based drug|
|Dietary supplements||Not applicable because the meal is conventional food|
1. Food Additives are substances “the intended use of which results or may reasonably be expected to result, directly or indirectly, in [their] becoming a component or otherwise affecting the characteristics of any food,” provided that the substances’ use does not fall under one of the other 6 categories described below. The “food additive” category includes substances intended for use in producing, manufacturing, packing, processing, preparing, treating, packaging, transporting, or holding food as well as radiation sources (21 USC 321(s) and 21 CFR 170.3).
The food additives category consists of the following 5 subcategories:
1A. Direct Food Additives are substances intentionally added directly to food and whose use has been expressly approved by FDA usually in response to food additive petitions from manufacturers. The subcategory includes substances known as “secondary directs” that have a technical effect in food during processing but are not intended to have an ongoing technical effect in the food. A substance does not affect the characteristics of food if it only protects the contents of the package, preserves a food's shape, or prevents moisture loss from the food (21 CFR 170.3). Before authorizing a new food additive by an administrative rule, such as in response to a food additive petition, FDA publishes its approvals as regulations in the CFR after notifying the public via the Federal Register of the proposal, providing an opportunity for the public to comment, and responding to those comments in a final rule published in the Federal Register (21 USC 348(c)). The regulations are codified at 21 CFR Parts 172, 173, 180, and 189 for all human food and 21 CFR Parts 573, 579, and 589 for animal feed and pet food only. The direct food additives subcategory is still the primary method for new food additive approval as specified in the statute even though it is not commonly used today.
However, the process of getting FDA approval of a petition is time consuming and a manufacturer will typically pursue direct food additive status for a substance only if it cannot qualify as a GRAS substance. A common reason why a substance is ineligible to be a GRAS substance is when the key safety studies are unpublished. From 2000 to 2010, FDA received 37 direct food additive petitions for 12 distinct substances used for human food (see Section “Trends in FDA Reviews for Human Food Since 1990”). Although written as a primary category in the law, in practice, the direct food additives subcategory now serves as a category of last resort for substances used in food that do not fall clearly into any other category or subcategory described below.
Regarding the sample frozen meal, according to the label, the direct food additives appear to consist of carrageenan (a gum), butylated hydroxytoluene (a preservative in the vegetable oil used to fry the chicken), modified food starch, and possibly some of the natural flavor. It may contain other substances not required to be specifically identified on the label such as natural flavors and extracts and substances used as additives in one of the ingredients or that have no functional or technical effect on the final product. For more information on label requirements, see 21 CFR101.100.
1B. Indirect Food Additives are substances not intentionally added directly to food but which may reasonably be expected to become a component of food and whose use has been expressly approved by the FDA (21 CFR 170.3). Generally, these are substances used in or on food packaging or the equipment used for processing or handling food. The regulations governing indirect food additives appear at 21 CFR Parts 174 through 178 for human food and 21 CFR 570.14 for animal feed and pet food. These regulations were promulgated pursuant to a food additive petition. As with direct food additives, FDA must notify the public in the Federal Register of the opportunity to submit comments and publish its approval as a regulation in the CFR (21 USC 348(c)). From 2000 to 2010, FDA has received 6 indirect food additive petitions and 1 after 2001 (see Section “Trends in FDA Reviews for Human Food Since 1990”). Most of the activity shifted to the food contact substance (FCS) notification subcategory described below.
Regarding the sample frozen meal, the indirect food additives are not required to be identified on the label, but they likely consist of additives in packaging and equipment used to make the food, such as polyethylene terephthalate (#1 PETE plastic), other plastics, paperboard, inks, adhesives, glues, cleaning products, antimicrobials, and coatings, that, if capable of migrating into the food should be covered by an indirect food additive regulation, a FCS notification, or a FCS below the threshold of regulation described below.
1C. Substances Covered by FCS Notifications are substances “intended for use as a component of materials used in manufacturing, packing, packaging, transporting, or holding food if such use is not intended to have any technical effect in such food” and that were the subject of a Food Contact Notification (FCN) to which FDA did not object (21 CFR 170.3(e)(3)). While “technical effect” is not defined, the term generally means the substance does not affect the characteristics of food so as to make the substance a direct food additive. This category has essentially replaced the indirect food additive subcategory for new substances.
The U.S. Congress created this subcategory with the Food and Drug Administration Modernization Act of 1997 (Public Law 105-115, 111 Stat. 2296). A new section 409(h) was added to the FFDCA, which replaced the premarket approval procedure for indirect food additives with a premarket notification procedure. FDA began accepting FCNs in 2000 when it proposed rules for its Premarket Notification for FCS program (21 CFR 170.100–170.106, 67 FR 35724, May 21, 2002). FDA finalized the regulations implementing the new procedure in 2002. Under the program, FDA reviews notifications from a manufacturer that has decided that the intended use of a FCS is safe. FDA has 120 d to object to a properly submitted notification. If FDA fails to act, the notification is essentially treated as approved and the manufacturer can use the FCS consistent with the FCN. If FDA has no objections, it typically issues a “no objection” letter. If the agency has concerns, a manufacturer will typically withdraw the notification rather than have FDA formally object (Kahl 2010). Manufacturers may withdraw a notification without prejudice (21 CFR 170.100–170.106). FDA posts affirmative decisions (or ones FDA has not objected to) on its website and describes the chemical and its use limitations and lists the name of the manufacturer (FDA 2011a). It does not post the manufacturer's notification or the contents of the agency's letter to the manufacturer on the website. Congress prohibited FDA from posting information on the notice prior to making a decision (21 USC 348(h)(4)). FDA's decision applies only to substances described in the notice from the manufacturer that submitted it. Competitors may not rely on the decision but can submit their own notification for the same substances and uses.
FCNs get a quicker response from FDA than indirect food additive petitions (described above) because FDA's inaction on an FCN would essentially serve as consent and FDA does not have to go through the process of issuing a new regulation. Therefore, this subcategory has largely replaced the indirect food additive subcategory for new substances indirectly added to food, as well as FCSs below the threshold of regulation (described below), and appears to have encouraged manufacturers to choose to submit FCNs for substances that they might otherwise have self-determined to be GRAS substances. From 2000 to 2010, FDA reviewed more than 1000 FCNs and issued no-objection letters for 778 of them (see Section “Trends in FDA Reviews for Human Food Since 1990”).
Regarding the sample frozen meal, substances covered by FCS notifications are not identified on the label, but they likely consist of substances similar to indirect additives described above.
1D. FCSs below Threshold of Regulation are substances used in food contact articles, for example, food packaging or food processing equipment, which migrate or may be expected to migrate into food at levels so low that FDA determines they are exempt from regulation as a food additive (21 CFR 170.39). FDA adds substances based on its affirmative review of a manufacturer's notification, called a Threshold of Regulation (TOR) exemption request (FDA 2011b).
FDA established this FCSs below Threshold of Regulation subcategory in 1995, 2 y before the U.S. Congress created the substances created by FCS notifications subcategory described above (60 FR 36582, July 17, 1995). For a substance to qualify for this subcategory, FDA must find that it has not been shown to be a carcinogen; has no technical effect in or on the food into which it migrates; has no significant adverse impact on the environment; and has no other health or safety concerns. FDA assumes there to be no other health or safety concerns if the dietary exposure is at or below 1.5 micrograms of the substance per person per day or if the substance is already regulated as a direct food additive and the dietary exposure is at or below 1% of the existing acceptable daily intake for the substance (Rulis and Levitt 2009; FDA 2011c).
As with substances covered by FCS notifications, after making a decision, FDA posts affirmative decisions on its website and describes the chemical and its use limitations and lists the name of the manufacturer (FDA 2011d). FDA does not post the manufacturer's notification or the contents of the agency's letter to the manufacturer on its website. Manufacturers made extensive use of this subcategory when it was launched in 1995. However, because FDA is not required to respond in 120 d, this subcategory appears to have largely been replaced by the substances covered by FCS notifications subcategory described above (Keller and Heckman 2001; FDA 2005). From 2000 to 2010, FDA affirmatively reviewed only 30 of these notifications (see Section “Trends in FDA Reviews for Human Food Since 1990”).
Regarding the sample frozen meal, FCSs below the threshold of regulations are not identified on the label, but they likely consist of substances similar to indirect additives described above.
1E. Radiation Sources are machines such as x-ray tubes or radioactive elements that produce radiation used for inspecting food, controlling food processing, irradiating food, heating food (including microwaves), and treating food packaging. FDA publishes its approvals as regulations in the Code of Federal Regulations after notifying the public via the Federal Register and providing an opportunity for the public to comment (21 USC 348(c)). The regulations appear at 21 CFR Part 179.
Regarding the sample frozen meal, it is not known to consumers whether or not the ingredients comprising the meal were irradiated. The law requires final products treated with ionizing radiation to be labeled; however, radiation sources may have been used on the packaging or individual additives without triggering the labeling requirement.
2. GRAS Substances are substances “generally recognized, among experts qualified by scientific training and experience to evaluate the safety as having been adequately shown . . . to be safe under conditions of their intended use” (21 USC 321(s)). General recognition of safety can be based on a substance's common use in food prior to 1958 or on scientific procedures. If a safety determination relies on scientific procedures, the determination “shall ordinarily be based upon published studies which may be corroborated by unpublished studies and other data and information” (“ordinarily” is not defined) (21 CFR 170.30(b)). The key feature of the GRAS category is that anyone, as long as they are experts qualified by scientific training and experience, not just FDA, may decide that a substance's use is safe and begin marketing it and adding it to food. If a manufacturer makes a determination that use is safe in accordance with 21 CFR 170.30, it has no explicit legal obligation to notify FDA.
A substance is GRAS for a specific use. As noted earlier, a single substance may have multiple uses, some of which may fit into the drugs in animal feed, pesticide chemicals or residues, food additives, or color additives categories, and some of which may qualify as GRAS.
The GRAS substances category consists of 6 subcategories. The first 3, common food ingredients in use prior to 1958, manufacturer self-determined GRAS substances, and association expert panel-determined GRAS substances, have been in place essentially unchanged since the early 1960s.
The remaining 3 subcategories reflect FDA's modification of the GRAS program which evolved from “FDA-listed GRAS substances” from 1958 to 1973, to “FDA-Affirmed GRAS substances” from 1973 to 1997, to the current “FDA-Reviewed GRAS notifications” subcategory in effect since 1997 (24 FR 9368, November 20, 1959, 62 FR 18938, April 17, 1997). With each of these changes, FDA's earlier decisions remained valid unless formally reversed, affirmed, or modified.
Before passage of the Food Additive Amendment of 1958, FDA presented to Congress a list of substances that the agency considered GRAS. After passage of the law, FDA published its initial version of FDA-listed GRAS substances (23 FR 9511, December 9, 1958) and added to the list over the years. In 1973, FDA replaced the listing approach with the GRAS affirmation process for FDA-affirmed GRAS substances, primarily to encourage firms to submit their GRAS determinations and enable the agency to address any safety issues with the new food substances. A successful GRAS affirmation petition provided incentive and reassurance to the manufacturer and its customers that FDA agreed with the safety determination.
Implementation of the GRAS affirmation process, however, broke down due to lack of resources and, perhaps, lack of priority within the agency. The GRAS affirmation process was created by the agency, not statute, and accordingly lacked statutory deadlines and mandates. The backlog of affirmation petitions increased every year until finally in 1997 when FDA proposed replacing affirmations with a notification process. Although FDA had not finalized its proposed regulations for GRAS notifications, the agency began almost immediately accepting notifications and refused further GRAS affirmation petitions (Kahl 2010; 62 FR 18938, April 17, 1997).
The FDA-reviewed GRAS notifications subcategory represents a major change in the FDA's food additive regulatory program because the agency's decision is in the form of a letter to the notifier which is posted on its website but lacks the publication or comments period associated with a proposed regulation (FDA 2006a). The process also represents a shift from petitions—where FDA made the formal safety decision—to manufacturer notifications—where a manufacturer makes the safety decision described in a notification, and FDA reviews the decision and issues a “no question” or “insufficient basis” letter (FDA 2009a). Despite the differences in process, the common element of all 3 subcategories is that FDA publishes its decision, and all manufacturers are entitled to rely on it—not just the manufacturer submitting the petition or notice (McQuate 2011) (75 FR 81536, December 28, 2010). Details on the GRAS subcategories are as follows:
2A. Common Food Ingredients in Use before 1958 are substances that are added to food that were commonly consumed before 1958 and are of natural biological origin. For example, a potato added to broth to make a can of soup would be considered a substance added to food and more specifically, a common food ingredient (21 CFR 170.30(d)). FDA adopted 2 regulations (21 CFR 182.1 for human food and 21 CFR 582.1 for animal feed) to generically designate staples of the American diet as GRAS. Included among these substances are salt, pepper, vinegar, monosodium glutamate, baking powder, flour, fruits, vegetables, meat, poultry, and seafood. No additional GRAS notification or food additive petition or determination on the part of FDA is required.
Regarding the sample frozen meal, common food ingredients include 34 of the 68 listed ingredients including chicken breast, water, bleached wheat flour, whole wheat flour, salt, spices, soybean oil, whey protein, and yeast.
2B. Manufacturer Self-determined GRAS Substances are those substances that manufacturers determine are GRAS independent of or absent FDA's review or approval. A manufacturer's decision must be consistent with 21 CFR 170.30 and should consider FDA's guidance, especially its “Toxicological Principles for the Safety Assessment of Food Ingredients” (FDA 2007) (also known as the “Redbook”). However, a manufacturer is not obligated to notify FDA of its decision to add a substance to food or of the way it intends to use the substance in food (21 USC 348 and 62 FR 18938, April 17, 1997). There is also no explicit legal obligation for the manufacturer to follow the Redbook. In some cases, such as with certain spices and flavors as well as with FCSs, a substance also does not have to be specifically identified on the product label (21 CFR 101.22).
A manufacturer can make a decision based on the safety assessment performed by its own employees or an expert panel it selects and convenes; however, the determination must be one accepted by experts in the field in order to satisfy the general recognition of safety requirement. If FDA learns of the decision and disagrees with it, the agency could take enforcement action claiming the firm violated the law by introducing into commerce an unapproved food additive. As a recent example, in October 2009 FDA sent a letter to 4 manufacturers of certain alcohol drinks with added caffeine. FDA gave them until April 2010 to submit a GRAS notification under item F below. One manufacturer submitted a GRAS notification. FDA found it insufficient in November 2010 and warned all 4 manufacturers to stop adding caffeine to alcohol drinks (FDA 2010a). They apparently complied within the 30 d FDA gave them. At least one has reformulated the product without caffeine.
Regarding the sample frozen meal, manufacturer self-determined GRAS substances appear to include microcrystalline carboxymethyl cellulose, soy protein concentrate, and soy protein isolate since they do not appear on any lists for the other categories or subcategories. It may contain other manufacturer self-determined GRAS substances not required to be identified on the label.
2C. Association Expert Panel-Determined GRAS Substances are substances found to be GRAS by an expert panel that is selected and convened by an association to evaluate potential GRAS substances that have been submitted by manufacturers seeking approval. It is not a distinct subcategory created by the rules. Rather it is a variation of the manufacturer self-determined GRAS substances subcategory where the manufacturer relies on the decision by the association's expert panel. The authors treated it separately because the expert panel publishes its affirmative decisions, allows all manufacturers to rely on the decision, and has a long track record of making many decisions. The association expert panel must follow 21 CFR 170.30 to enable a manufacturer to rely on the panel's safety decision.
Currently, the authors are aware of only one organization, the Flavor and Extract Manufacturers Association (FEMA), which has such a panel assessing GRAS substances in human food in a sustained and systematic manner. FEMA established an expert panel in the early 1960s and has systematically reviewed and published its findings evaluating the safety of flavors and extracts in human food since then (FEMA 2011). FEMA also submits its decisions and supporting documentation to FDA, but the agency does not conduct a formal evaluation of FEMA's findings. FEMA publishes the decisions of its expert panel so others may rely on them. In July 2011, FEMA published its 25th report in Food Technology Magazine (Smith and others 2011).
There is a second association that makes decisions that manufacturers routinely rely on for GRAS determinations. The Association of American Feed Control Officials (AAFCO) adopts ingredient definitions for animal feed and pet food and publishes these definitions annually in its “Official Publication” (OP). Although neither FDA's CVM nor AAFCO calls the OP definitions “GRAS determinations,” they operate as such under the law. AAFCO definitions are accepted by FDA and state and local officials enforced their laws for animal feed and pet food using the OP to determine whether a substance's use is permitted. The AAFCO's ingredient definitions are largely based on “no objection” letters sent to AAFCO by FDA's CVM in response to requests from AAFCO or manufacturers, but neither CVM nor AAFCO describes these substances as GRAS. In practice, manufacturers and regulators rely on them in the same way a food manufacturer would rely on GRAS determinations. CVM and AAFCO documented this program in an April 2007 Memorandum of Understanding (FDA-AAFCO 2007). This program is likely to go through significant changes because CVM began accepting official voluntary GRAS notifications in late 2010 from manufacturers as described below.
Manufacturers could also rely on the international standards set by the Codex Alimentarius Commission, which are based on the safety assessments by the Joint Expert Committees on Food Additives (JECFA). JECFA is a joint committee of the United Nation's Food Agriculture Organization (FAO) and the World Health Organization (WHO). An ingredient's safety standard published by Codex should meet the GRAS definition of generally recognition as safe.
Regarding the sample frozen meal, flavor and extract manufacturer association expert panel-determined GRAS substances include extractives of turmeric and paprika, carboxymethyl cellulose, and some flavoring. It may contain other association expert panel-determined substances not required to be identified on the label.
2D. FDA-Listed GRAS Substances are substances determined by FDA to be GRAS and expressly allowed to be added to food. FDA publishes its approvals as regulations in the CFR after notifying the public via the Federal Register and providing an opportunity for the public to comment. Any manufacturer can rely on these decisions. These regulations appear at 21 CFR Part 182 for human food and 21 CFR Part 582 for animal feed and pet food.
In 1973, when FDA adopted its GRAS Affirmation rule (discussed below), FDA stopped adding new FDA-listed GRAS substances and began to reassess its previous decisions, usually replacing them with new regulations pursuant to the new rule. As a result, the number of FDA-listed GRAS substances has gone down since 1973.
Regarding the sample frozen meal, FDA-listed GRAS substances include disodium phosphate, monocalcium phosphate, sodium acid pyrophosphate, sodium caseinate, sodium phosphate, cellulose gum, and, possibly, some of the spices and natural flavor. It may contain other FDA-listed GRAS substances not required to be identified on the label.
2E. FDA-Affirmed GRAS Substances are substances determined by FDA to be GRAS and expressly allowed to be added to food pursuant to the agency's GRAS affirmation regulation, usually in response to a manufacturer's voluntary GRAS Affirmation Petition. FDA adopted this rule in 1973, essentially replacing the GRAS listing program (21 CFR 170.35). Under the affirmation program, FDA would, of its own accord or in response to a petition, publish its approvals as regulations in the CFR after notifying the public via the Federal Register and providing an opportunity for the public to comment. The regulations appear at 21 CFR Part 184 for human food and 21 CFR Part 584 for animal feed and pet food.
In 1997, FDA ceased accepting new GRAS affirmation petitions and directed new and prior petitioners to submit a notification through FDA's new voluntary GRAS Notification Program described below. This shift created the new subcategory of “Substances Covered by FDA-Reviewed GRAS Notifications.” FDA completed its review of a few of the previously submitted GRAS affirmation petitions and no longer devotes resources to reviewing or affirming the petitions (FDA 2004). From 2000 to 2010, FDA did not receive any GRAS affirmation petitions (see Section “Trends in FDA Reviews for Human Food Since 1990”).
Regarding the sample frozen meal, FDA-affirmed GRAS substances include citric acid, garlic powder, guar gum, gum arabic, lactic acid, maltodextrin, potassium chloride, sodium bicarbonate, whey protein concentrate, yeast extract, soy lecithin, beta carotene, dextrose, dried sweet whey, acetic acid esters of mono- and diglycerides with maltodextrin, and, possibly, some of the natural flavor. It may contain other FDA-affirmed GRAS substances not required to be identified on the label.
2F. Substances Covered by FDA-Reviewed GRAS Notifications are substances described in notifications submitted by manufacturers pursuant to FDA's proposed GRAS Notification Program. In 1997, FDA proposed this program to replace the GRAS Affirmation Petition Program described above with a more streamlined voluntary approach. This new program is similar to the FCS Notification Program described earlier.
Under the GRAS notification program, a manufacturer voluntarily submits a notification to FDA announcing and justifying its safety decision. The agency evaluates the notification and then provides a response indicating that it either had no questions or that there was an insufficient basis for the manufacturer's GRAS determination. Before receiving FDA's written response, a manufacturer can withdraw its notice without prejudice. FDA publishes the manufacturer's notifications and the contents of its letter to the manufacturer including any limitations on use (FDA 2011e). FDA's evaluation applies to the substance's use described in the notification so competitors may rely on it. However, many of the substances are described in a manner that makes it difficult for a competitor to match the product in terms of proprietary manufacturing processes or by narrowly defining product specifications.
Despite not finalizing the 1997 proposed rule, FDA operates this program based on its proposal (62 FR 18938, April 17, 1997). CFSAN began accepting notifications for additives to human food in 1998 and CVM began accepting notifications in 2010 for animal feed and pet food (FDA 2009b, 2010b). In a March 2010 report, the U.S. Government Accountability Office criticized FDA's handling of this program and its failure to finalize the rule (GAO 2010). In late 2010, FDA requested additional comments on the proposed rule and indicated that it plans to finalize the rule in 2012 (75 FR 81536, December 28, 2010). The primary differences between the FCS and GRAS notification programs (both set up in the late 1990s) are that the GRAS notification program
- • is created by FDA rather than Congress;
- • does not have deadlines by which FDA must complete its review of a manufacturer's safety decision (although FDA set an unenforceable goal of 90 d) (62 FR 18938, April 17, 1997, 21 CFR 170.104);
- • allows existence of notifications to be made public before FDA makes its decisions (excluding confidential business information) (62 FR 18938, April 17, 1997, 21 CFR 170.102);
- • provides the nonconfidential portions of the actual notification and contents of the decision letter;
- • allows other manufacturers to rely on the notice and not just the manufacturer submitting it (21 CFR 170.100(a)); and
- • allows the manufacturer to summarize the data and information that are the basis of the safety decision rather than provide FDA with primary biological and chemical data (62 FR 18938, April 17, 1997 and 21 CFR 170.101(b)).
The final difference is significant since it fundamentally changes the nature of FDA's review. With GRAS notifications, FDA reviews a comprehensive discussion of the science data but not the underlying biological and chemical data. Instead of conducting an independent assessment, FDA's role is to identify potential flaws with the manufacturer's safety decision.
This program has been popular with manufacturers since they can usually get a more timely response from FDA than they may have received under the previous GRAS affirmation program. From 2000 to 2010, FDA received 330 GRAS notifications.
Regarding the sample frozen meal, substances covered by GRAS notifications do not appear to have been used based on the product label. However, not all substances covered by FDA-reviewed GRAS notifications are required to be identified on the label.
3. Prior-Sanctioned Substances are substances that FDA or USDA affirmatively approved before September 6, 1958, for use in food pursuant to the FFDCA, the Poultry Products Inspection Act, or the Meat Inspection Act (21 USC 321(s)). These substances were “grandfathered” into the food additive regulatory program and FDA cannot revoke this status. FDA has listed those approvals of which it is aware at 21 CFR Part 181 but acknowledged that “not all of these sanctions and approvals can be ascertained because of the destruction of old records and the retirement of personnel involved in these matters” (37 Fed. Reg. 16407, August 12, 1972). According to an industry expert, there are existing approvals that FDA has not captured in these regulations.
While prior-sanctioned substances cannot be regulated as food additives, FDA can override prior approval if it finds that a substance's use is “injurious to health” and, therefore, adulterated (21 CFR 181.1). At this time, 120 substances remain in the prior-sanctioned substances category based on those listed in the regulations.
Regarding the sample frozen meal, prior-sanctioned substances do not appear on the list of ingredients. However, it may contain other prior-sanctioned substances not required to be identified on the label such as FCSs and processing aids.
4. Color Additives are substances that are capable (alone or through reaction with other substances) of imparting color when added or applied to a food. The FFDCA requires FDA approval of all color additives, usually in response to a color additive petition (21 USC 321(t)(1)). The regulatory requirements for color additives are similar to those of food additives, but there are no GRAS or prior-sanctioned substance exceptions. This category does not include substances that FDA determines are used or intended to be used solely for purposes other than coloring. For example, cranberry juice will impart a red color when added to white grape and pear juice but is not regulated as a color additive if added for its flavor or juice content.
All color additives must be approved in order to be used in food. To approve a color additive, FDA publishes its approvals as regulations in the CFR after notifying the public via the Federal Register and providing an opportunity for the public to comment (21 USC 379e). The regulations appear at 21 CFR Part 73 for color additives exempt from certification, 21 CFR Part 74 for color additives subject to certification, 21 CFR Part 81 for provisional color additives, and 21 CFR Part 82 for certified provisionally listed colors. Certified colors are often referred to as “artificial food colors” or “synthetic colors” because they are synthesized from petroleum, tar, or other substances. FDA analyzes each batch of certified colors to ensure it complies with the standards in 21 CFR Part 80. Color additives exempt from certification are typically derived from plants or insects. From 2000 to 2010, FDA received only 4 color additive petitions for food uses.
Regarding the sample frozen meal, the color additives appear to be annatto, beta carotene, turmeric, and red cabbage extract because they are noted in the ingredients as colors. It does not contain any certified color additives.
5. Pesticide Chemicals or Residues are substances intended to prevent, destroy, repel, or mitigate any pest or to serve as a plant regulator, defoliant, or desiccant used in or on a raw agricultural commodity such as raw produce, grains, meat, or eggs or applied to food contact surfaces other than food packaging that has an ongoing antimicrobial effect on the surface (7 USC 136(u) and 21 USC 321(s)). This category is unusual because EPA, not FDA, makes the safety decision and approves the use of a pesticide as well as establishes a “tolerance” (the maximum allowable residue of the pesticide in food). EPA publishes its approvals as regulations in the CFR after notifying the public via the Federal Register and providing an opportunity for the public to comment (21 USC 346a). FDA is responsible for enforcing the tolerances (21 CFR 170.19 and 570.19) when pesticide chemical residues show up in processed agricultural commodities. Manufacturers may only use these substances in a manner consistent with a pesticide label approved by EPA and the tolerance (7 USC 136a).
Note that the line between pesticide chemicals or residues (regulated by EPA) and preservatives or antimicrobials (regulated by FDA as food additives or GRAS substances) is complicated and is based on a detailed understanding of their uses. For direct use on food, if applied to unprocessed food, the substance is regulated by EPA. If used on processed food, the substance is regulated by FDA. A food is still considered unprocessed if it is only being washed, colored, waxed, hydro-cooled, refrigerated, shelled (if a nut), handled to removed leaves, stems, and husks, fumigated, or packed. A food is considered processed when it is canned, frozen, cooked, pasteurized, irradiated, milled, peeled, ground, chopped, sliced, or cut. For use on food contact surfaces, EPA regulates a substance controlling pests (including microbes) only if used on the surface of equipment such as a conveyor, grinder, or countertop, and the use provides an ongoing sanitizing effect on the surface. FDA regulates it if used on food packaging, does not have an ongoing antimicrobial effect, or penetrates beyond the surface (FDA 1999).
Unlike the tolerance levels for substances covered by other categories, pesticide chemicals or residue tolerances (and exemptions) must be regularly reassessed to determine their safety pursuant to amendments to the FFDCA made by the Food Quality Protection Act of 1996 (FQPA) (Public Law 104-170, Section 103) (7 USC 136a(g)). The U.S. Congress directed EPA to reassess the tolerances within 10 y of the original enactment (21 USC 346a(q)(1)) and further required a reassessment of all pesticide's safety by 2022 with an additional review every 15 y using the detailed and rigorous standards in the FQPA (7 USC 136a(g)(1)(A)). EPA completed its first round in 2007 reviewing 9721 tolerances for 581 pesticides (EPA 2011a).
Regarding the sample frozen meal, pesticide chemicals or residues may be present from pesticides used in or on produce or crops in the meal, such as the corn, wheat, sugar, spices, and soybeans, or from sanitizing the surfaces of equipment used to prepare the food. Pesticide chemicals or residues may be present but only below the tolerance limit established by EPA and do not have to be listed on the product's label.
6. Drugs in Animal Feed are substances intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in animals that are expressly approved by FDA (21 USC 321(g) and 321(v)). Technically, this category only applies to drugs in animal feed that were approved after 1938, which essentially includes all approved drugs in animal feed (Cantin 2011). FDA publishes its approvals as regulations in the CFR after notifying the public via the Federal Register and providing an opportunity for the public to comment (21 USC 360b). The regulations appear at 21 CFR Part 556 for tolerances for residues of new drugs in animal feed in food, 21 CFR Part 558 for new drugs in animal feed for use in animal feeds, and 21 CFR 516.1215 for conditional approval for one minor animal species—catfish.
Regarding the sample frozen meal, drugs in animal feed such as antibiotics and arsenic-based substances may have been used in the chicken feed to prevent disease and promote growth. These substances are not required to be listed on the product's label.
7. Dietary Supplements are products, other than tobacco, intended to supplement the diet that bear or contain one or more “dietary ingredients.” These products are not intended to serve as a conventional food or as the sole item of a meal. They are intended to maintain structure and function of the body but not remedy a specific disease or illness. The dietary ingredients in these products may include vitamins, minerals, herbs or other botanicals, amino acids, and substances such as enzymes, organ tissues, glandulars, and metabolites (21 USC 321(ff) and FDA 2009c). A manufacturer must notify FDA of new dietary ingredients (any dietary ingredient not sold in the U.S. before October 15, 1994). However, it does not need FDA's review or approval before marketing or selling them in the United States if the new dietary ingredient has been in the food supply in a form that has not been chemically altered (21 CFR Part 190). If the new dietary ingredient is not eligible for this exemption, the company must submit a premarket notification prior to introducing into commerce a dietary supplement containing the new dietary ingredient. FDA has 75 d to review the notification and will reject the notification when it fails to provide the necessary safety information (21 U.S.C. 350b(a)). An absence of a response from FDA does not constitute a finding by the agency that a new dietary ingredient or dietary supplement that contains a new dietary ingredient is safe or not adulterated (21 CFR Part 190).
FDA may determine that a dietary supplement or dietary ingredient is adulterated and block its marketing or sale if the agency finds that the ingredient or supplement
- A. “presents a significant or unreasonable risk of illness or injury under conditions of use recommended or suggested in labeling, or if no conditions of use are suggested or recommended in the labeling, under ordinary conditions of use”;
- B. “is a new dietary ingredient for which there is inadequate information to provide reasonable assurance that such ingredient does not present a significant or unreasonable risk of illness or injury”;
- C. is declared by the Secretary [of the Department of Health and Human Services]“to pose an imminent hazard to public health or safety . . . [in which case] the Secretary shall promptly after such declaration initiate a proceeding . . . to affirm or withdraw the declaration”; or
- D. “is or contains a dietary ingredient that renders it adulterated . . .” (21 USC 342(f) and 21 USC 334).
Some of the substances categorized as dietary ingredients may also be categorized as food additives or GRAS substances if added to conventional foods. The essential difference is that dietary supplements are not conventional foods or the sole item of a meal or diet.
Regarding the sample frozen meal, dietary supplements or ingredients are not present because the meal is conventional food.
In summary, a single meal is likely to contain substances belonging to each of the categories and subcategories described above. Referring back to the microwave-ready, frozen children's dinner meal, half of the 68 ingredients identified on the label were common food ingredients in use before 1958. The remainder included 16 FDA-affirmed GRAS substances, 8 FDA-listed GRAS substances, 4 direct food additives, 4 color additives (including red cabbage extract approved as a vegetable juice), and 3 apparent manufacturer self-determined GRAS substances.
Although a substance used in food must fall under one of the previous categories and subcategories, there are situations when a substance may be present in food but not fit into one of the categories. This could occur, for example, because there was no intent to use it. These substances are generally considered contaminants. They may be naturally occurring ones, such as aflatoxins on peanuts, or they may be so widespread in the environment that they often end up in food products. Contaminants are not subject to the food additive definition. FDA regulates contaminants under the general adulteration provisions of 21 USC 342(a)(1). Formal tolerance for unavoidable contaminants can be established under 21 USC 346. Examples of unavoidable contaminants are mercury, a common contaminant in fish, and polychlorinated biphenyls (PCBs) and lead which can enter from FCSs. FDA has set a formal tolerance under 21 USC 346 for only one contaminant, PCBs (21 CFR 109.30). It also set labeling requirements for ornamental and decorative ceramic ware that contains lead to warn against use for food-handling purposes (21 CFR 109.16).
As should be clear, FDA's food additive regulatory program has evolved significantly since the U.S. Congress first established it over 50 y ago. The program was complex from the beginning and has become more so as FDA crafted alternatives to respond to new scientific developments, to make the program more rigorous, and to make it more efficient to administer.