Food Safety: FDA Should Strengthen Its Oversight of Food Ingredients Determined to Be Generally Recognized as Safe (GRAS)
Published: 2010-02-03T00:00:00

Fast Facts:

Highlights:
section_title: Why GAO Did This Study
paragraphs: The Food and Drug Administration (FDA), which is responsible for ensuring the safety of most of the U.S. food supply, is not required to review substances, such as spices and preservatives, added to food that are generally recognized as safe (GRAS) for their intended use. Currently, companies may determine a substance is GRAS without FDA's approval or knowledge. However, a few substances previously considered GRAS have later been banned; and concerns have been raised about the safety of other GRAS substances, including those containing engineered nanomaterials, materials manufactured at a tiny scale to take advantage of novel properties. GAO was asked to review the extent to which (1) FDA's oversight of new GRAS determinations helps ensure the safety of these substances, (2) FDA ensures the continued safety of current GRAS substances, and (3) FDA's approach to regulating engineered nanomaterials in GRAS substances helps ensure the safety of the food supply. GAO reviewed FDA data on GRAS substances and interviewed a range of stakeholders, among other things.
section_title: What GAO Found
paragraphs: FDA's oversight process does not help ensure the safety of all new GRAS determinations. FDA only reviews those GRAS determinations that companies submit to the agency's voluntary notification program--the agency generally does not have information about other GRAS determinations companies have made because companies are not required to inform FDA of them. Furthermore, FDA has not taken certain steps that could help ensure the safety of GRAS determinations, particularly those about which the agency has not been notified. FDA has not issued guidance to companies on how to document their GRAS determinations or monitored companies to ensure that they have conducted GRAS determinations appropriately. Lastly, FDA has yet to issue a final regulation for its 1997 proposed rule that sets forth the framework and criteria for the voluntary notification program, potentially detracting from the program's credibility. FDA is not systematically ensuring the continued safety of current GRAS substances. While, according to FDA regulations, the GRAS status of a substance must be reconsidered as new scientific information emerges, the agency has not systematically reconsidered GRAS substances since the 1980s. FDA officials said they keep up with new developments in the scientific literature and, on a case-by-case basis, information brought to the agency's attention could prompt them to reconsider the safety of a GRAS substance. However, FDA has largely not responded to concerns about GRAS substances, such as salt and the trans fats in partially hydrogenated vegetable oils, that individuals and consumer groups have raised through 11 citizen petitions submitted to the agency between 2004 and 2008. In fact, FDA has decided on the validity of these concerns in only 1 of 11 cases. In addition, FDA does not know to what extent, or even whether, companies track evolving scientific information about their GRAS substances. FDA's approach to regulating nanotechnology allows engineered nanomaterials to enter the food supply as GRAS substances without FDA's knowledge. While some uses of engineered nanomaterials have the potential to help ensure food safety, uncertainties remain about how to determine their safety in food. After reviewing the uncertainties associated with the safety of engineered nanomaterials, FDA has decided that it does not need additional authority to regulate products containing such materials. Rather, FDA encourages, but does not require, companies considering using engineered nanomaterials in food to consult with the agency regarding whether such substances might be GRAS. Because GRAS notification is voluntary and companies are not required to identify nanomaterials in their GRAS substances, FDA has no way of knowing the full extent to which engineered nanomaterials have entered the U.S. food supply as part of GRAS substances. In contrast to FDA's approach, all food ingredients that incorporate engineered nanomaterials must be submitted to regulators in Canada and the European Union before they can be marketed.

section_title: Letter
paragraphs: The Food and Drug Administration (FDA), which is responsible for  ensuring the safety of most of the U.S. food supply, does not review many  of the substances added to food that manufacturers determine to be  generally recognized as safe (GRAS) under the conditions of their  intended use. Manufacturers add these substances—hundreds of spices  and artificial flavors, emulsifiers and binders, vitamins and minerals, and  preservatives—to enhance a food’s taste, texture, nutritional content, or  shelf life. GRAS substances can be marketed without FDA’s approval or  even its knowledge because such substances are generally recognized  among qualified experts as having been shown, through scientific  procedures or experience based on common use, to be safe. Some  consider GRAS substances to warrant less oversight because they  generally pose a relatively low level of threat to public health. However, a  few substances previously assumed to be GRAS, such as cyclamate salts,  have later been banned; and more recently, consumer groups have raised  concerns about the safety of certain other GRAS substances, such as salt  and trans fats in partially hydrogenated vegetable oils.
The Federal Food, Drug, and Cosmetic Act exempts GRAS substances  from the act’s general requirement that companies obtain FDA approval  before marketing food additives (substances, when used as intended,  reasonably expected to become a component or otherwise affect the  characteristics of food). This exemption allows companies, without the  approval of FDA, to determine whether there is enough support to claim a  substance is GRAS. For a company to claim a substance is GRAS, it must  conclude that there is common knowledge about the safety of the  substance among experts qualified by scientific training and experience to  evaluate its safety. Under a program set forth in a rule FDA proposed in  1997, companies may voluntarily submit information on a substance they  conclude is GRAS to the agency’s GRAS notification program for review.  After reviewing this information, FDA may state in a letter that it has no  questions about the company’s GRAS determination. However, once a  company—domestic or foreign—concludes that a substance is GRAS, it  may market that substance as GRAS without informing FDA. Anyone may  request that FDA change or create an agency regulation through a citizen  petition, and groups and individuals submitted almost 50 such petitions to  FDA related to GRAS substances from 1975 through 2008.
In recent years, concerns have been raised about the potential for  engineered nanomaterials to be considered GRAS for use in food and food  packaging until more is known about their risks. Engineered, or  manufactured, nanomaterials are created through nanotechnology—the  creation and manipulation of materials at a very small (molecular) scale  that enhances certain of the resulting nanomaterials’ physical properties.  Applications of these nanomaterials in food and food packaging have the  potential to benefit food safety. For example, antimicrobial nanofilms— thin layers of substances that hamper the growth of bacteria and fungi—in  food packaging could decrease foodborne pathogens. While the underlying  chemical structure of a substance is not changed by the engineering  process, its physical properties may change. For example, while the  chemical structure of salt is the same—whether at its natural scale or at  the nanoscale—it may be possible to reduce the amount of salt in a  product by using it at the nanoscale to coat other particles.
In this context, you asked us to review FDA’s oversight of GRAS  substances. This report examines the extent to which (1) FDA’s oversight  of new GRAS determinations helps ensure the safety of these substances,  (2) FDA ensures the continued safety of current GRAS substances as new  scientific information emerges, and (3) FDA’s approach to regulating  engineered nanomaterials in GRAS substances helps ensure the safety of  the food supply. We also provide additional information on the safety of  two GRAS substances—salt and trans fats in partially hydrogenated  vegetable oils—including the views of the Dietary Guidelines for  Americans, Dietary Reference Intakes, and FDA’s Food Advisory  Committee; this information is discussed in appendix I.
To review FDA’s oversight of GRAS determinations, we compiled and  analyzed data on FDA’s voluntary notification program from 1998, the first  year a GRAS notice was submitted, through 2008. Specifically, we used  FDA’s GRAS Notice Inventory database. To assess the reliability of the  data used in this report from this source, we reviewed related  documentation, examined the data to identify obvious errors or  inconsistencies, and worked with agency officials to identify any data  problems and steps they took to ensure the reliability of the data. Based  on this examination, we concluded that these data were sufficiently  reliable for the purposes of this report. We also reviewed laws and  regulations regarding GRAS substances. To review the extent to which  FDA ensures the continued safety of GRAS substances, we examined the  11 citizen petitions related to GRAS substances that were submitted to  FDA during the recent 5-year period from 2004 through 2008 and gathered  information from FDA officials regarding the agency’s response to these  petitions. Finally, to review FDA’s approach to regulating engineered  nanomaterials as GRAS, we evaluated the agency’s policies and guidance  to companies, and collected information about the activities of foreign  governments—namely, Canada and the European Union—that have been  particularly active in considering regulation of engineered nanomaterials  in food. In addition, to address all of our objectives, we interviewed a wide  range of stakeholders, including officials from FDA, industry and trade  organizations, consumer advocacy groups, academia, and foreign  governments. Appendix II provides a more detailed description of our  scope and methodology.
We conducted this performance audit from October 2008 to February  2010, in accordance with generally accepted government auditing  standards. Those standards require that we plan and perform the audit to  obtain sufficient, appropriate evidence to provide a reasonable basis for  our findings and conclusions based on our audit objectives. We believe  that the evidence obtained provides a reasonable basis for our findings  and conclusions based on our audit objectives.
subsections: section_title: Background
paragraphs: In 1958, Congress amended the Federal Food, Drug, and Cosmetic Act to  state that food bearing or containing any unsafe food additive shall be  deemed adulterated and that a food additive is considered unsafe unless,  among other things, it and its use conform to a regulation prescribing the  conditions of its safe use. A regulation prescribing the conditions for safe  use could be obtained through a process established in the 1958  amendment. That process describes the data for companies to include in a  petition for a proposed regulation (known as a food additive petition), a  time frame and standards for agency review, and an opportunity for public  comment. Under this process, as further prescribed in FDA regulations,  the safety of an additive does not need to be established with absolute  certainty; instead, the regulations provide a science-based standard of  safety, requiring a reasonable certainty that no harm will result from the  intended use of an additive. If FDA finds a food additive to be safe for its  intended uses, the agency will issue a regulation specifying those uses.
The 1958 amendment defines “food additive” as any substance the  intended use of which results, or may reasonably be expected to result,  directly or indirectly, in its becoming a component of or otherwise  affecting the character of any food. However, this definition excludes  substances that are generally recognized as safe under the conditions of  their intended use, as shown through scientific procedures or based on  common usage in food prior to 1958. Therefore, unlike food additives, a  GRAS substance is not considered unsafe in the absence of a regulation  prescribing its safe use, allowing a company to market food containing the  substance without FDA approval.
Since the 1958 amendment, FDA has taken a variety of actions to  determine the GRAS status of substances used in food, as figure 1  illustrates.
Shortly after the passage of the 1958 amendment, FDA clarified the  regulatory status of many food substances that were used in food prior to  1958 and amended its regulations to include a list of food substances,  commonly referred to as the GRAS list, that, when used for the purposes  indicated and in accordance with current good manufacturing practices,  are GRAS. However, FDA also acknowledged the extreme difficulty in  listing all substances that are GRAS for their intended use, stating in its  regulations that such an effort would be “impracticable.” FDA added other  categories of substances—for example, spices, seasonings, and  flavorings—to the GRAS list in subsequent rule makings.
During the late 1960s, new scientific information raised questions about  the safety of cyclamate salts, a class of sweeteners that FDA previously  considered GRAS. As a result, FDA contracted for an independent review,  by contemporary standards, of the available safety information related to  substances it considered GRAS. If the review confirmed that the use of a  particular substance was GRAS, FDA would issue a new regulation,  affirming that finding. At about the same time as this review began, FDA  also established procedures—referred to as the petition affirmation  process—whereby companies could petition FDA to affirm the GRAS  status of substances not covered as part of the review. To the extent that  companies voluntarily submitted petitions to FDA as part of the  affirmation process, the agency became aware of companies’ independent  GRAS determinations.
Under FDA’s GRAS petition affirmation process—as described in FDA’s  1997 proposal for a new GRAS program—the agency (1) published a  notice in the Federal Register; (2) requested comments on the GRAS  petition; (3) comprehensively reviewed the safety of the substance; (4)  drafted a detailed explanation of why the use is GRAS; and (5) published  that explanation in the Federal Register. Each petition resulted in a rule  making that allowed the public to comment on the proposed rule and FDA  to respond to these comments before issuing the final rule.
In 1997, citing the resource intensive process required to conduct the  petition affirmation process, FDA proposed a new GRAS program that,  among other things, would eliminate the rule-making steps under the  affirmation process. FDA’s proposed rule would allow companies that had  made a GRAS determination to apply to FDA for its review under a  voluntary notification program. Under this new program, in which FDA  invited companies to participate under an interim policy discussed in the  proposed rule, FDA no longer affirms the GRAS status of a substance.  Rather, once FDA completes its review of a company’s notice of a GRAS  determination, it informs the company in a letter of one of the following  three responses:    FDA has no questions about the company’s conclusion that the substance  is GRAS (referred to as a no questions letter);    FDA concludes that the notice does not provide a sufficient basis for a  determination that the substance is GRAS because, for example, the notice  does not include appropriate data or the available data raise questions  about the safety of the substance; or    FDA has, at the company’s request, ceased to evaluate the GRAS notice.
In proposing the rule, FDA asserted that, from the companies’ standpoint,  the proposed voluntary notification program was simpler than the GRAS  petition affirmation process and, therefore, could provide an incentive for  manufacturers to inform FDA of their GRAS determinations. A flowchart  presenting steps in the voluntary notification program is found in  appendix III.
In the proposal, FDA invited companies to submit notifications to the  GRAS notification program described in the proposed rule until it  published a final rule. FDA did not formally terminate the petition  affirmation process, but has stated it no longer commits resources to the  process. Because the rule has not been made final, FDA has operated the  interim GRAS notification program under this proposed rule since 1997.
One way for citizens to question GRAS determinations is through citizen  petitions. FDA regulations establish procedures for petitioning FDA to  issue, amend, or revoke a regulation or order; or take or refrain from  taking any other form of administrative action. If a petition appears to  meet the requirements for submission, FDA is required to furnish a  response within 180 days of its receipt, if not sooner. In reviewing a  petition, FDA may use the following procedures: (1) conferences,  meetings, discussions, and correspondence; (2) a hearing; (3) a Federal  Register notice requesting information and views; (4) a proposal to issue,  amend, or revoke a regulation; or (5) other specifically established  procedures. The record of any of these steps becomes part of the  administrative record for the petition. FDA must generally respond to a  petition within 180 days and (1) approve it and, therefore, concurrently  take appropriate action implementing the approval (for example,  publishing a Federal Register notice); (2) deny it; or (3) provide a tentative  response, indicating why the agency has been unable to decide on it (for  example, because of the existence of other agency priorities, or a need for  additional information). FDA’s tentative response may indicate its likely  ultimate decision and may specify when this final decision is to be  provided. FDA must notify the petitioner in writing of its decision. FDA  may grant or deny citizen petitions, in whole or in part, and may take other  action as the petition warrants.
Researchers are studying nanotechnology—the creation and manipulation  of materials at a very small scale—to explore its many potential uses in  food manufacturing, including uses potentially beneficial to food safety.  Nanotechnology can involve processes, materials, and applications that  span physical, chemical, biological, engineering, and electronic sciences.  Although definitions of nanotechnology vary, the National  Nanotechnology Initiative, a federal program established in 2001 to  coordinate nanotechnology research and development, has defined it as  the understanding and control of matter between 1 and 100 nanometers,  known as the nanoscale. A nanometer is one billionth of a meter, a size  that can best be understood by comparison to other very small objects— for example, the diameter of a human hair is approximately 80,000-100,000  nanometers, that of a red blood cell is approximately 8,000 nanometers,  and that of a typical virus between 80 and 120 nanometers. Nanomaterials  are materials at the nanoscale; or they can be larger, if they retain the  characteristics of nanomaterials, such as novel properties compared with  the same materials at their natural scale. Nanomaterials can be found in  nature, such as in soot; or be an inadvertent product of traditional  manufacturing practices, such as nanomaterials present as emulsions in  homogenized milk or mayonnaise. Engineered nanomaterials, however,  are materials that are deliberately manufactured to take advantage of the  novel properties that occur at the nanoscale.
When reduced to the nanoscale, substances can take on novel properties  that allow them to be used in applications for many different purposes  across different industries. For example, by reducing materials to the  nanoscale, the materials’ surface area is increased, which can affect the  nanomaterials’ ability to react with other substances. In addition,  nanomaterials may have a greater ability to move across biological  membranes. Because of these properties, nanotechnology may offer  technological advancements in food packaging and storage that enhance  the shelf life of fresh foods. Applications of nanotechnology may also offer  more efficient nutrient delivery. Such applications in food and food  packaging are relatively new, and FDA has approved only a few such uses  in food contact substances so far.
section_title: FDA’s Oversight Process Does Not Help Ensure the Safety of All New GRAS Determinations
paragraphs: FDA reviews those GRAS determinations that companies choose to submit  to the voluntary notification program. However, FDA generally does not  have information about other GRAS determinations because companies  are not required to inform the agency of their GRAS determinations.  Furthermore, FDA has not taken certain steps that could help ensure the  safety of GRAS determinations, particularly those for which the agency  has not been notified. Notably, a trade association routinely informs FDA  of its GRAS determinations, even though it does not submit notices to  FDA’s voluntary notification program.
subsections: section_title: FDA Reviews Those GRAS Determinations that Companies Choose to Submit
paragraphs: From 1998—the first year a company submitted a notice of a GRAS  determination—through 2008, companies chose to submit 274 GRAS  determinations to FDA under the 1997 proposed voluntary notification  program, or about 25 annually. According to FDA, it has received notices  for substances such as carbohydrates, lipids, proteins, and chemicals. At  any given time, FDA may have pending notices—notices under review for  which FDA has not yet issued a final opinion. Table 1 shows the status of  FDA’s responses to these GRAS notices.
FDA encourages companies to meet with agency officials before formally  submitting their notices of GRAS determinations. In this presubmission  meeting, FDA informally reviews the scientific information the company  plans to submit. The company may forgo submitting the notice for several  reasons, including if the agency anticipates that the scientific support  would not meet the required safety standard for GRAS substances. Within  30 days of receiving a company’s notice of a GRAS determination, FDA  informs the company in writing of the date on which the notice was  received. FDA convenes a group of staff—referred to as its GRAS Notice  Review Team—to evaluate the evidence the company submitted with its  notice. FDA then evaluates whether the submitted notice provides a  sufficient basis for a GRAS determination and whether information in the  notice, or otherwise available to FDA, raises questions about whether the  substance is GRAS for its intended use. If, during the review, FDA finds  that the company’s GRAS notice lacks sufficient information, it gives the  company the opportunity to provide supplemental information. However,  once a company concludes that a substance is GRAS, it may market the  substance, even if FDA finds that the notice does not provide a sufficient  basis for a GRAS determination.
In the 1997 proposal, FDA indicated that it planned to complete its review  of companies’ notices within 90 days of receipt, but stated that it would  determine whether its experience in administering such notices suggested  modifications to the proposed procedures. In 2001, FDA lengthened this  time frame to 180 days for most notices because the agency found that it  took longer than anticipated to review the notices, according to FDA  officials. As shown in table 2, FDA has met the latter time frame for about  64 percent of notices over the course of the program.
According to FDA officials, delays in meeting its 180-day time frame for  review of a GRAS notice can occur for various reasons. For example, in its  internal guidance to the GRAS Notice Review Team, FDA stated that the  180-day time frame is contingent on the degree of the notice’s  complexity—the 180-day time frame is designed as an achievable goal for  GRAS notices that are of low to moderate complexity. FDA officials also  explained that delays can occur in meeting the time frame because the  agency sometimes requests additional information from companies during  its review. FDA expects that companies would respond to such requests in  a timely manner; but they do not always do so, and FDA does not require a  response within a certain amount of time. If a company does not respond  to the agency’s request for additional information, FDA may eventually  contact the company and ask it to consider withdrawing its application.  Recently, as shown in figure 2, FDA has met the 180-day time frame less  frequently than in the past—excluding pending notices, the agency met  this time frame in 44 percent of cases from 2005 through 2008, while it met  this time frame in 79 percent of cases from 1998 through 2004. According  to FDA officials, this delay in reviews has generally occurred because of  budget limitations, increased demands on staff time, and loss of key staff  for the office that conducts the reviews. Agency officials said they  anticipate that their ability to complete reviews in a timely manner should  improve in the future because they have recently hired additional staff,  including some staff under contract with limited terms, for that office.
FDA officials and industry representatives explained that a company that  manufactures a GRAS substance has incentive to submit a notice to the  voluntary notification program for review because FDA’s no questions  letter improves the company’s ability to market its GRAS substance to  companies that purchase GRAS substances as ingredients for their food  products. Companies that purchase GRAS substances may require or  prefer that these substances have been reviewed by FDA. One company’s  representative explained that FDA’s voluntary notification program is also  beneficial because FDA scientists’ review provides the company with  additional assurance of safety.
FDA has also taken steps to make information about the GRAS  notification program available to the public by posting its inventory of all  GRAS notices FDA has received on its Web site. The Web site describes  FDA’s response to each notice as either (1) FDA has no questions; (2)  notice does not provide a basis for a GRAS determination; or (3) at the  company’s request, FDA ceased to evaluate the notice. The Web site also  provides a hyperlink to the agency’s response letter and, in many cases, to  the GRAS notice as well. By placing information about the GRAS notice  and its response on its Web site, FDA enhances the ability of Congress,  stakeholders, and the general public to be better informed about GRAS  substances.
section_title: FDA Generally Has No Information about GRAS Determinations That Are Not Submitted to Its Notification Program
paragraphs: Although FDA’s voluntary notification program allows the agency to  review those GRAS determinations companies submit, FDA generally does  not have information about other GRAS substances in the marketplace  because companies are not required to provide information to FDA  regarding their GRAS determinations. For example, officials representing  one international marketer of food indicated the company makes about 5  GRAS determinations each year without notifying FDA. These are usually  new uses of substances that have been deemed GRAS for other uses. In  another case, a company began marketing a purified version of stevia, a  plant-based sweetener, as a GRAS substance before submitting a notice to  FDA and before FDA had indicated it had no questions about other GRAS  notices related to stevia.
Once a GRAS substance has entered the marketplace, FDA would find it  difficult to identify that substance as the potential source of a food safety  problem, especially if FDA is unaware that the substance has been  determined to be GRAS. Food products may contain numerous  ingredients, including GRAS substances, making it difficult, if not  impossible, for public health authorities to attribute a food safety problem  to a specific GRAS substance. Moreover, while FDA receives reports of  adverse reactions to food, it is difficult to clearly identify any specific  GRAS substance as the likely cause of a foodborne illness from these  reports. Because of the difficulty of identifying GRAS substances as the  source of food safety problems after they have entered the food supply,  FDA’s oversight of their safety would be improved if companies were  required to make the agency aware of their GRAS determinations. In this  way, FDA would already have at least some information in its databases  about GRAS substances, which could help its investigations of food safety  problems.
Furthermore, without overseeing all companies’ GRAS determinations,  FDA is less informed about the nation’s food supply and consumers’  cumulative dietary exposure to GRAS substances—both of which were  viewed by FDA as beneficial potential outcomes of its 1997 proposal. FDA  maintains a database named Everything Added to Food in the United  States (EAFUS). Despite its name, FDA acknowledges that this database is  incomplete because companies are not required to participate in the GRAS  notification program or even inform FDA of their GRAS determinations,  and FDA officials cannot estimate the number of determinations that  occur about which they are not notified. Although approximately 180  companies submitted notices of GRAS determinations to FDA’s voluntary  notification program from 1998 through 2008, the agency does not know to  what extent these or other companies made GRAS determinations during  this period but chose not to notify the agency. Without information about  all GRAS determinations, FDA has less awareness of substances in the  nation’s food supply and less knowledge of the potential cumulative  dietary exposure of GRAS substances. However, FDA officials said that  EAFUS incorporates information on most food ingredients, and they  indicated they are not significantly concerned about missing GRAS  substances in the database because, as some food scientists have  indicated, GRAS substances generally pose a relatively low risk to public  health.
The safety of imported food products, including those containing GRAS  substances, is also a matter of concern. GRAS substances may be  manufactured anywhere in the world and FDA does not track where they  are manufactured. FDA has stated that it knows of no other country that  has a law comparable to the GRAS provision of the Federal Food, Drug,  and Cosmetic Act. While other countries do not have this GRAS provision,  GRAS substances brought into the United States can be manufactured  anywhere if in compliance with U.S. food safety law and FDA regulations.  However, FDA has expressed concerns about the food safety regulatory  systems of some foreign countries. In 2007, FDA issued the Food  Protection Plan, which sets forth FDA’s framework for overseeing food  safety, including the safety of imported food; and, at the same time, a 12-  agency working group—with FDA participation—issued the Action Plan  for Import Safety, which contains, among other things, recommendations  for improving the safety of food imports entering the United States.  According to the Food Protection Plan, while many foreign countries have  well-developed regulatory systems to ensure food safety, other countries  have systems that are less well developed and that may not be able to  ensure food safety to the same degree.
The Federal Food, Drug, and Cosmetic Act does not require FDA to  consider where food ingredients are manufactured and the agency does  not require companies to identify this information as part of their GRAS  determinations, whether they submit that determination to the agency or  not. As a result, FDA is not informed about the nature or extent of foreign  GRAS substances in the nation’s food supply—notwithstanding its  concerns about the food safety regulatory systems of some foreign  countries, as expressed in the Food Protection Plan. However, FDA  officials noted that if a concern arises about the safety of an imported  GRAS substance, the agency could take enforcement action, such as  requiring that the product be brought into compliance, destroyed, or re- exported. FDA has taken action on imported GRAS substances, including  stevia.
section_title: FDA Has Not Taken Steps that Could Help Ensure the Safety of GRAS Determinations
paragraphs: While FDA has issued guidance to minimize the potential for conflicts of  interest among its own staff who look at scientific issues and the safety of  GRAS substances, it has not issued any guidance on the subject for  companies to use with their own scientific experts. FDA has a number of  guidelines and policies to ensure that FDA employees, including those  who serve on the agency’s GRAS Notice Review Teams, as well as  individuals who serve on agency scientific and advisory panels, are free  from financial conflicts of interest. These federal guidelines, however, do  not extend to expert panels convened by private companies to establish  consensus for GRAS determinations. In determining whether a substance  is GRAS, companies must show that there is common knowledge among  qualified experts about the safety of the GRAS substance. According to the  1997 proposal, companies can demonstrate this consensus in a variety of  ways, such as assembling scientific review articles, convening a panel of  experts, or using reports from authoritative bodies, such as the National  Academies. These approaches can also be used in combination. Expert  panels can be comprised of a company’s own staff or outside experts hired  by the company or by a consulting firm. According to FDA officials, it is  not uncommon for companies to use expert panels to demonstrate that  there is a consensus regarding the safety of their GRAS substance.  However, FDA has not issued any conflict of interest guidance that  companies can use to help ensure that the members of their expert panels  are independent in their determinations of GRAS status. Furthermore,  FDA does not call for any information or assurance from companies in  their GRAS notices regarding their expert panelists’ independence and  potential conflicts of interest; thus, FDA does not know whether the  determinations of companies’ expert panels are arrived at independently.
Scientific, industry, and consumer group officials have raised concerns  about the potential for conflicts of interest among members of expert  panels used by companies in making GRAS determinations. For example,  two food scientists noted that there is a relatively small community of  experts qualified to sit on these panels and, inevitably, these experts may  have corporate or financial affiliations that could bias their decisions.  These officials also said FDA should issue conflict of interest guidelines  for expert panels as a way to minimize bias and promote transparency.  Similarly, an industry consultant stated that experts who serve on panels  come from narrow fields of science and may have developed some of the  information that the panels are assessing. In another case, officials from a  consumer group questioned whether company GRAS determinations are  based on independent scientific evaluations, noting that companies can  create an expert panel from either their own staff or from individuals they  hire. Furthermore, a food industry official indicated that although this  official’s company had developed its own conflict of interest guidelines for  expert panels, FDA’s issuance of conflict of interest guidelines for  company use would, among other things, create consistent definitions of  expert and independence. Finally, while an official from a consulting firm  that convenes expert panels for GRAS manufacturers was confident in the  independence of the experts employed by his firm, this official  acknowledged that the experts chosen were not asked to complete  financial disclosure statements or otherwise provide information on their  financial investments.
FDA officials stated that while the agency has the statutory authority to  develop guidance for companies’ expert panels, FDA officials do not know  of any generally available industry guidelines that companies could draw  upon in ensuring the independence of their expert panels. Companies may  seek to avoid such conflicts on their own. For example, officials of one  company stated that they seek to ensure independence by determining if  members of their expert panels have any contractual ties that might  conflict with their responsibilities. FDA, however, does not have any  information on what steps companies take to ensure independence. FDA  officials explained that, as a counterbalance to any potential conflicts of  interest among companies’ experts, the agency’s review of GRAS notices  does not depend entirely on the conclusions of the expert panels—the  agency also considers other available information, such as scientific  review articles or the opinions of authoritative bodies. However, while this  step may apply to GRAS notices submitted to the agency, it would not  apply to GRAS determinations that were not submitted to FDA’s voluntary  notification program.
In addition, FDA has not taken certain steps to ensure companies maintain  proper documentation to support their GRAS determinations. FDA has  indicated that it would take steps to help ensure that GRAS determinations  were arrived at soundly and that appropriate documentation was  maintained. In its 1997 proposal, FDA stated that it would be prudent for  companies, including those participating in the voluntary notification  program, to maintain documentation of their GRAS determinations and for  FDA to monitor compliance with the essence of the statutory  requirement—that there is common knowledge among qualified experts  that there is reasonable certainty that the GRAS substance is not harmful  under the intended conditions of use. Accordingly, FDA announced in the  1997 proposal that it intended to conduct random audits of data and  information maintained by these companies. However, according to FDA  officials, the agency has not conducted such audits. Agency officials  explained that, instead, they have decided to ask for additional supporting  documentation only when they determine it is needed.
FDA has not addressed appropriate levels of documentation for  companies that do not notify the agency of their GRAS determinations,  either in the 1997 proposed rule or in any guidance. To conduct random  audits of these companies’ GRAS determinations, FDA would need to  require them to inform the agency of those determinations. FDA officials  stated that companies making GRAS determinations without notifying  FDA were not a concern because the Federal Food, Drug, and Cosmetic  Act makes companies, not FDA, responsible for GRAS determinations.
Agency officials maintained that they would take enforcement action  against any company that had inappropriately determined a substance to  be GRAS. However, the possibility of random audits of supporting  documentation would provide an added incentive for companies to  conduct GRAS determinations appropriately. Without random audits of all  companies that make GRAS determinations, FDA has less assurance that  these companies have conducted these determinations appropriately,  including appropriately documenting the determination and maintaining  this documentation.
Lastly, finalizing the 1997 proposed rule, which FDA considers interim  policy, would firmly establish the framework and criteria for FDA’s  voluntary notification program. It would also reduce the inherent  uncertainties for companies of working with an interim policy. For  example, FDA could clarify changes it has made in its time frame for  completing reviews. Furthermore, according to representatives from the  Grocery Manufacturers Association, issuing a final rule would bring more  credibility to the voluntary notification program. In addition, FDA has not  yet responded to public comments on the proposed rule from over 30  organizations. For example, a consumer group—the Center for Science in  the Public Interest—recommended in a 1997 comment that FDA seek  authority from Congress to require companies to inform FDA of all GRAS  determinations they make. According to FDA officials, while the agency  plans to issue a final rule, the agency has had higher priorities and  currently has no specific schedule for doing so. However, these officials  also said that the program has been operating effectively under the  proposed rule.
section_title: A Trade Association Informs FDA of Its GRAS Determinations, Even Though It Does Not Participate in the Agency’s Voluntary Notification Program
paragraphs: Actions taken by the Flavor and Extract Manufacturers Association help  FDA better ensure the independence of scientific assessments of the  association’s GRAS determinations and obtain information about these  determinations. This association conducts GRAS determinations  exclusively for its approximately 70 member companies that manufacture  these substances. Once a member company submits a flavor or extract— known as a flavoring substance—to the association’s GRAS process, the  company is not supposed to market it until the association determines the  substance is GRAS. To conduct its GRAS determinations, association staff  first assess whether the substance will likely meet the criteria for a GRAS  determination and whether additional support is needed. When the staff  determine that they have sufficient information, they submit the substance  to the association’s own expert panel, a standing panel of eight academic  experts. In hiring panelists, the association requires that they complete a  financial conflict of interest form. To further avoid the potential for  conflicts of interest, panelists do not know which company has submitted  a substance and do not have any contact with applicants’ representatives  regarding individual substances. Once the expert panel has completed its  review, it determines if the substance is GRAS. Association members  generally do not seek review through FDA’s voluntary notification  program, instead relying on the integrity and credibility of the  association’s process to ensure the marketability of their GRAS  substances.
In addition, the Flavor and Extract Manufacturers Association voluntarily  informs FDA of its GRAS determinations, including the name of the  substance, its properties, and the basis of the determination. According to  association officials, the association has provided such information to  FDA on all of its GRAS determinations—over 2,600 since 1960. In addition,  the association has published journal articles on the workings of its expert  panel. It also announces its GRAS determinations in a food industry trade  magazine and makes these publications available on the association’s Web  site for a fee. As table 3 shows, the association’s GRAS process achieves a  level of public disclosure and agency notification similar to FDA’s  voluntary notification program.
FDA incorporates the information provided by the Flavor and Extract  Manufacturers Association about its GRAS substances into the agency’s  toxicological database, as well as into EAFUS. FDA officials said that the  agency uses the information in these databases to enhance its  understanding of the range and amount of GRAS substances likely to be  ingested by the public, as well as individual substances’ toxicological  profiles. FDA would otherwise have to develop some of this information at  its own cost. More generally, the information provided by the association  enables FDA to be better informed about the composition of the food  supply.
FDA officials stated that the agency would have to seek authority from  Congress in order to require all companies to inform it of their GRAS  determinations. These officials also expressed concern about the potential  burden on companies and the availability of resources at FDA to process  and assimilate this information in its databases. However, they also said  that receiving such information may have the potential to provide  additional food safety protection and would allow FDA to be more fully  informed about food in the marketplace, including GRAS determinations  made by foreign companies in countries with less stringent food safety  standards that may pose a threat to the U.S. food supply. These officials  added that if the provision of such information was made mandatory, it  would be important for FDA to implement this requirement efficiently to  emphasize the provision of only information that will be useful to the  agency, such as information on novel applications of substances in food.  We note that this focused approach, along with implementing this change  moving forward rather than retrospectively, as well, could limit the burden  of such a requirement on companies and FDA.
section_title: FDA Is Not Systematically Ensuring the Continued Safety of Current GRAS Substances
paragraphs: FDA does not systematically reconsider the safety of GRAS substances as  new information or new methods for evaluating safety become available.  In addition, FDA is generally unaware of companies’ reconsiderations of  their GRAS determinations because companies are not required to share  information about their reviews of the continued safety of their GRAS  substances.
subsections: section_title: FDA Does Not Systematically Reconsider the Safety of GRAS Substances as New Information Becomes Available
paragraphs: The GRAS status of a substance can change and must be reconsidered as  new information comes to light or new methods of evaluating its safety  arise, according to FDA regulations. The GRAS status of a substance is  subject to review as new scientific information is developed that raises  questions about the substance’s continued safe use. FDA may also  consider whether specific information brought to the agency’s attention  through routine correspondence from interested parties or through a  citizen petition raises such safety questions. If FDA decides to review a  substance’s GRAS status, it may advise companies and other interested  parties of those questions by letter.
FDA last engaged in a systematic reconsideration of the safety of GRAS  substances in the 1970s and 1980s. This effort raised questions about the  safety of almost three dozen GRAS substances. FDA undertook this  reconsideration because, during the late 1960s, new scientific information  raised questions about the safety of cyclamate salts, a class of artificial  sweeteners previously considered GRAS. FDA decided to evaluate, by  contemporary standards, the available safety information related to  substances it considered GRAS. If the evaluation confirmed that the use of  a particular substance was GRAS, FDA issued a new regulation affirming  that finding.
To conduct this systematic reconsideration, FDA contracted with an  independent scientific organization—the Federation of American Societies  for Experimental Biology, which set up the Select Committee on GRAS  Substances—to systematically evaluate ingredients considered GRAS at  the time. FDA asked the committee to recommend any restrictions that the  agency should place on the use of the substances to ensure their safe use  in food. Over 10 years—from about 1972 through 1982—the committee  reviewed the safety of 422 substances directly added to food and  transmitted reports on these substances to FDA. In all, the committee  questioned the safety of 35 of these substances. For 30 of these  substances, the committee reported that, unless evidence was provided to  FDA showing these substances’ safety, it expected FDA to revoke their  GRAS status. For example, the committee reported that it could find no  information in the scientific literature regarding carnauba wax—a  substance of plant origin used at a low level in food products since 1900— and that it, thus, had insufficient data upon which to evaluate its safety.  For the remaining 5 substances, the committee found that the current  evidence did not show the substance was not harmful at current levels of  consumption. For example, the committee reached this finding in  examining sodium chloride, or salt, and suggested the development of  guidelines for restricting the amount of salt in processed foods and  labeling the sodium content of foods. See appendix I for additional  information on the GRAS status of salt. As of December 2009, FDA had  affirmed 17 of these 35 substances as GRAS by issuing regulations,  including a regulation for carnauba wax. FDA had not issued regulations  on the remaining 18 substances and could not readily explain why, even  though almost 30 years had passed since the committee completed its  work. FDA has not revoked the GRAS status of any of these 18 substances  whose safety the committee questioned.
Since 1982, FDA has not systematically reconsidered the safety of  substances considered to be GRAS as new scientific information has come  to light. Specifically, the agency has not contracted for or performed any  comprehensive reviews of substances considered to be GRAS and has not  developed a formal approach for reviewing these substances. Agency  officials stated that they use a database called the Priority-Based  Assessment of Food Additives—which contains administrative, chemical,  and toxicological information about food ingredients, including GRAS  substances—to help prioritize substances for assessment. However, FDA  officials could not provide any examples of a reconsideration of the safety  of a GRAS substance that resulted from their use of this database. FDA  officials also said they keep up with new developments in the scientific  literature as part of their professional responsibility as scientists and, on a  case-by-case basis, information brought to the agency’s attention could  prompt it to reconsider the safety of a GRAS substance. Specifically, FDA  officials said they may become aware of safety concerns related to GRAS  substances through other means, such as through reports in the media or  trade press; informal inquiries or complaints from consumers, interest  groups, or companies; citizen petitions; or reports published by  authoritative bodies. For example, FDA officials stated they are reviewing  the issue of companies adding caffeine, a GRAS substance, to certain  products, such as alcoholic beverages, after becoming aware of the  practice through media reports and from other sources.
Concerns about the safety of certain GRAS substances have led to changes  in their GRAS status in the past. According to FDA officials, the agency  has not revoked the GRAS status of any substance approved through the  petition affirmation process that began in 1972 or retracted its no  questions letter for any GRAS notice receiving that agency response since  1997. Nevertheless, questions about the safety of an ingredient previously  considered to be GRAS, and changes to that GRAS status, have occurred.  In addition to banning cyclamate salts in 1969, other examples of FDA  action on the status of GRAS substances include the following:  In 1985, FDA banned cinnamyl anthranilate, a flavoring agent that had  been previously considered GRAS, after studies linked it to liver cancer in  mice.
In 1986, FDA prohibited the use of sulfites, considered GRAS since 1959,  on fresh fruits and vegetables intended to be served raw because of  potentially severe allergic reactions among those with a sulfite sensitivity;  the agency also implemented labeling requirements for other foods  containing any added sulfites.
In another more recent case, studies have raised health concerns about the  trans fats in partially hydrogenated vegetable oils, and several government  and scientific organizations have recommended minimizing consumption  of trans fats. FDA has not, however, revoked the GRAS status of these oils.  Rather, agency officials indicated that, in response to a 2004 citizen  petition, FDA set up a review team in 2004 that is actively reviewing the  oils’ GRAS status and plans to issue its findings in 2010. See appendix I  for additional information on the GRAS status of these oils.
FDA officials told us that information brought to the agency’s attention  could prompt the agency to reconsider the safety of a GRAS substance.  However, we found that FDA has largely not responded to the concerns  that individuals and consumer groups have raised through 11 citizen  petitions submitted to the agency between 2004 and 2008. Citizen petitions  must be submitted according to a prescribed format and are the most  formal path an individual or organization can take to bring a problem to  FDA’s attention. The agency is to respond to these petitions within 180  days, either indicating its decision or informing the petitioner that the  agency has not yet reached a decision.
Nine of the 11 citizen petitions raised specific concerns about the safety of  GRAS substances or the way they are used in food. For example, a petition  submitted in 2006 cited studies linking diacetyl (a substance used to  impart a buttery flavor to processed foods, including microwave popcorn)  to severe respiratory reactions and called for FDA to revoke diacetyl’s  GRAS status. FDA has not yet issued a decision on this petition. As table 4  shows, FDA has not issued a decision on 10 of the 11 petitions submitted  between 2004 and 2008. The agency most often cited limited resources and  other agency priorities to explain why it had not yet reached a decision on  these 10 petitions.
As shown in table 4, in three cases, FDA did not provide evidence that it  had sent a 180-day letter. FDA officials indicated that in two of the three  cases—those related to carbon monoxide—the agency had no record that  it had sent a 180-day letter and stated that this was an oversight on the  agency’s part. In the third case—the petition on milk protein  concentrate—agency officials said a 180-day letter had been sent but they  could not find it. A majority of the 180-day letters FDA sent stated that the  agency had not reached a decision on the petition because of limited  resources and other priorities. In the case of the citizen petition on salt,  however, FDA indicated that it needed to collect more information before  responding and subsequently held a hearing for interested parties in  November 2007. As of December 2009, FDA officials stated that they were  still evaluating the comments collected at this hearing, among other  actions (for information on additional actions FDA is taking related to salt,  see appendix I).
FDA has reviewed some of the 10 unanswered citizen petitions more  intensively than others. For several of the petitions, FDA officials provided  documentation showing extensive review of the concerns raised. For  example, in response to one of these petitions, FDA’s review included  contracting for an independent evaluation of published literature and a  calculation of the intake estimates for dietary exposure to the substance.  FDA appears to have extensively reviewed the information needed to  respond to the citizen petition in this and other cases, but had still not  responded to the petitions. In two of these cases, FDA officials had  developed internal memoranda recommending a particular response, but  the agency had not yet finalized its responses as of December 2009, and  agency officials cautioned that final decisions were not necessarily  imminent. On the other hand, FDA appears to have only minimally  reviewed three of the citizen petitions—those on milk protein concentrate,  carbon monoxide in the packaging of fresh tuna, and iodized salt. The  agency did not provide documentation to show that any review of these  three petitions had occurred.
While some of these citizen petitions may help FDA better ensure the  safety of GRAS substances, GRAS determinations made without notice to  the agency remain outside a third party’s independent evaluation.  Others—including academic experts, consumer groups, and scientific  organizations—can play a useful role in helping FDA oversee the safety of  GRAS ingredients. In addition to the independent reconsideration of the  safety of GRAS substances FDA contracted for in the 1970s and 1980s,  independent scientific research has also contributed to FDA’s  reconsideration of GRAS substances in the past. However, without  knowledge of companies’ GRAS determinations, third parties, such as the  ones that have filed citizen petitions in the past, do not have the  opportunity to investigate the potential health effects of such GRAS  substances, leaving an additional gap in the oversight of their continued  safety.
section_title: FDA Is Generally Not Aware of Companies’ Reconsiderations of their GRAS Determinations
paragraphs: FDA generally does not know to what extent, or even whether, companies  track the evolving scientific information regarding substances the  companies have determined are GRAS. Food companies are responsible  for ensuring they market safe food, including ensuring the continued  safety of the GRAS substances they use as new scientific information  emerges. However, companies are not required to share information about  their reviews of the continued safety of GRAS substances with FDA. When  companies determine a substance is GRAS without notifying FDA, they are  the only ones who can ensure the continued safety of that GRAS  substance. Representatives of one company told us that they review the  status of their GRAS ingredients and keep up with the scientific literature,  although they do not generally share the findings of such reviews with  FDA. However, FDA officials stated that, in some cases, companies do  share with the agency updated scientific information on GRAS substances  that were previously reviewed by FDA. As an example, FDA officials  stated that, in the past, industry representatives had provided the agency  information favorable to the safety of monosodium glutamate, marketed as  a flavor enhancer.
FDA is aware of some reconsiderations conducted by companies because  the Flavor and Extract Manufacturers Association periodically reconsiders  the thousands of substances it has determined to be GRAS and publishes  the results of these reviews. According to the association, its GRAS  assessment process incorporates new information as it becomes available.  In fact, the association’s expert panel periodically conducts  comprehensive and systematic reviews of all GRAS flavoring substances  that its members manufacture and reviews any individual substances for  which potentially significant new data become available. The expert panel  conducted its first comprehensive review from 1965 to 1985, evaluating all  available new data on the approximately 1,200 substances it had  previously determined to be GRAS. The panel affirmed the GRAS status of  almost all of the GRAS flavoring substances, but did revoke GRAS status  for three. The expert panel conducted a second systematic review  between 1994 and 2005 and reviewed all available information relevant to  the safety assessment and GRAS status of the approximately 2,000  flavoring substances it had designated as GRAS. This second review  process did not result in the revocation of GRAS status for any flavoring  substance. In 2009, the association began its third comprehensive review,  focusing on flavoring substances in certain structural classes that showed  a significant increase in the association’s 2005 survey. The results of this  review will, as with previous reviews, be published in the peer-reviewed  scientific literature, according to an association representative. In addition  to these comprehensive reviews, the panel periodically becomes aware of  significant new data on prior GRAS decisions during its review of the  available scientific data related to flavoring substances. In these cases, the  panel re-evaluates the safety of the flavoring substance and may conclude  the substance is no longer GRAS. In some instances, the expert panel  requests that additional studies be performed by industry members. Over  the last four decades, these two review processes have led to numerous  studies to address a variety of safety assessment issues that arose during  the reviews. Most of these studies have been published. The two review  processes also resulted in 11 substances being removed from the  association’s list of GRAS flavoring substances.
section_title: FDA’s Regulatory Approach Allows Engineered Nanomaterials to Enter the Food Supply without the Agency’s Knowledge
paragraphs: Nanotechnology presents potential challenges to the regulation of food  safety, especially because companies may conclude that their engineered  nanomaterials are GRAS without informing FDA. FDA has issued some  guidance to companies regarding applications of nanotechnology in food.  In Canada and the European Union, any such engineered nanomaterials  are required to undergo review by government regulators before they can  be marketed.
subsections: section_title: Nanotechnology Presents Potential Challenges to the Regulation of Food Safety
paragraphs: Nanotechnology has many potentially beneficial uses in food. For  example, engineered nanomaterials could be used to monitor food quality  and freshness; improve the traceability of food products (the ability to  track these products from point of origin to retail sale); and modify the  taste, texture, and fat content of food. However, the largest area of current  usage appears to be in food packaging, where applications such as  antimicrobial nanofilms—thin layers of substances meant to hamper the  growth of bacteria and fungi—may help bolster food safety.
While applications of nanotechnology with potential food safety benefits  have been proposed, reports issued or commissioned by FDA and foreign  food safety agencies have identified a number of challenges to the  regulation of engineered nanomaterials in food. Specifically, in 2007 an  FDA taskforce reported on how nanotechnology might affect the products  the agency regulates, including its potential applications in food. The  taskforce concluded that the use of engineered nanomaterials presents  several challenges, including ensuring the adequacy of methods for  evaluating the safety of these engineered nanomaterials in food. The  report highlighted the shortcomings of FDA’s knowledge about the use of  nanotechnology in food, such as the difficulties in identifying its use and in  extrapolating natural-scale safety information to nanoscale materials. The  taskforce specifically refrained from defining nanotechnology, stating that  a definition would be premature given the current limited knowledge. In  December 2009, FDA officials said that although the agency’s scientific  understanding of nanotechnology continues to evolve, in their view, the  principles expressed in the taskforce’s 2007 report are sound.
Similarly, a Canadian expert panel gathered at the request of the Minister  of Health reported in September 2008 that the scientific knowledge needed  to assess the risks associated with engineered nanomaterials is limited,  especially given the diversity of these materials and their potential  applications. The panel found that (1) nanomaterials can pose particular  challenges to risk assessment and, hence, to regulation, because they  exhibit properties based on both their physical structure and their  chemistry; (2) while human and ecological risk assessment frameworks  are robust, their application to nanomaterials requires new ways of  measuring exposure, dose, and response; and (3) data are inadequate for  informing quantitative risk assessments on current and emerging  nanomaterials. Because of the limited state of scientific knowledge  regarding many nanomaterials, the expert panel stated that priority should  be given to a strategic research agenda to improve the understanding of  the risks associated with different types of nanomaterials. The panel also  found that high priority should be given to research on how to measure  and detect the presence of nanomaterials, nanomaterials’ properties that  are linked to biological responses, and effective monitoring and  surveillance strategies.
Finally, in a February 2009 scientific opinion on nanotechnology and food,  the European Union’s Food Safety Authority concluded that several  challenges still must be addressed in order to ensure the safe inclusion of  engineered nanomaterials in food. It recommended further development of  risk assessment and safety evaluation methods. The opinion emphasized  that, although case-by-case evaluation of specific engineered  nanomaterials may currently be possible, risk assessment processes are  still under development for characterizing and analyzing these materials in  food, optimizing methods to test their toxicity, and interpreting the  resulting data. It also stated that there may be additional toxic effects  caused by engineered nanomaterials that are not readily detectable by  current standard protocols. The opinion concluded that, under these  circumstances, any individual risk assessment is likely to be subject to a  high degree of uncertainty until more data on and experience with testing  of engineered nanomaterials become available.
section_title: Companies May Market Engineered Nanomaterials as GRAS without Informing FDA
paragraphs: Despite the challenges inherent in assessing the safety of food ingredients  containing engineered nanomaterials, under the Federal Food, Drug, and  Cosmetic Act and FDA regulations, a company may market such an  ingredient without informing FDA as long as the company has concluded  the substance is GRAS. FDA’s nanotechnology taskforce began its  regulatory policy inquiry by reviewing the agency’s authorities to meet any  unique challenges that may be presented by FDA-regulated products  containing nanoscale materials. The taskforce recognized that, although  FDA’s authorities may be adequate to meet these challenges, in some  cases the evolving state of the science regarding nanotechnology may  warrant a case-by-case approach to assess whether sufficient evidence  exists to show that products satisfy the applicable statutory and regulatory  standards. After reviewing the uncertainties associated with the safety of  food ingredients containing engineered nanomaterials, FDA has decided  that, at this time, it does not need additional authority to regulate such  products, nor does it need to significantly alter its regulatory approach.
FDA has, instead, encouraged companies considering using nanomaterials  in food and food packaging to consult with the agency about which  regulatory track to follow, including whether such a substance might be  GRAS. In these presubmission meetings, companies may discuss this and  other issues relevant to their potential submission with FDA officials. FDA  officials explained that they were wary of a “one size fits all” regulatory  approach for food substances containing engineered nanomaterials. They  also stated that some substances that are GRAS at their natural scale may  still be GRAS if they were engineered at the nanoscale, so they do not see  a need for changing the agency’s approach to GRAS substances at this  time. However, others, such as some academic experts and consumer  groups, have pointed out that engineered nanomaterials are used  specifically because of the novel properties they exhibit at the nanoscale;  therefore, the fact that a substance is GRAS at its natural scale may not be  a good indicator that the new properties the substance takes on at the  nanoscale are safe. Nevertheless, the decision to notify FDA of a GRAS  substance, even one that contains engineered nanomaterials, is still  voluntary.
While FDA officials said that allowing companies to voluntarily provide  information about the use of engineered nanomaterials in GRAS  substances is sufficient to ensure food safety, few companies participated  in another federal agency’s voluntary program to gather information about  applications of nanotechnology in products. In 2006, the Environmental  Protection Agency (EPA) began developing the Nanoscale Materials  Stewardship Program, which sought to build the capacity of the agency to  deal with materials at the nanoscale. The program consisted of two parts:  asking companies to voluntarily (1) supply existing information about  their products and (2) conduct further studies to produce new information  about their products. According to EPA’s interim report, the program  suffered from underreporting on the part of nanotechnology  manufacturers. EPA reached this conclusion after comparing participation  in the program with databases compiled by other organizations that list  nanomaterials available for commercial and research sale or commercial  products for which the manufacturer makes a claim that the product  contains nanomaterials. As of September 1, 2008, the program had  received information on 106 engineered nanomaterials from 21 companies  and associations. Other organizations’ databases, however, listed  thousands of engineered nanomaterials that companies were advertising  as such to potential customers.
The extent to which GRAS substances incorporating engineered  nanomaterials have entered the U.S. food supply is unclear. FDA officials  indicated that, as of December 2009, no substances that companies  described as containing engineered nanomaterials had been submitted to  the agency’s GRAS notification program. However, the Acting Deputy  Director of FDA’s Center for Food Safety and Applied Nutrition said that  companies have submitted GRAS notices dealing with substances that  some might consider engineered nanomaterials, including cyclodextrins— substances used in a number of foods as flavor carriers or protectants,  among other things—and synthetic lycopene—an ingredient for use in  breakfast cereals, drinks, and several other foods. However, because  companies are not specifically required to identify whether substances  they submit to FDA contain engineered nanomaterials and GRAS  notification is voluntary, FDA has no way of knowing the full extent to  which engineered nanomaterials have entered the U.S. food supply in  GRAS substances.
FDA does, however, have some information regarding the inclusion of  engineered nanomaterials in food contact substances, for which notice to  the agency is required prior to marketing. Food contact substances are  defined as substances that are intended as components 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. From 2007  through September 2009, FDA has had eight presubmission meetings  concerning food contact substances that companies have described as  incorporating engineered nanomaterials. As a result, FDA has received  food contact substance notifications for four of these substances and  two—applications of titanium nitride added to a certain kind of plastic— have been approved.
section_title: FDA Has Issued Some Guidance to Companies on Nanotechnology in Food
paragraphs: While it did not recommend changes to the agency’s regulatory approach,  FDA’s nanotechnology taskforce did make recommendations that seek to  address the regulatory challenges nanomaterials may present, as detailed  in table 5. The taskforce stated in its July 2007 report that the steps it  recommended would give affected manufacturers and other interested  parties timely information about FDA’s expectations in order to foster  predictability in the agency’s regulatory processes. According to the  taskforce, this predictability would foster innovation and enhance  transparency while protecting public health. Specifically, the taskforce  recommended that, for products not subject to premarket authorization,  such as GRAS substances, FDA should develop guidance for industry. This  guidance should describe what types of additional information companies  should include in their GRAS notices submitted to FDA if the products  contain engineered nanomaterials. The task force also recommended that  FDA issue a notice in the Federal Register requesting that companies  voluntarily provide information about their use of engineered  nanomaterials in such products.
As shown in table 5, FDA has implemented some, though not all, of the  recommendations made by its taskforce and endorsed by the FDA  Commissioner in 2007. FDA has updated three of its chemistry guidance  documents—for food contact substances, issued in 2007; and for direct  food additives and color additives, both issued in 2009—to include  guidance regarding identification of the particle size in the substances.  FDA officials indicated that the GRAS voluntary notification program  relies on the chemistry guidance for food additive petitions and food  contact substances, depending on the substance’s use. In August 2008,  FDA also issued a notice in the Federal Register for a public meeting on  nanotechnology and requested data and information addressing the effects  on product safety of nanoscale materials in all products, including those  not subject to premarket authorization. According to FDA officials, during  the public meeting, held in September 2008, FDA repeated its request for  the voluntary submission of this type of information to the agency, which  was due by October 24, 2008. As of December 2009, FDA officials said that  they were still evaluating this information. FDA is in the process of  implementing the remainder of the recommendations of the 2007 taskforce  report, according to agency officials, though they could not provide a  timetable for when these recommendations would be implemented.
section_title: Food Ingredients That Incorporate Engineered Nanomaterials Must Be Reviewed in Other Countries Before They Can Be Marketed
paragraphs: Foreign entities we identified as being particularly active in regulating  nanotechnology—Canada and the European Union (which regulates food  on behalf of its 27 member countries)—do not have a GRAS exemption  that would allow companies to market a food ingredient containing  engineered nanomaterials without first notifying and obtaining approval  from regulators. According to officials of these entities, all novel foods and  food additives they oversee are subject to regulatory review before they  are introduced into the market.
The European Union has also taken a step to more directly regulate  engineered nanomaterials in food. The European Parliament and the  Council of the European Union, the European Union’s legislative bodies,  recently revised their regulations on food additives. These revised  regulations include language clarifying that when there is a change in the  particle size of a food additive that has previously been approved, for  example through nanotechnology, premarket approval for the altered food  additive is required. These regulations took effect in January 2010. The  same rules would apply to food contact materials produced through  nanotechnology. In contrast, FDA has no similar regulations that would  require the agency to review changes in the particle size of a substance  being used in food.
The European Parliament and Canadian government are also considering  additional steps related to nanomaterials in food, according to European  and Canadian officials, respectively. The European Parliament is  considering an update to its regulations on novel foods—foods or  ingredients that have not been used for human consumption to a  significant degree in the European Union prior to May 15, 1997—that, in its  draft form, includes measures to regulate engineered nanomaterials in  food. Specifically, the proposed update would require that all foods  containing engineered nanomaterials undergo premarket authorization.  The draft novel food regulation also includes a definition of engineered  nanomaterials. In addition, in 2008, the Canadian government developed a  new initiative proposing to conduct a survey that would require Canadian  importers and manufacturers to report their use of engineered  nanomaterials produced or imported in excess of 1 kilogram during the  2008 calendar year. The authority for such a survey would be a one-time  request and would not require users to submit information on a continual  basis. Canada planned to use this information to aid developing a  regulatory framework for nanomaterials and determining which  information requirements should best be used for subsequent risk  assessment under such framework. Canadian officials stated that they  originally hoped to issue this regulation in the spring of 2009, but could not  predict, as of November 2009, when they would actually issue it.
section_title: Conclusions
paragraphs: One of FDA’s principal missions is to ensure the safety of the nation’s food  supply, but a growing number of substances that companies have  determined are GRAS may effectively be excluded from federal oversight.  While some view GRAS substances as generally presenting a relatively low  risk, questions have been raised about the safety of numerous GRAS  substances over the last 50 years, and some have been banned as a result.  In the future, other substances now considered GRAS may also prove to  be unsafe. However, FDA may be constrained in detecting any such future  problems because it lacks information about an unknown number of  substances companies have determined to be GRAS without informing the  agency. FDA’s public Web site and some of its databases, including its  Everything Added to Food in the United States database, are incomplete  without information on these GRAS substances. Furthermore, without  issuing guidance on how to prevent conflicts of interest and information in  companies’ GRAS notices regarding expert panelists’ independence, FDA  has less assurance of the independence of the experts companies employ  to support their GRAS determinations. In addition, how companies are to  document their GRAS determinations remains unclear and, because FDA  does not randomly audit GRAS determinations, FDA has less assurance  that companies have conducted and documented their determinations  appropriately. Finally, without reconsidering and updating the 1997  proposed rule, FDA may be falling short of fulfilling its food safety  responsibilities.
The petition affirmation process and the voluntary notification program  have allowed FDA to perform detailed evaluations of companies’ GRAS  determinations at one point in time. Nonetheless, because FDA now only  addresses safety in response to possible concerns that come to its  attention, nearly three decades have passed since the agency last  systematically reconsidered the safety of all current GRAS substances.  Developing a strategy to systematically reconsider the safety of GRAS  substances in light of evolving scientific information and methodologies— including allocating sufficient resources to this effort, developing criteria  for review, and collecting information on companies’ GRAS  reconsiderations—would provide better assurance regarding the  continued safety of GRAS substances.
Uncertainties persist about how to evaluate the safety of engineered  nanomaterials in food. Nevertheless, FDA has only partially implemented  its nanotechnology taskforce’s 2007 recommendations that the agency  issue guidance documents on the use of these materials in GRAS  substances, and the agency does not have a schedule for completing the  remaining guidance. Moreover, because FDA has not developed a  definition of engineered nanomaterials and does not require companies to  identify whether their GRAS substances incorporate such materials, the  agency may not receive information about the extent to which these  materials are being used. Without a strategy to address the potential for  engineered nanomaterials to enter the food supply as GRAS substances  without the agency’s knowledge, FDA may have less oversight over  substances whose safety is uncertain.
We recognize there would be some cost to FDA associated with  addressing these issues. However, we believe that developing strategies  and collecting information to address these issues would cost-effectively  contribute to improving the safety of the food supply. For example, FDA  has acknowledged the usefulness and cost-effectiveness of the GRAS  determination information provided voluntarily by the Flavor and Extract  Manufacturers Association. Receiving similar information from other  companies on GRAS determinations made outside of the voluntary  notification program would likely provide similar benefits.
section_title: Recommendations for Executive Action
paragraphs: To better ensure FDA’s oversight of the safety of GRAS substances, we  recommend that the Commissioner of FDA take the following six actions:    develop a strategy to require any company that conducts a GRAS  determination to provide FDA with basic information—as defined by the  agency to allow for adequate oversight—about this determination, such as  the substance’s identity and intended uses, and to incorporate such  information into relevant agency databases and its public Web site;    develop a strategy to minimize the potential for conflicts of interest in  companies’ GRAS determinations, including taking steps such as issuing  guidance for companies on conflict of interest and requiring information in  GRAS notices regarding expert panelists’ independence;    develop a strategy to monitor the appropriateness of companies’ GRAS  determinations through random audits or some other means, including  issuing guidance on how to document GRAS determinations;    develop a strategy to finalize the rule that governs the voluntary  notification program, including taking into account the experience of the  program to date, incorporating input from a new public comment period,  and reporting to Congress and the public the agency’s timeline for making  it final;    develop a strategy to conduct reconsiderations of the safety of GRAS  substances in a more systematic manner, including taking steps such as  allocating sufficient resources to respond to citizen petitions in a timely  manner, developing criteria for the circumstances under which the agency  will reconsider the safety of a GRAS substance, and considering how to  collect information from companies on their reconsiderations; and    develop a strategy to help ensure the safety of engineered nanomaterials  that companies market as GRAS substances without the agency’s  knowledge, including taking steps such as issuing guidance recommended  by the agency’s nanotechnology taskforce, developing an agency definition  of engineered nanomaterials, and requiring companies to inform FDA if  their GRAS determinations involve engineered nanomaterials.
If FDA determines that it does not have the authority to implement one or  more of these recommendations, the agency should seek the authority  from Congress.
section_title: Agency Comments and Our Evaluation
paragraphs: We provided a draft of this report to FDA for review and comment. In  written comments, which are included in appendix IV, FDA generally  agreed with the report’s findings and recommendations, while raising  concerns about certain aspects of several of the recommendations. The  agency also stated that it regards the report as an important contribution  to its internal deliberations for improving the agency’s oversight of all  ingredients added to food. For example, FDA noted that the report’s  recommendations are aimed at strengthening the rigor of independent  GRAS determinations, improving FDA’s awareness of and oversight of  GRAS determinations, and strengthening postmarket oversight of GRAS  substances to address new safety concerns, and said it would fully  consider the recommendations and other ideas when it moves to finalize  the regulation governing the current voluntary GRAS notification program.  FDA did not state when it will finalize the regulation.
FDA said it agreed with the first recommendation in the case of a  voluntary GRAS submission, noting that it has practices and procedures in  place to collect information on the basis for a company’s GRAS  determination as part of the agency’s notification program. However, from  a food safety perspective, FDA said it did not agree with a strategy to  require any company that conducts a GRAS determination to provide FDA  with basic information only and to put such limited information into an  agency database or on its public Web site. Specifically, FDA said that, in  theory, it would be informative for the agency to have at least an  awareness of the existence of substances that are independently  determined to be GRAS, even in the absence of a GRAS notice submitted  by the company. However, without a regulatory framework that makes  notification mandatory, FDA said it cannot ensure that GRAS  determinations that are not submitted to the agency’s notification program  are rigorous, robust, or consistent with the agency’s criteria, as outlined in  its 1997 GRAS proposal. Thus, FDA indicated that its ability to oversee the  safety of added food ingredients, including GRAS substances, would be  enhanced if the manufacturer were required, prior to marketing any new  substance or new use of an existing substance, to notify FDA and submit  scientific evidence demonstrating the safety and legality of the intended  use. These comments suggest that FDA would prefer to make notifications  mandatory, a step that we agree would allow the agency to better ensure  the sufficiency of company GRAS determinations. If this is FDA’s intended  strategy in response to our recommendation, we encourage the agency to  seek legal authority from Congress, as needed, to implement this  approach. However, in the meantime, we continue to believe that requiring  companies to provide FDA with basic information—as defined by the  agency to allow for adequate oversight—on GRAS determinations that are  not submitted to the voluntary notification program would be useful to  FDA, such as for potential postmarket enforcement actions. We clarified  our recommendation to make this clear.
In addition, FDA said that publishing basic information on company  determinations that were not submitted to the voluntary notification  program might mislead the public into thinking FDA validated these  determinations, which could result in an increased use of the substance in  food without FDA being aware of the basis for its safety. We believe that if  FDA were to post this information on its Web site with an appropriate  disclaimer, the public would not be misled into thinking that FDA had  validated these determinations. Moreover, publishing this information  could be useful to academic experts, consumer groups, scientific  organizations, and others, who in turn could alert FDA to information that  may be pertinent for evaluating the safety of a GRAS substance.
Regarding our second recommendation, FDA stated that it recognizes that,  because the notifier has an inherent interest in the outcome of its GRAS  notice, there is the potential for a conflict of interest. To address this  concern, the agency noted that GRAS determinations are required to  consider the totality of the publicly available information, including  potentially unfavorable information. However, FDA said that it could  develop nonbinding guidance for convening expert panels as part of GRAS  determinations. The agency also said it plans to finalize its GRAS proposal,  including the criteria for making and documenting independent GRAS  determinations, and would consider the conflicts issue in that rule making.  However, because the time frame for finalizing FDA’s GRAS proposal is  uncertain—the proposal was promulgated in 1997—and companies  continue to make GRAS determinations without notifying the agency, we  believe that FDA should consider taking additional action until it finalizes  its proposal, as an interim step, to minimize the potential for conflicts of  interest in these determinations, such as issuing suggested guidance for  companies on this issue.
Concerning our third recommendation, FDA noted that in the case of a  voluntary GRAS submission, it does not hesitate to ask a notifier to  provide certain data or information as an amendment to a GRAS notice.  However, the agency said in cases of GRAS determinations that were not  submitted to FDA, it has a very limited basis on which to do an audit  because it does not know which companies made determinations about  particular substances and uses. We note that our recommendation allows  for FDA to monitor the appropriateness of such GRAS determinations  through means other than random audits. FDA also said that its 1997  GRAS proposal contains extensive information on how to document GRAS  determinations, and that it has posted additional information on its Web  site. Nevertheless, the agency indicated it would further consider the  documentation issue as it moves toward finalizing the GRAS proposal.  Again, we note that the time frame for finalizing this proposal is uncertain.  We also note that the information included in FDA’s GRAS proposal and  on its Web site generally pertains to documenting GRAS determinations  that are submitted to FDA’s notification program, and not the remainder of  GRAS determinations. Furthermore, as discussed, FDA generally has no  information on determinations that are not submitted to the agency and,  therefore, less assurance that these determinations have been done and  documented appropriately. For these reasons, we continue to believe that  FDA should also take steps until it finalizes its proposal to better ensure  its oversight of the safety of GRAS substances, including issuing guidance  on how to document GRAS determinations that are not submitted to the  agency’s voluntary notification program.
FDA agreed with our fourth recommendation that it finalize its GRAS  proposal. The agency indicated that it anticipates reopening the comment  period prior to issuance of a final rule. It also said that after analyzing any  comments received, it would determine a time frame for finalizing the rule.
Regarding our fifth recommendation, FDA agreed that a system of  postmarket oversight for GRAS substances and also for food additives and  food contact substances would help to better ensure the safety of the food  supply. However, it also said a more comprehensive, sustainable and  systematic approach to postmarket review has been hampered by  resource constraints; but that it would continue to work on strategies that  efficiently use its available resources to mitigate concerns regarding the  safety of foods that contain GRAS substances. FDA also agreed that it  should develop criteria for circumstances warranting postmarket review  of GRAS substances, and that it should allocate sufficient resources to  respond to citizen petitions related to GRAS substances in a timely  manner. Regarding the latter, FDA noted that an effective strategy would  need to include a means of triaging these petitions for their scientific and  legal merit, if its limited resources are to be spent wisely. Regarding the  potential collection of information on company reconsiderations of the  safety of GRAS substances, FDA said that because, under current law,  companies are not required to notify FDA of their GRAS determinations,  FDA could ask, but not require, companies to provide information on their  reconsiderations. While collecting information from companies on their  reconsiderations is but one of the steps we suggest FDA take to implement  this recommendation, we note that we recommended that, if FDA  determines it does not have legal authority to implement a  recommendation, the agency should seek this authority from Congress.
FDA agreed with our sixth recommendation that it develop a strategy to  help ensure the safety of engineered nanomaterials that companies market  as GRAS substances without the agency’s knowledge. The agency  observed that current scientific uncertainty regarding potential novel  properties of nanomaterials and how to test their safety raises questions  about the applicability of the GRAS concept to these substances.  Accordingly, FDA stated that it will soon issue draft guidance that will  help developers of food applications of nanotechnology determine the  applicability of this concept. The agency also indicated that it would  continue to consider the viability of establishing an FDA-wide or even a  foods definition of nanotechnology.
Finally, FDA did not discuss our recommendation that if FDA determines  that it does not have the authority to implement one or more of these  recommendations, the agency should seek the authority from Congress.
FDA also provided technical comments that we incorporated in the report,  as appropriate.
As agreed with your offices, unless you publicly announce the contents of  this report earlier, we plan no further distribution until 30 days from the  report date. At that time, we will send copies to the Commissioner of FDA  and other interested parties. The report will also be available at no charge  on the GAO Web site at http://www.gao.gov.
If you or your staff members have questions about this report, please  contact me at 202-512-3841 or shamesl@gao.gov. Contact points for our  Offices of Congressional Relations and Public Affairs may be found on the  last page of this report. Key contributors to this report are listed in  Appendix V.
section_title: Appendix I: Additional Information on Selected Generally Recognized as Safe (GRAS) Substances
paragraphs: This appendix provides information on three sources’ views on two GRAS  substances—salt and the trans fats in partially hydrogenated vegetable  oils—and the Food and Drug Administration’s (FDA) views on the impact  of these sources’ findings on the GRAS status of each substance. The three  sources are the following:    Dietary Guidelines for Americans, 2005. These guidelines have been  published jointly every 5 years since 1980 by the U.S. Department of  Health and Human Services and the U.S. Department of Agriculture. The  guidelines provide authoritative advice for people 2 years of age and older  about how good dietary habits can promote health and reduce risk for  major chronic diseases. They serve as the basis for Federal food and  nutrition education programs.
Dietary Reference Intakes. These are reports developed by the Food and  Nutrition Board of the Institute of Medicine, a part of the National  Academies, along with Health Canada. These publications provide  recommended levels considered safe for consumption of a wide range of  nutrients.
FDA’s Food Advisory Committee. The committee and its subcommittees  provide advice to the FDA Commissioner and others on emerging food  safety, food science, nutrition, and other food-related health issues that  the FDA considers of primary importance for its food programs. The  committee is charged with reviewing and evaluating available data and  making recommendations on matters such as those relating to nutrient  needs and nutritional adequacy.
subsections: section_title: Salt
subsections: section_title: Dietary Guidelines for Americans
paragraphs: Health effects. The guidelines found that, on average, the higher an  individual’s salt intake, the higher an individual’s blood pressure.  Decreasing salt intake is advisable to reduce the risk of elevated blood  pressure. Keeping blood pressure in the normal range reduces an  individual’s risk of coronary heart disease, stroke, congestive heart failure,  and kidney disease. Many American adults will develop hypertension (high  blood pressure) during their lifetime. The guidelines also found that some  individuals tend to be more salt sensitive than others, including people  with hypertension, African Americans, and middle-aged and older adults.
Recommended limits. The guidelines recommended that individuals  consume less than 2.3 grams of sodium per day, or approximately 1  teaspoon of salt (salt is sodium chloride; sodium amounts are discussed  because food labels list sodium rather than salt content). Individuals with  hypertension, African Americans, and middle-aged and older adults should  aim to consume no more than 1.5 grams of sodium per day and meet the  potassium recommendation (4.7 grams per day) with food, as shown in  table 6. The guidelines also recommended choosing and preparing foods  with little salt and consuming potassium-rich foods, such as fruits and  vegetables.
Actual consumption. The guidelines found that nearly all Americans  consume substantially more salt than they need. On average, the natural  salt content of food accounts for only about 10 percent of total intake,  while discretionary salt use (salt added at the table or while cooking)  provides another 5 to 10 percent of total intake. Approximately 75 percent  is derived from salt added by manufacturers. In addition, foods served by  food establishments may be high in sodium. Any program for reducing the  salt consumption of a population should concentrate primarily on  reducing the salt used during food processing and on changes in food  selection (for example, more fresh, less processed items; less sodium- dense foods) and preparation.
Dietary Reference Intakes  Health effects. The intakes report found that the major adverse effect of  increased salt intake is elevated blood pressure, a risk factor for  cardiovascular and renal diseases. On average, blood pressure rises  progressively with increased salt intake. Individuals with hypertension,  diabetes, and chronic kidney disease, as well as older persons (over age  50) and African Americans, tend to be more sensitive to the blood  pressure-raising effects of salt intake than their counterparts. Genetic  factors and an individual’s diet also influence the blood pressure response  to salt.
Recommended limits. The report developed an adequate intake and a  tolerable upper level intake for sodium. To ensure that the overall diet  provides an adequate intake of other important nutrients, for young adults,  the adequate intake level was set at 1.5 grams of sodium per day; the daily  adequate intake for men and women 50 through 70 years of age was set at  1.3 grams; and for those 71 years of age and older at 1.2 grams (see table  7). For adults, a sodium tolerable upper intake level of 2.3 grams per day  was set, although the report noted that this level is not a recommended  intake and there is no benefit to consuming levels above the adequate  intake. The tolerable upper intake level may well be lower for those  groups of individuals who are most sensitive to the blood pressure effects  of increased sodium intake (for example, older persons; African  Americans; and individuals with hypertension, diabetes, or chronic kidney  disease). In contrast, for individuals who are unacclimatized to prolonged  physical activity in a hot environment, their needs may exceed the  tolerable upper intake level because of sodium sweat losses.
Actual consumption. The report found that it was well-recognized that the  current intake of sodium for most individuals in the United States greatly  exceeded both the adequate intake and the tolerable upper intake level.  Progress in achieving reduced sodium intake will require changes in  individual behavior toward salt consumption, replacement of high salt  foods with lower salt versions, increased collaboration of the food  industry with public health officials, and a broad spectrum of additional  research.
section_title: Food Advisory Committee
paragraphs: FDA’s Food Advisory Committee and its subcommittees did not examine  the health effects of salt or sodium consumption in their most recent  meetings, which occurred at various times from 2000 through 2005. The  Committee and its subcommittees have not met since 2005.
section_title: FDA Response to Findings on Salt
paragraphs: We provided FDA with a draft of this appendix and asked the agency to  provide its views on the impact of these sources’ findings on the GRAS  status of salt. In its response, the agency stated that salt is listed as an  example of a common food ingredient that is regarded as GRAS in Section  182.1(a) of Title 21 of the U.S. Code of Federal Regulations. In 1982, FDA  discussed the GRAS status of uses of salt, opting to defer any change. In  2007, the agency held a public hearing seeking public comment on a  citizen petition seeking to reclassify salt as a food additive, requiring  reductions in the salt content of processed foods. The citizen petition is  actively under review, and FDA has committed to carefully considering  approaches to reducing salt and sodium, with particular attention being  given to consumer-focused efforts intended to improve food choice in  general through public education and potential labeling changes, as well as  focusing on cooperative efforts with the food industry to encourage salt  reductions in the food supply.
With regard to the findings of the Dietary Guidelines for Americans and  the Dietary Reference Intakes, the agency stated they are important facets  of the discussion regarding the safety of dietary sodium. The FDA Food  Advisory Committee has not been asked to comment on the safety of salt  or its regulatory status; however, FDA has taken another approach to get  expert input. FDA is a sponsor of the current effort by the Institute of  Medicine to review and make recommendations about various means that  could be employed to reduce dietary sodium intake to levels  recommended by the Dietary Guidelines for Americans. The Dietary  Guidelines for Americans and the Dietary Reference Intakes report have  informed FDA activities related to salt and sodium. For example, in a 2007  Federal Register notice announcing the “Salt and Sodium Public Hearing,”  both the Dietary Guidelines and Dietary Reference Intakes are cited as  part of the background discussion regarding dietary sodium leading up to  questions about the agency’s approach to salt and sodium.
FDA also indicated that it has the authority to revisit salt’s GRAS status.  The agency has the authority to reevaluate any GRAS ingredient where  questions about the safe use of the ingredient may exist. The agency  considers GRAS determinations for uses of substances to be dependant on  the available science and current evidence of consensus.
The agency also indicated that, since 1982, FDA has primarily relied on  labeling policies and regulation, and consumer education to help reduce  the sodium content of processed foods and to allow consumers to make  more informed choices that will reduce the sodium content of their diets.  These labeling policies require sodium content declaration as part of the  nutrition facts panel present on most processed foods; require limits on  sodium for products labeled as “healthy;” and establish definitions for  foods to be labeled as “low,” “reduced,” or “no” sodium. Additionally, the  agency has authorized health claims for foods low in sodium relating to  reductions in the risk of heart disease. The agency is now re-examining a  variety of approaches for reducing sodium consumption, including, for  example, consumer-focused efforts intended to improve food choices and  cooperative efforts with the food industry to encourage salt reductions in  processed foods.
Regarding whether the agency has the legal authority to regulate the  amount of sodium added to or present in foods, FDA indicated that it has  the legal authority to regulate the safe use of ingredients, including salt,  added to foods in interstate commerce. The agency also noted that other  ingredients, such as sodium bicarbonate, are dietary sources of sodium in  addition to salt, and regulations promulgated regarding the amount of salt  added to foods would not apply to other sodium-containing ingredients, or  to sodium naturally present in foods.
In terms of available regulatory options for reducing the addition of  sodium to processed foods and restaurant foods, FDA indicated that it  could pursue regulatory actions to reduce the addition of sodium to  processed foods, depending on the administrative record it is able to  assemble. For example, food ingredient regulations could be crafted that  would propose to place limits on some uses of salt in processed foods in  interstate commerce. In other cases, for example, foods harvested and  prepared intrastate (as in some restaurants) would not be within FDA’s  statutory authority. However, processed foods in interstate commerce  used by restaurants are subject to FDA’s regulatory authority.
Regarding whether FDA had consulted with the Surgeon General in  determining its regulatory approach to salt in foods, the agency stated that  reports and information from the Surgeon General serve as important  reference materials utilized by the agency, much in the same way that the  Dietary Guidelines for Americans or the Dietary Reference Intakes  reports inform agency activity. The Surgeon General’s Report on  Nutrition and Health (1988) is often cited as one of the driving forces  behind the Nutrition Labeling and Education Act of 1990 that put in place  the legal authority for mandatory nutrition labeling (including sodium  declaration), as well as most of the other labeling initiatives mentioned  previously.
section_title: Trans Fats in Partially Hydrogenated Vegetable Oils
subsections: section_title: Dietary Guidelines for Americans
paragraphs: Health effects. The guidelines found that a high intake of trans fats  increases the risk of unhealthy blood lipid levels, which, in turn, may  increase the risk of coronary heart disease.
Recommended limits. The guidelines found that, to decrease their risk of  elevated low-density lipoprotein cholesterol in the blood, most Americans  need to decrease their intake of trans fats. In fact, the guidelines  recommended that Americans keep consumption of trans fats as low as  possible. They also recommended limiting intake of fats and oils high in  trans fats and choosing products low in such fats and oils.
Actual consumption. The guidelines found that, based on 1994-1996 data,  the estimated average daily intake of trans fats in the United States was  about 2.6 percent of total energy intake. Processed foods and oils provided  approximately 80 percent of trans fats in the diet, compared to 20 percent  that occur naturally in food from animal sources. Because the trans fats  produced in the partial hydrogenation of vegetable oils account for more  than 80 percent of total intake, the food industry has an important role in  decreasing the trans fat content of the food supply. The guidelines also  found that the trans fat content of certain processed foods had decreased  and was likely to continue to decrease as the industry reformulated  products.
Dietary Reference Intakes  Health effects. The intakes report found that there was a body of evidence  suggesting that trans fats increase total cholesterol and low density  lipoprotein cholesterol concentrations in blood and, therefore, the risk of  coronary heart disease. Because the intake of trans fats and risk of  coronary heart disease is a positive linear trend, even very low intakes of  trans fats may increase risk.
Recommended limits. The report recommended that trans fat  consumption be as low as possible while consuming a nutritionally  adequate diet. Because trans fats are not essential and provide no known  benefit to human health, no adequate intake or recommended daily  allowance was set. Moreover, a tolerable upper intake level was not set for  trans fats because the level at which risk begins to increase is very low and  a tolerable level cannot be achieved by usual diets and still have adequate  intakes of all other required nutrients.
Actual consumption. The report noted that estimating the amount of trans  fats in the food supply has been hampered by the lack of an accurate and  comprehensive database from which to derive the data and the trend  toward the reformulation of products over the past decade to reduce  levels. Nevertheless, it also mentioned that early reports suggested a wide  range of trans fat intakes, from 2.6 to 12.8 grams per day, and that the most  recent estimate placed the mean trans fat intake for the U.S. population  aged 3 years and older at 2.6 percent of total energy intake. The report also  noted that, while trans fats are present in dairy products and meats, they  are high in stick margarine and those foods containing vegetable  shortenings that have been subjected to hydrogenation. Examples of foods  that contain relatively high levels of trans fats include cakes, pastries,  doughnuts, and french fries. Therefore, the intake of trans fats can be  reduced without limiting the intake of most essential nutrients by  decreasing the serving size and frequency of intake of these foods, or by  using oils that have not been hydrogenated.
section_title: Food Advisory Committee
paragraphs: The Nutrition Subcommittee of FDA’s Food Advisory Committee met in  April 2004 and answered two questions posed by the agency related to  trans fats:  (1)  The Dietary Guidelines Committee may suggest that less than 1  percent of energy should be obtained from trans fats (2 grams per day  for a 2,000 calorie diet). Does the scientific evidence support this  level?
Members of the subcommittee voted 5-3 to answer the question “no.”  However, a majority of subcommittee members agreed to transmit a  statement to FDA, as an addendum to their response, that although  current scientific evidence did not indicate a specific acceptable daily  intake for trans fats, the evidence was consistent with reducing trans fat  intake to a level of less than 1 percent of energy (2 grams per day for a  2,000 calorie diet).  (2)  When compared to saturated fats, are trans fats considered to be  more, less, or similarly adverse with respect to coronary heart  disease?
The eight members of the subcommittee all voted “yes,” that trans fats are  more adverse with respect to coronary heart disease. One member of the  subcommittee commented that the yes answer did not reflect the  considerable uncertainty discussed by the subcommittee as to whether  this difference is significant from a public health perspective at the level of  trans fat intake that is typical in the United States.
section_title: FDA Response to Findings on Trans Fats in Partially Hydrogenated Vegetable Oils
paragraphs: We provided FDA with a draft of this appendix and asked the agency to  provide its views on the impact of these sources’ findings on the GRAS  status of trans fats in partially hydrogenated vegetable oils. In its response,  the agency stated that partially hydrogenated oils (which contain trans  fats) are considered GRAS based on a history of use prior to 1958. The  partial hydrogenation process was developed in the 1930s and has been in  widespread commercial use since the 1940s. Two partially hydrogenated  oils have been affirmed by FDA as GRAS—partially hydrogenated low  erucic acid rapeseed oil and partially hydrogenated menhaden oil. A  number of “standards of identity” in FDA’s regulations also implicitly  permit their use (for example, those for margarine and shortening). FDA is  in the process of re-evaluating the GRAS status of partially hydrogenated  oils, and has received two citizen petitions on this topic.
With regard to the findings of the Dietary Guidelines for Americans, the  Dietary Reference Intakes, and the FDA Food Advisory Committee, FDA  indicated that it is aware of the findings from these sources and will take  them into account in its review of the GRAS status of trans fat. Previous  versions of the Dietary Guidelines for Americans and the Dietary  Reference Intakes were referenced in the 2003 trans fat labeling rule.
FDA indicated that it has the authority to review and revoke the GRAS  status of partially hydrogenated oils that are used as ingredients  intentionally added to food. The agency also indicated that it has the legal  authority to regulate the amount of trans fat added to foods in interstate  commerce. In addition, the agency noted that naturally occurring trans fats  (such as those in meat and dairy products) would not be subject to  regulatory action.
Regarding what the agency has done to reduce the use of partially  hydrogenated vegetable oils and the levels of trans fat in foods, FDA  indicated that it published a final rule in 2003 (effective on January 1,  2006) that required that trans fat content be declared in the Nutrition Facts  panel of food immediately under the line for saturated fat. As a result of  this labeling change, consumers have additional information to help them  make heart-healthy dietary choices. In addition, because of trans fat  labeling, industry has voluntarily reformulated foods by reducing the  levels of added trans fat. FDA is currently evaluating the effect of trans fat  labeling on daily intake.
In terms of its available regulatory options, FDA indicated that it could  pursue regulatory actions for reducing or eliminating the addition of  partially hydrogenated oils and trans fat to processed food depending on  what actions the administrative record would support. For example, FDA  could propose to revoke the GRAS status of partially hydrogenated  vegetable oils, thereby making such oils unapproved food additives.  Alternatively, FDA could propose to set limits restricting the amount of  trans fat allowed to be added to food in general, or to specific food  categories. FDA also could explore whether it can use labeling authorities  to provide industry with greater incentive to voluntarily reduce trans fat  levels, such as nutrient content claims and disqualifying levels for making  health claims. An increase in consumer outreach also is an option to  encourage consumers to read food labels and avoid trans fats or choose  foods low in trans fat.
Regarding whether FDA had consulted with the Surgeon General in  determining its regulatory approach to partially hydrogenated oils and  trans fat in foods, the agency stated that reports and information from the  Surgeon General serve as important reference materials for the agency.  FDA considers all relevant information when making regulatory decisions  and would consult with the Surgeon General on this issue as necessary.
section_title: Appendix II: Objectives, Scope, and Methodology
paragraphs: The overall objective of this review was to assess the Food and Drug  Administration’s (FDA) oversight of substances generally recognized as  safe (GRAS). Specifically, we assessed the extent to which (1) FDA’s  oversight of new GRAS determinations helps ensure the safety of these  substances; (2) FDA ensures the continued safety of current GRAS  substances as new scientific information emerges; and (3) FDA’s approach  to regulating engineered nanomaterials in GRAS substances helps ensure  the safety of the food supply. We also gathered additional information on  the safety of two GRAS substances—salt and trans fats in partially  hydrogenated vegetable oils—including the views of the Dietary  Guidelines for Americans, Dietary Reference Intakes, and FDA’s Food  Advisory Committee; this information is discussed in Appendix I.
To address the extent to which FDA’s oversight of GRAS determinations  helps ensure the safety of these substances, we reviewed applicable laws  and regulations. Specifically, we reviewed relevant portions of the Federal  Food, Drug, and Cosmetic Act, including provisions added and modified by  the Food Additives Amendment of 1958, and FDA’s 1997 proposed rule,  which describes the GRAS voluntary notification program. We also  reviewed the public comments made on the proposed rule by 32  commenters. In addition, we obtained information on the agency’s oversight  of GRAS determinations from FDA officials and documentation they  provided. We reviewed FDA’s 2007 Food Protection Plan and the 2007  Action Plan for Import Safety issued by a 12-agency working group with  FDA participation, and we obtained various FDA guidance documents on  conflict of interest. We also obtained information about FDA’s Everything  Added to Food in the United States (EAFUS) and Priority-Based  Assessment of Food Additives databases from FDA’s Web site and agency  officials. We developed information on the history of FDA’s implementation  of the GRAS program from information on FDA’s Web site and other  sources. We gathered information on the 274 GRAS notices submitted to  FDA between 1998 and 2008 from FDA’s Web site. We then analyzed this  information to determine: the number of notices filed, FDA’s response to  each notice, and the amount of time it took FDA to complete its review of  each notice. We compared the number of days it took FDA to respond to a  notice to the 180-day time frame the agency has adopted as a goal for  completing most reviews. To assess the reliability of the data on GRAS  notices from FDA’s Web site, we interviewed FDA officials regarding the  processes they follow to enter the data and ensure they are complete and  accurate. We also reviewed related documentation and examined the data  to identify any obvious errors or inconsistencies. Based on this assessment,  we concluded that the data from FDA’s Web site were sufficiently reliable  for the purposes of this report.
To obtain the views of stakeholders on the GRAS process, we interviewed  representatives from (1) trade associations, including the Grocery  Manufacturers Association and the International Food Additive  Council/Calorie Control Council; (2) companies, including a company that  had notified FDA of several GRAS determinations and a company we  identified as having made a GRAS determination without notifying FDA;  (3) consumer groups, including Consumers Union, the Center for Science  in the Public Interest, and Food and Water Watch; (4) authoritative bodies,  including the Institute of Medicine of the National Academies, the Institute  of Food Technologists, and United States Pharmacopeia; and (5) academic  institutions, including the George Washington University and the  University of Maryland. In addition, we obtained information about the  Flavor and Extract Manufacturers Association’s GRAS determination  process from its representatives and from FDA officials.
To determine the extent to which FDA ensures the continued safety of  GRAS substances, we analyzed the 11 citizen petitions regarding GRAS  substances that were submitted to FDA during the recent 5-year period from  2004 through 2008, and discussed with FDA officials the agency’s response  to these petitions. Specifically, we first asked FDA to identify citizen  petitions related to GRAS substances; in its response, FDA identified  whether these petitions had been closed or were still pending. We then  obtained documentation related to the petitions filed between 2004 and  2008, including the petition itself, any FDA correspondence with the  petitioner, and documents demonstrating FDA’s review of the petition. In  addition, we discussed with FDA officials how they ensure the continued  safety of GRAS substances, including whether they have revoked the GRAS  status of any substance, retracted any no questions letter for any GRAS  notice, or taken any other actions affecting the status of GRAS substances.  We also reviewed a previous reconsideration of GRAS determinations  carried out by the Select Committee on GRAS Substances in the 1970s and  1980s and analyzed FDA’s response to the committee’s recommendations.  Finally, we reviewed documents from the Flavor and Extract Manufacturers  Association on its process to ensure the continued safety of its GRAS  determinations and discussed this process with association representatives.
To assess whether FDA’s approach to regulating engineered nanomaterials  as GRAS helps ensure the safety of the food supply, we reviewed FDA’s  policies related to regulating engineered nanomaterials in food.  Specifically, we reviewed FDA’s July 2007 nanotechnology taskforce  report, which examined how nanotechnology might affect the products  the agency regulates, including its potential applications in food; and we  gathered information on the status of implementing the taskforce’s  recommendations from agency officials. In addition, we met with officials  at the Environmental Protection Agency to discuss that agency’s  Nanoscale Materials Stewardship Program and reviewed related  documentation. To identify a nonprobability sample of foreign entities that  are particularly active in considering regulation of engineered  nanomaterials in food, we first spoke with representatives from the  Woodrow Wilson International Center for Scholars Project on Emerging  Nanotechnologies and an academic expert on nanotechnology from the  University of Michigan identified by an official at the National Academies’  Institute of Medicine. These experts identified Canada, the United  Kingdom, the European Union, and the United Nations as being  particularly active on this issue. However, after reviewing documentation  from each of these entities and discussions with their officials, we  eliminated the United Kingdom and the United Nations as sources  because, while they have taken certain steps to investigate the safety of  nanotechnology in food, they are not directly responsible for regulating  nanotechnology in food. To examine Canada’s efforts in this area, we  reviewed a September 2008 study conducted by an expert panel at the  request of the Canadian Minister of Health and interviewed officials from  Health Canada, the federal department responsible for helping Canadians  maintain and improve their health, and the Canadian Food Inspection  Agency, the department in charge of the safety of the Canadian food  supply. To examine the European Union’s efforts, we reviewed the  European Food Safety Authority’s February 2009 scientific opinion on  nanotechnology in food and interviewed officials from the European  Union’s Directorate General for Health and Consumers and from the  European Food Safety Authority. We did not independently verify  statements of foreign law. We also collected the views of a variety of  stakeholders on engineered nanomaterials in food, including  representatives from the Woodrow Wilson International Center for  Scholars Project on Emerging Nanotechnologies, the International Center  for Technology Assessment, and Food and Water Watch. Finally, we  attended the Food and Drug Law Institute’s Second Annual Conference on  Nanotechnology Law, Regulation, and Policy held in February 2009.
To present more detailed information on two GRAS substances—salt and  trans fats in partially hydrogenated vegetable oils—we gathered the views  of expert organizations on the safety of these substances. Specifically, we  collected the views on these substances expressed in the Dietary  Reference Intakes, publications that provide recommended levels  considered safe for consumption of a wide range of nutrients, issued by  the Institute of Medicine of the National Academies; the Dietary  Guidelines for Americans, 2005, authoritative guidelines that serve as the  basis for Federal food and nutrition education programs, issued by the  Departments of Agriculture and of Health and Human Services; and the  views of FDA’s Food Advisory Committee, which provides advice to FDA  on emerging food safety, food science, nutrition, and other food-related  health issues. We then presented this information to FDA officials to  gather their reaction on the impact of these views on the GRAS status of  these substances. Our findings are presented in appendix I.
We conducted this performance audit from October 2008 to February  2010, in accordance with generally accepted government auditing  standards. Those standards require that we plan and perform the audit to  obtain sufficient, appropriate evidence to provide a reasonable basis for  our findings and conclusions based on our audit objectives. We believe  that the evidence obtained provides a reasonable basis for our findings  and conclusions based on our audit objectives.
section_title: Appendix III: Illustration of Options Available to a Company Submitting a Notice to the Food and Drug Administration’s (FDA) Generally Recognized as Safe (GRAS) Voluntary Notification Program
paragraphs: Appendix III: Illustration of  Availa to the Food and Gener Voluntarble to a Company Submitting a Notice  Drug Administration’s (FDA) ally Recognized as Safe (GRAS)
FDA has no qution abt the bas for the compny’ determintion (not the same as FDA pprovl or greement)
section_title: Appendix IV: Comments from the Food and Drug Administration
section_title: Appendix V: GAO Contact and Staff Acknowledgments
subsections: section_title: Staff Acknowledgments
paragraphs: In addition to the individual named above, James R. Jones, Jr., Assistant  Director; Nico Sloss, Analyst in Charge; Kevin Bray; James J. Burns; Anne  Rhodes-Kline; Bruce Skud; and Carol Herrnstadt Shulman made key  contributions to this report. Also contributing to this report were Hai Tran  and Elizabeth Erdmann.