Food Safety
FDA Should Strengthen Its Oversight of Food Ingredients Determined to Be Generally Recognized as Safe (GRAS) Gao ID: GAO-10-246 February 3, 2010The 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.
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.
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Director: Team: Phone:GAO-10-246, Food Safety: FDA Should Strengthen Its Oversight of Food 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:
