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Ingredients Determined to Be Generally Recognized as Safe (GRAS)' 
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Report to Congressional Requesters: 

United States Government Accountability Office: 
GAO: 

February 2010: 

Food Safety: 

FDA Should Strengthen Its Oversight of Food Ingredients Determined to 
Be Generally Recognized as Safe (GRAS): 

GAO-10-246: 

GAO Highlights: 

Highlights of GAO-10-246, a report to congressional requesters. 

Why GAO Did This Study: 

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. 

What GAO Found: 

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. 

What GAO Recommends: 

GAO recommends that FDA take steps to better ensure the safety of GRAS 
substances, including developing a strategy to require any company 
that conducts a GRAS determination to provide FDA with basic 
information about it. FDA generally agreed, while raising concerns 
about certain aspects of several of the recommendations. 

View [hyperlink, http://www.gao.gov/products/GAO-10-246] or key 
components. For more information, contact Lisa Shames at (202) 512-
3841 or shamesl@gao.gov. 

[End of section] 

Contents: 

Letter: 

Background: 

FDA's Oversight Process Does Not Help Ensure the Safety of All New 
GRAS Determinations: 

FDA Is Not Systematically Ensuring the Continued Safety of Current 
GRAS Substances: 

FDA's Regulatory Approach Allows Engineered Nanomaterials to Enter the 
Food Supply without the Agency's Knowledge: 

Conclusions: 

Recommendations for Executive Action: 

Agency Comments and Our Evaluation: 

Appendix I: Additional Information on Selected Generally Recognized as 
Safe (GRAS) Substances: 

Appendix II: Objectives, Scope, and Methodology: 

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: 

Appendix IV: Comments from the Food and Drug Administration: 

Appendix V: GAO Contact and Staff Acknowledgments: 

Tables: 

Table 1: FDA Responses to GRAS Notices Received under Voluntary 
Notification Program, 1998-2008: 

Table 2: FDA Performance in Meeting 180-Day Time Frame for Completing 
Review of GRAS Notices, 1998-2008: 

Table 3: Comparison of the Transparency of FDA's Voluntary 
Notification Program, Company GRAS Determinations without Notification 
to FDA, and the Flavor and Extract Manufacturers Association's GRAS 
Determinations: 

Table 4: Status of FDA Response to Citizen Petitions on GRAS 
Substances Filed from 2004 through 2008: 

Table 5: Selected Actions Recommended by FDA's Nanotechnology 
Taskforce in July 2007 and Status of Their Implementation: 

Table 6: Recommendations from the Dietary Guidelines for Americans, 
2005, on Daily Levels of Sodium and Salt in the Diet: 

Table 7: Dietary Reference Intakes Recommendations on Daily Levels of 
Sodium and Salt in the Diet: 

Figures: 

Figure 1: Timeline of Significant Events in FDA's GRAS Program: 

Figure 2: FDA's Annual Performance in Meeting the 180-Day Time Frame 
for Completing GRAS Notice Reviews, 1998-2008: 

Figure 3: Options Available to a Company Participating in the GRAS 
Voluntary Notification Program: 

Abbreviations: 

EAFUS: Everything Added to Food in the United States: 

EPA: Environmental Protection Agency: 

FDA: Food and Drug Administration: 

GRAS: generally recognized as safe: 

[End of section] 

United States Government Accountability Office:
Washington, DC 20548: 

February 3, 2010: 

The Honorable Tom Harkin:
Chairman:
Committee on Health, Education,
Labor and Pensions:
United States Senate: 

The Honorable Rosa L. DeLauro:
Chair:
Subcommittee on Agriculture, Rural Development, Food and Drug 
Administration and Related Agencies:
Committee on Appropriations:
House of Representatives: 

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.[Footnote 1] 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,[Footnote 2] Dietary Reference 
Intakes,[Footnote 3] 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. 

Background: 

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. 

Figure 1: Timeline of Significant Events in FDA's GRAS Program: 

[Refer to PDF for image: illustration] 

1958: Food Additives Amendment of 1958 passes. 

1959: FDA issues first GRAS list. 

1969: President orders review of existing GRAS substances. 

1972: FDA begins GRAS petition affirmation process. 

1982: Select committee’s independent review of existing GRAS 
substances ends. 

1997: FDA proposes GRAS notification program and, under an interim 
policy discussed in the proposal, begins implementation. 

Source: GAO analysis of FDA information. 

[End of figure] 

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.[Footnote 4] 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. 

FDA's Oversight Process Does Not Help Ensure the Safety of All New 
GRAS Determinations: 

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. 

FDA Reviews Those GRAS Determinations that Companies Choose to Submit: 

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. 

Table 1: FDA Responses to GRAS Notices Received under Voluntary 
Notification Program, 1998-2008: 

FDA response: FDA has no questions; 
Number of response letters: 211; 
Percentage of responses: 77%. 

FDA response: Notice does not provide a basis for a GRAS determination; 
Number of response letters: 16; 
Percentage of responses: 6%. 

FDA response: At company's request, FDA ceased to evaluate the notice; 
Number of response letters: 41; 
Percentage of responses: 15%. 

FDA response: Pending; 
Number of response letters: 6; 
Percentage of responses: 2%. 

FDA response: Total; 
Number of response letters: 274; 
Percentage of responses: 100%. 

Source: GAO analysis of FDA data. 

Notes: (1) In 16 cases, companies resubmitted the notice after 
withdrawing it and in 6 cases, companies resubmitted the notice after 
FDA stated the notice did not provide a basis for a GRAS 
determination; FDA assigns a new GRAS notice number when substances 
are resubmitted. (2) Data are as of October 29, 2009. 

[End of table] 

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. 

Table 2: FDA Performance in Meeting 180-Day Time Frame for Completing 
Review of GRAS Notices, 1998-2008: 

Amount of time for FDA to complete review after receiving notice: 
Within 180 days; 
Number of notices: 175; 
Percentage of notices: 64%. 

Amount of time for FDA to complete review after receiving notice: 181 
or more days; 
Number of notices: 93; 
Percentage of notices: 34%. 

Amount of time for FDA to complete review after receiving notice: 
Pending[A]; 
Number of notices: 6; 
Percentage of notices: 2%. 

Amount of time for FDA to complete review after receiving notice: 
Total; 
Number of notices: 274; 
Percentage of notices: 100%. 

Source: GAO analysis of FDA data. 

Notes: (1) Until 2001, FDA's goal was to complete its review of 
companies' notices within 90 days of receipt. (2) Data are as of 
October 29, 2009. 

[A] In these cases, FDA has not completed its review of the company's 
notice. 

[End of table] 

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. 

Figure 2: FDA's Annual Performance in Meeting the 180-Day Time Frame 
for Completing GRAS Notice Reviews, 1998-2008: 

[Refer to PDF for image: stacked vertical bar graph] 

Year: 1998; 
Within 180 days: 9; 
181 or more days: 3; 
Pending: 0. 

Year: 1999; 
Within 180 days: 16; 
181 or more days: 7; 
Pending: 0. 

Year: 2000; 
Within 180 days: 18; 
181 or more days: 12; 
Pending: 0. 

Year: 2001; 
Within 180 days: 24; 
181 or more days: 4; 
Pending: 0. 

Year: 2002; 
Within 180 days: 25; 
181 or more days: 1; 
Pending: 0. 

Year: 2003; 
Within 180 days: 19; 
181 or more days: 4; 
Pending: 0. 

Year: 2004; 
Within 180 days: 17; 
181 or more days: 3; 
Pending: 0. 

Year: 2005; 
Within 180 days: 13; 
181 or more days: 13; 
Pending: 0. 

Year: 2006; 
Within 180 days: 17; 
181 or more days: 10; 
Pending: 3. 

Year: 2007; 
Within 180 days: 2; 
181 or more days: 16; 
Pending: 2. 

Year: 2008; 
Within 180 days: 15; 
181 or more days: 20; 
Pending: 1. 

Source: GAO analysis of FDA data. 

Note: Data on pending reviews are current as of October 29, 2009. 

[End of figure] 

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. 

FDA Generally Has No Information about GRAS Determinations That Are 
Not Submitted to Its Notification Program: 

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.[Footnote 5] 

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; 
[Footnote 6] 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.[Footnote 7] 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. 

FDA Has Not Taken Steps that Could Help Ensure the Safety of GRAS 
Determinations: 

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.[Footnote 8] 

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. 

A Trade Association Informs FDA of Its GRAS Determinations, Even 
Though It Does Not Participate in the Agency's Voluntary Notification 
Program: 

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. 

Table 3: Comparison of the Transparency of FDA's Voluntary 
Notification Program, Company GRAS Determinations without Notification 
to FDA, and the Flavor and Extract Manufacturers Association's GRAS 
Determinations: 

GRAS process: FDA voluntary notification program; 
FDA is informed about GRAS determinations: Yes; 
FDA is informed about scientific basis of GRAS determination: Yes; 
Information about GRAS determinations publicly available: Yes; 
Number of GRAS substances: 274[A]. 

GRAS process: Company GRAS determination without notification to FDA; 
FDA is informed about GRAS determinations: No; 
FDA is informed about scientific basis of GRAS determination: No; 
Information about GRAS determinations publicly available: No; 
Number of GRAS substances: Unknown. 

GRAS process: Flavor and Extract Manufacturers Association GRAS 
determination; 
FDA is informed about GRAS determinations: Yes; 
FDA is informed about scientific basis of GRAS determination: Yes; 
Information about GRAS determinations publicly available: Yes; 
Number of GRAS substances: 2,648[B]. 

Source: GAO analysis of FDA and Flavor and Extract Manufacturers 
Association data. 

[A] For the period 1998 through 2008. 

[B] For the period 1960 through June 2009. 

[End of table] 

FDA incorporates the information provided by the Flavor and Extract 
Manufacturers Association about its GRAS substances into the agency's 
toxicological database,[Footnote 9] 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. 

FDA Is Not Systematically Ensuring the Continued Safety of Current 
GRAS Substances: 

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. 

FDA Does Not Systematically Reconsider the Safety of GRAS Substances 
as New Information Becomes Available: 

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.[Footnote 10] 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. 

Table 4: Status of FDA Response to Citizen Petitions on GRAS 
Substances Filed from 2004 through 2008: 

Subject of citizen petition: Milk protein concentrate; 
Concerns raised: Lack of evidence for GRAS status; 
Date filed: 4/28/2004; 
180-day letter sent: No; 
Decision: Pending. 

Subject of citizen petition: Partially hydrogenated vegetable oils; 
Concerns raised: Increased risk of coronary heart disease from trans 
fats; 
Date filed: 5/18/2004; 
180-day letter sent: 12/21/2004; 
Decision: Pending. 

Subject of citizen petition: Aluminum-based food additives; 
Concerns raised: Link to Alzheimer's disease and elderly cognitive 
impairment; 
Date filed: 9/14/2005; 
180-day letter sent: 3/13/2006; 
Decision: Pending. 

Subject of citizen petition: Salt; 
Concerns raised: Risk of elevated blood pressure from excess 
consumption of salt; 
Date filed: 11/8/2005; 
180-day letter sent: 6/5/2006; 
Decision: Pending. 

Subject of citizen petition: Carbon monoxide gas in fresh meat 
packaging; 
Concerns raised: Consumer deception and food safety risks; 
Date filed: 11/15/2005; 
180-day letter sent: No; 
Decision: Pending. 

Subject of citizen petition: Carbon monoxide gas in fresh tuna 
packaging; 
Concerns raised: Consumer deception and food safety risks; 
Date filed: 3/16/2006; 
180-day letter sent: No; 
Decision: Pending. 

Subject of citizen petition: Diacetyl; 
Concerns raised: Lung disease and impairment from inhalation of the 
substance; 
Date filed: 9/12/2006; 
180-day letter sent: 3/6/2007; 
Decision: Pending. 

Subject of citizen petition: Iodized salt; 
Concerns raised: Lack of information on food ingredient labels; 
Date filed: 5/7/2007; 
180-day letter sent: 11/2/2007; 
Decision: Pending. 

Subject of citizen petition: Monosodium glutamate; 
Concerns raised: Substance's links to rise in obesity, diabetes, and 
autism; 
Date filed: 12/28/2007; 
180-day letter sent: 7/18/2008; 
Decision: Pending. 

Subject of citizen petition: Carrageenan and similar substances; 
Concerns raised: Harmful effects on human intestinal cells; 
Date filed: 6/11/2008; 
180-day letter sent: 12/9/2008; 
Decision: Pending. 

Subject of citizen petition: Stevia extracts; 
Concerns raised: Therapeutic uses of the substances and questions 
about their safety; 
Date filed: 10/7/2008; 
180-day letter sent: 12/16/2008; 
Decision: Petition denied. 

Source: GAO analysis of FDA data. 

Note: Information in the table is as of December 2009. 

[End of table] 

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. 

FDA Is Generally Not Aware of Companies' Reconsiderations of their 
GRAS Determinations: 

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. 

FDA's Regulatory Approach Allows Engineered Nanomaterials to Enter the 
Food Supply without the Agency's Knowledge: 

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. 

Nanotechnology Presents Potential Challenges to the Regulation of Food 
Safety: 

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. 

Companies May Market Engineered Nanomaterials as GRAS without 
Informing FDA: 

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.[Footnote 11] 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. 

FDA Has Issued Some Guidance to Companies on Nanotechnology in Food: 

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. 

Table 5: Selected Actions Recommended by FDA's Nanotechnology 
Taskforce in July 2007 and Status of Their Implementation: 

Recommended action: Issue guidance to companies regarding 
identification of the particle size for products not subject to 
premarket authorization, but for which the company may choose to 
provide notice (such as a GRAS notification); 
Status of implementation: Implemented. 

Recommended action: Issue a notice in the Federal Register requesting 
submission of data and other information addressing the effects on 
product safety of nanoscale materials in products not subject to 
premarket authorization. The notice would address both new products 
made with nanoscale materials and existing products that are changed 
to include or include greater proportions of nanoscale materials; 
Status of implementation: Implemented. 

Recommended action: Issue guidance or amend existing guidance to 
describe what additional or distinct information should be submitted 
to FDA or generated with regard to the use of nanoscale materials in 
food ingredients for which a GRAS notification is submitted or the 
reduction of particle size into the nanoscale range for food 
ingredients for which an earlier notification had been submitted and 
not objected to by FDA; 
Status of implementation: Not implemented. 

Recommended action: Issue guidance recommending manufacturers consider 
whether and how the presence of nanoscale materials affects the 
manufacturing process. Relevant considerations would include both 
situations when the product contains nanoscale materials and when any 
part of the manufacturing process involves nanoscale materials, even 
if those materials do not become part of the finished product; 
Status of implementation: Not implemented. 

Source: GAO analysis of FDA information. 

[End of table] 

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. 

Food Ingredients That Incorporate Engineered Nanomaterials Must Be 
Reviewed in Other Countries Before They Can Be Marketed: 

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. 

Conclusions: 

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. 

Recommendations for Executive Action: 

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. 

Agency Comments and Our Evaluation: 

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 [hyperlink, 
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. 

Signed by: 

Lisa Shames: 
Director, Natural Resources and Environment: 

[End of section] 

Appendix I: Additional Information on Selected Generally Recognized as 
Safe (GRAS) Substances: 

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.[Footnote 12] 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.[Footnote 13] 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. 

Salt: 

Dietary Guidelines for Americans: 

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.[Footnote 14] The guidelines also 
recommended choosing and preparing foods with little salt and 
consuming potassium-rich foods, such as fruits and vegetables. 

Table 6: Recommendations from the Dietary Guidelines for Americans, 
2005, on Daily Levels of Sodium and Salt in the Diet: 

Population: General population; 
Recommended limits of sodium intake: <2.3 grams; 
Equivalent amount of salt: <5.9 grams. 

Population: Middle-aged; 
Recommended limits of sodium intake: 1.5[A] grams; 
Equivalent amount of salt: 3.8[A] grams. 

Population: Older adults; 
Recommended limits of sodium intake: 1.5[A] grams; 
Equivalent amount of salt: 3.8[A] grams. 

Population: Individuals with hypertension; 
Recommended limits of sodium intake: 1.5[A] grams; 
Equivalent amount of salt: 3.8[A] grams. 

Population: African Americans; 
Recommended limits of sodium intake: 1.5[A] grams; 
Equivalent amount of salt: 3.8[A] grams. 

Source: GAO analysis of Dietary Guidelines for Americans, 2005 data. 

[A] Individuals in these groups should also meet the potassium 
recommendation (4.7 grams per day) with food. 

[End of table] 

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.[Footnote 15] 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. 

Table 7: Dietary Reference Intakes Recommendations on Daily Levels of 
Sodium and Salt in the Diet: 

Population: Young adults (age 19-50); 
Adequate intake for sodium: 1.5 grams; 
Equivalent adequate intake for salt: 3.8 grams; 
Tolerable upper intake level for sodium: 2.3 grams; 
Equivalent tolerable upper intake level for salt: 5.9 grams. 

Population: Older adults (age 50-70); 
Adequate intake for sodium: 1.3 grams; 
Equivalent adequate intake for salt: 3.3 grams; 
Tolerable upper intake level for sodium: 2.3 grams; 
Equivalent tolerable upper intake level for salt: 5.9 grams. 

Population: Elderly (over age 70); 
Adequate intake for sodium: 1.2 grams; 
Equivalent adequate intake for salt: 3.1 grams; 
Tolerable upper intake level for sodium: 2.3 grams; 
Equivalent tolerable upper intake level for salt: 5.9 grams. 

Source: GAO analysis of Dietary Reference Intakes for Water, 
Potassium, Sodium, Chloride, and Sulfate data. 

[End of table] 

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. 

Food Advisory Committee: 

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. 

FDA Response to Findings on Salt: 

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. 

Trans Fats in Partially Hydrogenated Vegetable Oils: 

Dietary Guidelines for Americans: 

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. 

Food Advisory Committee: 

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. 

FDA Response to Findings on Trans Fats in Partially Hydrogenated 
Vegetable Oils: 

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. 

[End of section] 

Appendix II: Objectives, Scope, and Methodology: 

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[Footnote 16] and the 2007 Action Plan for Import Safety[Footnote 
17] 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.[Footnote 18] 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,[Footnote 19] 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[Footnote 20] 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[Footnote 21] 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. 

[End of section] 

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: 

Figure 3: Options Available to a Company Participating in the GRAS 
Voluntary Notification Program: 

[Refer to PDF for image: illustration] 

1) Company decides it wants to add substance X to its cereal. 

2) Company conducts a determination of whether substance X is 
generally recognized as safe for this particular use. 

3) Company determines no: Go to step 9. 

4) Company determines yes. 

5) Company submits a GRAS notice to FDA. 

6) Company adds substance X to its cereal and markets it. 

7) FDA’s goal is to review most notices within 180 days; three 
possible outcomes: 
* FDA says notice does not provide a basis for a GRAS determination: 
go to step 8 and 9; 
* At company’s request, FDA ceases to evaluate the notice: go to step 
9; 
* FDA has no questions about the basis for the company’s determination 
(not the same as FDA approval or agreement): return to step 6. 

8) Company does additional work and resubmits GRAS notice; return to 
step 7. 

9) Depending on the issues involved, company could decide not to 
include substance X in its cereal or take necessary steps to develop a 
food additive petition. 

Source: GAO analysis of FDA information. 

Notes: (1) This graphic shows some of the steps in FDA's voluntary 
notification program and options potentially available to a company; 
it is not intended to show all possible variations. For a more 
detailed description of the program, see FDA's "Guidance for Industry: 
Frequently Asked Questions About GRAS" at [hyperlink: 
http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/Guidance
Documents/FoodIngredientsandPackaging/ucm061846.htm] (accessed 
December 11, 2009). (2) At any point, a company might decide not to 
include the substance in its product or might proceed to market 
without FDA's response; if the use of a food substance is GRAS, it is 
not subject to premarket review and approval by FDA. (3) The analysis 
assumes the company is acting in accordance with the law; while 
participation in the notification program is voluntary, companies must 
comply with the law. (4) Regardless of whether the use of a substance 
is a food additive use or is GRAS, there must be evidence that the 
substance is safe under the conditions of its intended use; a GRAS 
substance is distinguished from a food additive on the basis of the 
common knowledge about the safety of the substance for its intended 
use. 

[End of figure] 

[End of section] 

Appendix IV: Comments from the Food and Drug Administration: 

Department Of Health & Human Services: 
Office Of The Secretary: 
Assistant Secretary for Legislation: 
Washington, DC 20201: 

January 21, 2010: 

Lisa Shames: 
Director: 
Natural Resources and Environment: 
Government Accountability Office: 
441 G Street NW: 
Washington, DC 20548: 

Dear Ms. Shames: 

Enclosed are the Department's comments on the U.S. Government 
Accountability Office's (GAO) draft report entitled: "Food Safety: FDA 
Should Strengthen Its Oversight of Food Ingredients Determined to Be 
Generally Recognized as Safe (GRAS) (GAO-10-246).
The Department appreciates the opportunity to review and comment on 
this report before its publication. 

Sincerely, 

Signed by: 

Andrea Palm: 
Acting Assistant Secretary for Legislation: 

Enclosure: 

[End of letter] 

General Comments Of The Department Of Health And Human Services (HHS) 
On The Government Accountability Office's (GAO) Draft Report Entitled, 
"Food Safety: FDA Should Strengthen Its Oversight Of Food Ingredients 
Determined To Generally Recognized As Safe (GRAS)" (GAO-10-246): 

Introduction: 

The Department appreciates the opportunity to review and comment on 
the Government Accountability Office's (GAO's) draft report. The GAO 
report identifies important challenges that FDA faces when overseeing 
the safety of all food ingredients and new food technologies, not just 
those classified as generally recognized as safe (GRAS) for their 
intended use. The FDA is committed to exercising all its legal 
authorities and making efficient use of its resources to ensure the 
safety of substances added intentionally to food. 

In 2009, FDA initiated internal discussions centered on developing a 
strategy for improving the agency's oversight of all ingredients added 
to food, either indirectly or directly. Thus, FDA welcomes GAO's 
review and recommendations and regards the report as an important 
contribution to FDA's internal deliberations. Any new strategies FDA 
develops would build on positive aspects of FDA's current pre-market 
review programs for food ingredients (i.e., food contact substances, 
food additives, and GRAS substances) and improve the agency's ability 
to conduct appropriate pre- and post-market reviews of the safety of 
ingredients added to food, based on current and emerging data and 
information. 

As discussed more fully in the FDA's comments that follow, the Federal 
Food, Drug, and Cosmetic Act has several criteria that must be met 
before the intended use of the substance in food can be generally 
recognized as safe (GRAS): that its safety be established 
scientifically (or by common use prior to 1958), and that the basis 
for concluding it is safe mutt be generally accepted, publicly 
available, and transparent to experts. The parties producing or using 
the substance have the ultimate burden of proof with respect to 
demonstrating its safety for the intended use, and because a GRAS 
determination is time-dependent, the GRAS status could change as new 
science or factual data become available. 

The law requires new food substances or new uses of substances to be 
approved by FDA prior to marketing unless the substance is GRAS for 
its intended use, with sponsors being allowed under the law to make 
their own independent determination of the GRAS status of a new 
ingredient or use. As outlined in these comments, however, the same 
safety standards and public health principles apply to all added food 
ingredients (other than prior-sanctioned substances), whether FDA 
approval is required or not. 

The GRAS concept was included in the law as a means to avoid wasteful 
use of government and industry resources in formal approval processes 
when the safety of an ingredient has already been established and is 
recognized by qualified experts. The GRAS concept has served well as a 
source of flexibility to avoid unnecessary FDA reviews of substances 
with a long history of safe use in food, as well as new substances and 
uses of substances whose safety is well-established and known. 

As the implementation of the GRAS concept has evolved since its 
enactment in 1958, however, it has become the general rule, rather 
than the exception, that new substances and new uses of substances 
enter the market on the basis of the sponsor's independent safety 
assessment and GRAS determination, rather than through approval by 
FDA. FDA has established a voluntary mechanism for companies to notify 
the agency of independent GRAS determinations, but, as the GAO report 
points out, the inherent nature of the GRAS concept and the evolution 
in its implementation raise legitimate questions about the scope of 
FDA's knowledge concerning the uses of food ingredients and the 
ability of FDA to assess and ensure the rigor of the scientific 
evaluations underlying independent GRAS determinations. 

The existence of these questions impinges on one of the goals that 
motivated adoption of the law governing food ingredients, namely 
ensuring public confidence in their safety based on affirmative FDA 
oversight, and is one of the reasons FDA is reviewing how it oversees 
food ingredient safety. New food technologies, such as nanotechnology, 
further challenge FDA's ability to ensure the safety of added food 
substances. 

The GAO's draft report responds to legitimate questions about the GRAS 
concept and FDA's implementation of it by making several 
recommendations aimed at strengthening the rigor of independent GRAS 
determinations, improving FDA's awareness of and oversight of GRAS 
determinations, and strengthening post-market oversight of GRAS 
substances to address new safety questions. FDA believes that the GRAS 
concept has continuing utility as a practical tool for distinguishing 
between substances and new uses of substances that merit a full pre-
market safety evaluation by FDA and those that do not. FDA also agrees 
broadly, however, that its oversight of GRAS substances and the manner 
in which independent GRAS determinations are made should be 
strengthened, and the agency will fully consider GAO's recommendations 
and other ideas when it moves to finalize the regulation governing the 
current voluntary GRAS notification program. 

FDA is actively considering steps it can take under current law to 
improve both pre-market and post-market oversight of all added food 
substances, whether they enter the market based on a GRAS 
determination or through a formal FDA approval process. In particular, 
FDA believes 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. 
FDA also agrees with GAO that there is a need for enhancement of post-
market oversight, including more effective tools for FDA to obtain 
from sponsors new information related to the safety of marketed food 
ingredients so that FDA is better able to identify substances meriting 
a substantive post-market review. Implementation of these ideas would 
require additional resources, and some may require new legislation. 

Regulatory Framework for Food Ingredients under Section 409 of the 
Federal Food, Drug, and Cosmetic Act: 

In 1958, Congress enacted the Food Additives Amendment (the 1958 
amendment) to the Federal Food, Drug, and Cosmetic Act (the Act). The 
1958 amendment requires that, before a new additive can be used in 
food, its safety must be demonstrated to the satisfaction of the FDA 
(i.e., premarket approval). The 1958 amendment, however, also exempted 
several categories of substances from the definition of a "food 
additive," including food ingredients that are generally recognized as 
safe (GRAS) for their intended conditions of use (the GRAS exemption), 
which is discussed in greater detail below, and food ingredients used 
in accordance with a "sanction" granted by either FDA or the U.S. 
Department of Agriculture prior to 1958. Therefore, these exempted 
food ingredients are not subject to FDA's pre-market review for food 
additives. 

Under section 409 of the Act, if FDA grants a petition for a food 
additive, it is required to by order establish a regulation that 
specifies the conditions under which the additive may be safely used. 
In addition to a regulation, there are other administrative actions 
pertaining to a food additive petition that involve publications in 
the Federal Register, including the decision to file a petition, deny 
a petition, stay the effective date of a regulation, respond to 
objections, respond to a request for a hearing, and amend or repeal a 
regulation. Rulemaking is also required for FDA to obtain data and 
information to substantiate the safety of an interim food additive or 
to remove the additive from the market in light of information 
establishing a safety concern. FDA must also initiate rulemaking to 
adopt new food additive specifications of identity and purity or to 
otherwise amend conditions for the safe use of food substances in its 
regulations. These administrative procedures for food additives are 
cumbersome and costly but add little to the quality of FDA's 
scientific review. Moreover, they provide a disincentive for firms to 
seek approval of new ingredients as food additives and an incentive 
for them to make independent GRAS determinations. Thus, a lack of 
sufficient resources and the time consuming and resource intensive 
process of rulemaking has often slowed or prevented the FDA from 
adopting through rulemaking more modem standards even if they improve 
food safety and are widely implemented by the food industry. 

The GRAS Exemption: 

It is on the basis of the GRAS exemption to the food additive 
definition that many substances are lawfully added to food without 
premarket approval by FDA. In establishing the GRAS exemption, 
Congress determined that many substances intentionally added to food 
should not require a formal premarket review by FDA to ensure their 
safety, either because their safety had been established by a long 
history of use in food or because their safety had been established by 
the information generally available to, and accepted by, qualified 
scientists about the substances. 

Specifically, under the Act and FDA's regulations, use of a food 
ingredient may be GRAS through scientific procedures, which include 
both a technical element and a common knowledge element, as explained 
in greater detail below. In addition, an ingredient used in food 
before 1958 may be GRAS instead of through experience that the 
intended conditions of use are safe based on common use in food. 

Under "scientific procedures," a GRAS determination for a particular 
use of a substance requires both technical evidence of safety 
(technical element) and a basis to conclude that this technical 
evidence of safety is generally known and accepted (the common 
knowledge element). 

The technical element of the GRAS standard requires that information 
about the substance establish that the intended use of the substance 
is safe. FDA has defined "safe" (21 CFR 170.3(i)) as a reasonable 
certainty in the minds of competent scientists that the substance is 
not harmful under its intended conditions of use. The same quality and 
quantity of data and information are necessary to establish the safety 
of the use of a GRAS substance as for a food additive use. 

The common knowledge element of the GRAS standard includes two 
criteria: (1) the data and information relied on to establish the 
technical element must be generally available; and (2) there must be a 
basis to conclude that there is consensus among qualified experts 
about the safety of the substance for its intended use. Neither 
criterion is, by itself, sufficient to satisfy the common knowledge 
element of the GRAS standard. 

As described below, FDA lists a number of food ingredients in its 
regulations that it considers to be GRAS. In addition to the 
ingredients listed in FDA's regulations, a company can make an 
independent determination that the use of a substance is GRAS. If FDA 
does not agree with an independent GRAS determination, the agency can 
take enforcement action, including judicial action through the 
Department of Justice, to stop distribution of the foods containing it 
on the grounds that such foods are or contain an unlawful food 
additive. 

History of FDA's Approach to the GRAS Provision/Exemption: 

Following enactment of the 1958 amendment, FDA solicited information 
on the then current uses of added ingredients that stakeholders 
considered GRAS with a view toward establishing an initial GRAS list 
in the Code of Federal Regulations (CFR). The initial GRAS list was 
included in the CFR in 1961. In addition, during the 1960s, many 
manufacturers requested FDA's opinion on whether their conclusions of 
GRAS status were justified and received "opinion letters" from FDA. 
These "opinion letters" were often only available to the requestor and 
were formally revoked by FDA in 1970 (21 CFR 170.6; 35 FR 5810; April 
9, 1970). 

In 1969, FDA removed cyclamate salts from its GRAS list as a result of 
safety questions, and then-President Nixon directed FDA to reexamine 
the safety of GRAS substances listed in the CFR. In the 1970s, FDA 
conducted a comprehensive review of substances presumed to be GRAS. 
FDA contracted with the Life Sciences Research Office (LSRO) of the 
Federation of the American Societies for Experimental Biology (FASEB) 
to summarize the available scientific literature and to recommend 
restrictions, if any, on the use of the substances needed to ensure 
their safe use in food. By 1982, the FASEB/LSRO Select Committee on 
GRAS Substances (SCOGS) had submitted opinions to the FDA on the 
health aspects of more than 400 substances. 

As part of its reexamination of GRAS substances, in the 1970s, FDA 
developed and continues to maintain and expand a data retrieval and 
evaluation system to assist in FDA's ability to monitor food 
ingredients (Priority Based Assessment of Food Additives [PAFA]). Due 
in part to the increasingly global nature of the food supply chain, 
the development of novel ingredients and foods and the diversity of 
available foods, FDA's ability to conduct post-market review and 
monitoring of food ingredients is a challenge. In response to this 
challenge, FDA will continue to develop strategies and tools to enable 
FDA to protect public health through improved oversight of food 
ingredients. 

Also during the 1970s, FDA established a voluntary GRAS affirmation 
petition process similar to the mandatory food additive petition 
process. In many cases, those companies that took part in the 
voluntary GRAS affirmation petition process began to market their 
products based on FDA's filing of their petition and well before FDA 
reached a decision on the GRAS status of the petitioned use.
Due to the resource intensive nature of the GRAS affirmation petition 
process and in the interest of improving efficiencies, in 1997, FDA 
proposed to replace the voluntary GRAS affirmation petition process 
with a voluntary notification procedure (GRAS notification program) 
that directs FDA's resources more effectively to questions about GRAS 
status that are a priority with respect to public health protection 
(62 FR 18937; April 17, 1997; Substances Generally Recognized as Safe; 
the GRAS proposal). To date, FDA has filed over 300 notices. 

Challenges Posed by Novel Technologies and Uses: 

The widespread reliance on the GRAS concept as the basis for market 
entry of new food ingredients and uses raises challenging issues in 
the context of novel technologies and novel uses of food ingredients. 
FDA agrees with the finding in the GAO report that nanotechnology 
presents particular challenges, since it may involve dramatically 
reducing the particle size, and in turn altering the physical and 
biological properties, of familiar GRAS substances without changing 
the chemical identity of the substance. Similarly, familiar substances 
are being added to products as varied as infant formula, energy 
drinks, and alcoholic beverages to produce "novel foods." Overly 
expansive reliance on the GRAS concept, coupled with the legally 
available option for companies to make their own GRAS determination 
without notifying FDA, can undermine FDA's ability to ensure either 
the safety or legality of novel food ingredients and technologies. The 
proliferation in the marketplace of products obtained through novel 
technologies and/or novel uses of food ingredients is another 
important motivation for FDA's reexamination of the scientific, legal, 
and regulatory bases for evaluating the implementation of the food 
additive law. 

Response to Recommendations: 

Under the current legal authorities, a company can either notify FDA 
through a GRAS notice of its GRAS determination through FDA's 
voluntary notification program or make a GRAS determination without 
submitting a GRAS notice to FDA. In terms of GAO's recommendations, 
five of the six recommendations refer to GRAS determinations generally 
and are not limited solely to GRAS determinations where a GRAS notice 
is submitted to FDA. In responding to each of GAO's recommendations, 
FDA is responding primarily within the context of the agency's current 
legal authorities and is addressing both types of GRAS determinations, 
where applicable. 

GAO Recommendation 1: 

To better ensure FDA's oversight of the safety of GRAS substances, GAO 
recommends that the Commissioner of FDA develop a strategy to require 
any company that conducts a GRAS determination to provide FDA with 
basic information 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. 

FDA Response to Recommendation 1: 

In the case of a voluntary GRAS submission, FDA agrees with GAO's 
first recommendation and has practices and procedures currently in 
place as part of the GRAS notification program that are consistent 
with it. When a company voluntarily submits a GRAS notice to FDA, FDA 
reviews the submission to see that it includes appropriate information 
before the submission is filed. If lacking important information, such 
as information about the substance's identity and intended uses, the 
GRAS notice would not be filed. In such a case, the notifier is 
contacted and given an opportunity to correct such deficiencies. If 
the deficiencies are not corrected to FDA's satisfaction, the FDA 
ceases to review the notification. 

Once FDA has completed its review of a GRAS notice and responded to 
it, information about the notice is posted in FDA's GRAS inventories 
on the agency's public Web site. Since January 2009, the agency has 
been publicly posting GRAS notices on its Web site. The Office of Food 
Additive Safety in CFSAN is currently working on a long-term project 
to develop a system for data retrieval and evaluation that will 
incorporate new approaches including computer-assisted analyses; this 
system will include information from submissions sent to FDA for food 
contact substances, food additives and GRAS substances (Chemical 
Evaluation and Risk Estimation System [CERES]). 

FDA has also considered how the recommendation to obtain and publicly 
post basic information about GRAS substances might apply to the 
situation in which a company makes a GRAS determination for its 
intended use of a substance and does not notify FDA. This is lawful 
according to the 1958 amendment to the Act if the use of the substance 
meets the GRAS criteria. Regardless of whether a company notifies FDA 
of its GRAS determination, the company is responsible for compliance 
with the applicable statutes. In addition, FDA expects the criteria 
for GRAS eligibility and determination through scientific procedures 
that are outlined in the 1997 GRAS proposal to be met in a firm's GRAS 
determination. However, without a regulatory framework that makes 
notifications mandatory, FDA cannot ensure that GRAS determinations 
that are not currently notified to FDA are rigorous, robust, or 
consistent with agency's proposed criteria. 

In theory, it would be informative for FDA to have, as GAO suggests, 
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 a company. For example, such information could 
assist FDA with potential post-market enforcement actions. FDA is, 
however, concerned that, while the legal responsibility for safety and 
legal compliance would remain with the firm, there might be a public 
perception or expectation that the listed GRAS determinations were in 
some way validated by FDA, which could result in an increased use of 
the substance in food without FDA being aware of the basis for its 
safety. Thus, from a food safety perspective, FDA does not agree with 
the recommendation to develop 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. FDA shares the transparency goal underlying this 
recommendation, however, and will consider other ways to achieve it. 

GAO Recommendation 2: 

To better ensure FDA's oversight of the safety of GRAS substances, GAO 
recommends that the Commissioner of FDA 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. 

FDA Response to Recommendation 2: 

FDA 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 (this is also true for food additive petitions). To 
address this concern, GRAS determinations are required to consider the 
totality of the publicly available information, including potentially 
unfavorable information. In theory, the FDA could develop guidance for 
convening expert panels as part of GRAS determinations, but this 
guidance would necessarily be non-binding. As discussed in FDA's 
response to GAO's Recommendation 4, FDA plans to finalize its GRAS 
proposal, including the criteria for making and documenting 
independent GRAS determinations, and will consider the conflicts issue 
in that rulemaking. 

FDA's GRAS rulemaking proposal explains that the bases to demonstrate 
the common knowledge element of GRAS are varied. These may include 
publication of data and information in the secondary scientific peer-
reviewed literature, documentation of an "expert panel" that is 
specifically-convened for this purpose; or the opinion or 
recommendation of an authoritative body such as the National Academy 
of Sciences. The opinion of an expert panel is useful when multiple 
studies bearing on the safety of a substance are published but there 
are no secondary sources that evaluate these studies and draw general 
conclusions based on this comprehensive body of knowledge. Moreover, 
the opinion of a specially-convened expert panel can contribute toward 
providing a basis for showing expert consensus when an individual 
published study raises safety questions. 

There is no requirement to submit the findings of an expert panel to 
FDA as part of a GRAS notice. When evaluating a GRAS notice containing 
a report of an expert panel commissioned by a company, the FDA 
considers the totality of the publicly available and corroborative 
evidence about the safety of the substance for its intended use, 
including favorable and potentially unfavorable information. FDA 
considers that the use of an expert panel is one way to demonstrate 
consensus (i.e., the common knowledge element of safety). FDA does not 
consider the view of an expert panel alone to be determinative for 
establishing safety. 

When FDA finds that the composition of the expert panel is 
scientifically deficient in terms of the breadth of scientific 
expertise or that the data and information considered by the expert 
panel does not adequately reflect the totality of scientific 
knowledge, FDA takes this into account during the agency's review or 
when preparing its response to the GRAS notice. 

FDA notes that GAO's report mentions FDA's advisory committees. FDA 
has a history of using such committees to seek expert scientific 
advice. The agency has guidance that applies to special government 
employees and regular government employees (the advisory committee 
"members") invited to participate in FDA advisory committees subject 
to the Federal Advisory Committee Act. The agency bears the costs for 
advisory committees including compensation and travel expenses for 
members. As such, FDA considers it appropriate to provide guidance 
that pertains to its advisory committees. In part, the agency issues 
such guidance to describe the applicable laws and regulations to 
promote transparency and to ensure the integrity of the deliberations 
of its advisory committees. 

GAO Recommendation 3: 

To better ensure FDA's oversight of the safety of GRAS substances, GAO 
recommends that the Commissioner of FDA 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. 

FDA Response to Recommendation 3: 

In the case of a voluntary GRAS submission, FDA does not hesitate to 
ask a notifier to provide certain data or information as an amendment 
to a GRAS notice. Though such requests are not random, the agency uses 
its resources to seek access to data and information as focused-
queries, rather than on a random audit, basis. 

FDA has also considered how this recommendation might apply to the 
situation in which a company does not notify FDA of its GRAS 
determination. Regardless of whether the company notifies FDA of its 
GRAS determination, the company is responsible for compliance with the 
applicable statutes, including the requirement that for a substance to 
be GRAS there must be common knowledge among qualified experts that 
there is reasonable certainty that the substance is not harmful under 
the intended conditions of use. Absent knowledge of which companies 
have made GRAS determinations about particular substances and uses, 
however, FDA has a very limited basis on which to audit those 
determinations. 

In terms of how to document GRAS determinations, the preamble of the 
GRAS proposal provides extensive information, including the elements 
of the GRAS standard (62 FR 18937 at 18940). Specific to the GRAS 
notification program, information exists in the GRAS proposal for the 
documentation of GRAS determinations (62 FR 18937 at 18947).[Footnote 
22] As proposed, the notification procedure would allow FDA to direct 
its resources to questions about GRAS status that are a priority with 
respect to public health protection. FDA will further consider the 
documentation issue as it moves toward finalizing the notification 
proposed rule. 

FDA has posted guidance on the agency's website that answers common 
questions about the food ingredients classified as GRAS in the form of 
frequently asked questions.[Footnote 23] This guidance addresses 
common questions about the regulatory process and regulatory 
considerations regarding whether the use of a food substance is GRAS. 

GAO Recommendation 4: 

To better ensure FDA's oversight of the safety of GRAS substances, GAO 
recommends that the Commissioner of FDA 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. 

FDA Response to Recommendation 4: 

FDA agrees with GAO's recommendation to finalize the GRAS proposal on 
a timeframe that is in keeping with FDA's other public health and 
rulemaking priorities. The agency anticipates reopening the comment 
period prior to the issuance of a final rule. After analyzing any 
comments received, FDA would be able to outline a timeframe for 
finalizing the GRAS proposal. 

GAO Recommendation 5: 

To better ensure FDA's oversight of the safety of GRAS substances, GAO 
recommends that the Commissioner of FDA 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. 

FDA Response to Recommendation 5: 

FDA agrees that a system of post-market oversight for GRAS substances, 
and also for food additives and food contact substances, would help to 
better ensure the safety of the food supply. In fact, FDA has engaged 
in post-market review of many substances, including GRAS substances, 
over time as evidenced, for example, by its issuance of numerous 
Warning Letters for violative substances and by data collection via 
the Priority-based Assessment of Food Additives (PAFA). In the 1970s, 
FDA contracted with the FASEB/LSRO Select Committee on GRAS Substances 
to undertake an exhaustive effort to reevaluate GRAS substances 
specifically. A more comprehensive, sustainable and systematic 
approach to post-market review has been hampered by resource 
constraints. FDA will continue to work on its strategies that 
efficiently utilize available resources to mitigate concerns regarding 
the safety of foods on the market that contain added GRAS substances 
(or new intended uses of GRAS substances) or food additives. FDA notes 
that post-market oversight involves both review units as well as units 
that are specialized in enforcement activities. 

The FDA also agrees with GAO's recommendation that criteria be 
developed for the circumstances warranting post-market review of GRAS 
substances. Generally, post-market reviews are triggered by new or 
previously unavailable information that suggests adverse effects in 
animals or man. Such information may point to a real risk and lead to 
measures taken by FDA or industry that are protective of public 
health. In other cases, such information may be of uncertain value due 
to lack of scientific merit or other shortcomings (e.g., the data are 
contradicted by other data or relate to an area of science that is not 
well understood). Consequently, FDA agrees that established criteria 
will help guide FDA in conducting efficient and effective post-market 
reviews of substances added to marketed foods and that such reviews 
serve the best interest of public health. 

In general, FDA agrees with GAO's recommendation that FDA allocate 
sufficient resources to respond in a timely manner to Citizen 
Petitions that relate to GRAS substances as well as food additives, in 
keeping with other public health priorities. FDA considers Citizen 
Petitions an important component of post-market review when 
scientifically sound safety issues are raised and appropriately 
documented with scientific data and information. Unfortunately, this 
is not always the case. An effective FDA strategy would need to 
include a means of triaging Citizen Petitions for their scientific and 
legal merit if limited FDA resources are to be spent wisely. FDA would 
need additional resources to ensure timely reviews of Citizen 
Petitions, various types of regulatory submissions and FDA-initiated 
reviews (e.g., post-market reviews). 

FDA appreciates the intent of GAO's recommendation to collect 
information from companies on their reconsiderations of the safety of 
GRAS substances. However, FDA notes that effective implementation of 
this recommendation is outside of FDA's current authority. The Act 
does not require companies to notify FDA of GRAS determinations; 
consequently, under the statute FDA could ask, but could not require, 
companies to provide information about all GRAS re-determinations. 

GAO Recommendation 6: 

To better ensure FDA's oversight of the safety of GRAS substances, GAO 
recommends that the Commissioner of FDA 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. 

FDA Response to Recommendation 6: 

FDA agrees that it needs to develop a strategy to help ensure the 
safety of engineered nanomaterials that companies market as GRAS 
substances without the agency's knowledge. To that end, FDA will soon 
issue regulatory guidance to developers of nanomaterials describing 
the agency's thinking regarding how the GRAS concept and other 
elements of the regulatory framework apply to such materials. 

Like all food ingredients, nanomaterials would need to satisfy the 
statutory standard for GRAS in order to be exempt from FDA's premarket 
review requirements. From the standpoint of safety evaluation, FDA's 
concern about engineered nanomaterials is not their size per se. It is 
rather the fact that, by design, they typically have properties that 
are different from the conventional-scale versions of the same 
chemical substance, coupled with the current scientific uncertainty 
regarding differences in biological interactions between nano- and 
conventional-scale materials and how to test the safety of the often 
novel properties associated with nanomaterials. This state of the 
science suggests that meeting the general recognition standard for 
GRAS status may be difficult. In some cases the answer may be clear, 
such as when a nanoscale particle exhibits novel properties 
potentially affecting its toxicological profile and has not been 
tested and found safe using validated toxicity testing protocols. In 
other cases, the analysis may be more complicated, and the answer may 
change as the science evolves. 

FDA has recognized previously that nanotechnology food applications 
raise difficult scientific and regulatory questions, including in the 
FDA Nanotechnology Task Force Report published in 2007. As scientific 
knowledge advances to help FDA better understand technical issues 
about nanotechnology, FDA's strategy for addressing the safety of 
nanomaterials used in food and food packaging will continue to evolve. 
FDA has thus far published three guidance documents dealing with 
nanomaterials, all of which address with the safety assessment of food 
ingredients or food packaging components. 

FDA is also developing or considering the development of further 
guidance on the regulatory status and safety of nanomaterials used in 
food and food packaging, including the remaining guidance recommended 
in the Nanotechnology Task Force Report that has not yet been 
completed. FDA agrees that a critical element of its overall strategy 
for addressing the safety of nanomaterials used in food and food 
packaging is the likelihood and feasibility of GRAS determinations for 
such materials used in food and food packaging. FDA thus plans to 
issue a draft guidance that will help developers of food applications 
of nanotechnology determine the applicability of the GRAS concept. 

The agency will continue to consider the viability of establishing an 
FDA-wide or even a foods definition of nanotechnology. While a single 
definition for nanomaterials for all FDA-regulated products may have 
certain utility, the key issue for safety evaluation is not whether a 
bright line on the nano-scale has been crossed but whether the 
modification at the nano-scale creates new properties that require 
testing to ensure safety under intended conditions of use. 

[End of section] 

Appendix V: GAO Contact and Staff Acknowledgments: 

GAO Contact: 

Lisa Shames, (202) 512-3841 or shamesl@gao.gov: 

Staff Acknowledgments: 

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. 

[End of section] 

Footnotes: 

[1] Although we generally refer to GRAS substances in this report, 
under the Federal Food, Drug, and Cosmetic Act, it is the substance 
under conditions of its intended use, rather than the substance 
itself, that is eligible for the GRAS exemption. 

[2] U.S. Department of Health and Human Services and U.S. Department 
of Agriculture, Dietary Guidelines for Americans, 2005, 6th ed. 
(Washington, D.C., U.S. Government Printing Office, 2005). 

[3] Institute of Medicine of the National Academies, Dietary Reference 
Intakes for Water, Potassium, Sodium, Chloride, and Sulfate 
(Washington, D.C., The National Academies Press, 2004); Institute of 
Medicine of the National Academies, Dietary Reference Intakes for 
Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, 
and Amino Acids (Macronutrients) (Washington, D.C., The National 
Academies Press, 2005). 

[4] Some definitions have an upper limit higher than 100 nanometers. 

[5] For more information on stevia and dietary supplements, see GAO, 
Dietary Supplements: FDA Should Take Further Actions to Improve 
Oversight and Consumer Understanding, [hyperlink, 
http://www.gao.gov/products/GAO-09-250] (Washington, D.C.: Jan. 29, 
2009). 

[6] Department of Health and Human Services, FDA, Food Protection Plan 
(Rockville, Md., 2007). For more information on the Food Protection 
Plan, see GAO, Federal Oversight of Food Safety: FDA Has Provided Few 
Details on the Resources and Strategies Needed to Implement its Food 
Protection Plan, [hyperlink, http://www.gao.gov/products/GAO-08-909T] 
(Washington, D.C.: June 12, 2008); and Federal Oversight of Food 
Safety: FDA's Food Protection Plan Proposes Positive First Steps, but 
Capacity to Carry Them Out Is Critical, [hyperlink, 
http://www.gao.gov/products/GAO-08-435T] (Washington, D.C.: Jan. 29, 
2008). 

[7] Interagency Working Group on Import Safety, Action Plan for Import 
Safety (Washington, D.C., 2007). 

[8] Guidance includes FDA, Guidance for the Public, FDA Advisory 
Committee Members, and FDA Staff on Procedures for Determining 
Conflict of Interest and Eligibility for Participation in FDA Advisory 
Committees (Rockville, Md., 2008) and FDA, Guidance for the Public, 
FDA Advisory Committee Members, and FDA Staff: Public Availability of 
Advisory Committee Members' Financial Interest Information and Waivers 
(2008). 

[9] FDA's Priority-Based Assessment of Food Additives database 
contains administrative, chemical, and toxicological information on 
over 2,000 substances directly added to food. 

[10] FDA has also required labeling of the trans fat content of foods 
since January 1, 2006. 

[11] Besides the GRAS notification program, other regulatory tracks 
include pursuing a food contact substance notification or a food 
additive petition. 

[12] U.S. Department of Health and Human Services and U.S. Department 
of Agriculture, Dietary Guidelines for Americans, 2005, 6th ed. 
(Washington, D.C., U.S. Government Printing Office, 2005). 

[13] Institute of Medicine of the National Academies, Dietary 
Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate 
(Washington, D.C., The National Academies Press, 2004); Institute of 
Medicine of the National Academies, Dietary Reference Intakes for 
Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, 
and Amino Acids (Macronutrients) (Washington, D.C., The National 
Academies Press, 2005). 

[14] The guidelines found that a potassium-rich diet blunts the 
effects of salt on blood pressure. 

[15] Adequate intake represents the recommended average daily intake 
level based on observed or experimentally determined approximations or 
estimates of nutrient intake by a group (or groups) of apparently 
healthy people that are assumed to be adequate; adequate intake is 
used when a recommended daily allowance cannot be determined. 
Tolerable upper intake level is the highest average daily nutrient 
intake level that is likely to pose no risk of adverse health effects 
to almost all individuals in the general population; as intake 
increases above this level, the potential risk of adverse effects may 
increase. 

[16] Department of Health and Human Services, FDA, Food Protection 
Plan (Washington, D.C., 2007). 

[17] Interagency Working Group on Import Safety, Action Plan for 
Import Safety (Nov. 2007), [hyperlink, http://www.importsafety.gov/] 
(accessed Sept. 18, 2009). 

[18] FDA contracted for an independent review, by contemporary 
standards, of the available safety information related to substances 
it considered GRAS after new scientific information in the late 1960s 
raised questions about the safety of cyclamate salts, a class of 
sweeteners that FDA previously considered GRAS. 

[19] FDA, Nanotechnology: A Report of the U.S. Food and Drug 
Administration Nanotechnology Task Force (Washington D.C., 2007). 

[20] Council of Canadian Academies, Small Is Different: A Science 
Perspective on the Regulatory Challenges of the Nanoscale (Ottawa, 
Canada, 2008). 

[21] European Food Safety Authority, "Scientific Opinion of the 
Scientific Committee on a Request from the European Commission on the 
Potential Risks Arising from Nanoscience and Nanotechnologies on Food 
and Food Safety," The EFSA Journal, no. 958 (2009). 

[22] FDA excerpted a portion of proposed 170.36, and posted this text 
on the Internet as "How to Submit a GRAS Notice." 

[23] This guidance is available at [hyperlink, 
http://www.fda.gov/Food/GuidanceComplianceRegulatoryinformation/Guidance
Documents/FoodIngredientsandPackaging/ucm061846.htm]. 

[End of section] 

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