http://www.caloriecontrol.org/pdf/Rulis_08.pdf

9. How do food ingredients qualify for GRAS status and how does FDA administer the GRAS Notice process?

As we noted above, the FD & C Act exempts from premarket approval those food ingredients that qualify for the food additive definition but whose use is generally recognized as safe (GRAS), (i.e.,
for which there is a general recognition by qualified30 experts that
these ingredients are safe for their intended uses). The so-called
‘‘GRAS exemption” to the statutory definition for food additives in
Section 201(s) of the FD & C Act expresses Congress’ recognition that
many commonly used food ingredients, some with long histories of
safe use in food or whose safety based on scientific procedures is
widely recognized and accepted by qualified experts, need not be
subjected to further government scrutiny. As we pointed out above,
in the absence of such an exemption, the wide reach of the ‘‘component
part” of the food additive definition in the Act would needlessly
require many common and ostensibly safe food ingredients and their
uses to become the subject of new food additive petitions.
The GRAS exemption has been much misunderstood and misinterpreted
over the years. Others have provided cogent insights (see
for example, Degnan, 1991). Many people mistakenly associate
GRAS with a sort of ‘‘second” tier of safety protection, based on a
less-than-rigorous standard compared to petitioned food additives.
31 This is not true. In fact, the safety standard applicable to
GRAS food ingredients is the same as for food additives, namely ‘‘reasonable
certainty of no harm.” What the statute does not provide,
however, is an easy-to-follow roadmap describing precisely how
one satisfies this standard for GRAS ingredients, other than to say
that they must either have a long history of safe use in food by a sufficiently
large population of eaters, or that, based on scientific procedures
there is a consensus among experts qualified by scientific
training and experience to judge such matters that the use of the
ingredient is safe.32
What truly distinguishes GRAS ingredients from food additives
is information in the form of common knowledge about the safety
of the substance for its intended use, and in addition, the general
availability and general acceptance of that information across the
scientific community of food ingredient safety experts. An excellent
source of information on the history of the GRAS concept and the
agency’s implementation of programs to assist food manufacturers
in making their decisions about the GRAS status of food ingredient
uses, is the April 17, 1997, Federal Register proposal published by
FDA to reform the GRAS process (Federal Register, 1997).33
In that document, FDA not only reviewed the regulations defining
GRAS and administering the GRAS process, but also proposed
replacing the then-existing voluntary but resource-intensive GRAS
Affirmation Petition process the agency put in place in the 1970’s,
with a more streamlined voluntary GRAS notification process. In
the 1997 notice, the agency made it clear that both food additives
and GRAS ingredients require the same strength of evidence of
safety. For food additives, the FDA reviews and approves the use
based on evidence supplied by the petitioner in the form of a petition.
For GRAS ingredient uses, the extra added element is the general
recognition required that the available safety evidence is both
widely known (e.g., available in the published literature or in commonly
accessible knowledge sources such as text books) and that
there is a consensus among qualified experts about that evidence
in support of the safe use of the material in food. In fact, the GRAS
criteria are in some ways more difficult to satisfy than the food
additive criteria because of the additional requirement of public
availability of the data and general recognition and acceptance of
a safety conclusion based on those data. For GRAS ingredients,
although there may not always be a need for an extensive set of
toxicological tests that support the safety of the use of the substance
(as is usually the case for food additives), especially if the
material is a common constituent of normal bodily fluids, or is ubiquitous in nature and its biochemistry well known, the socalled
‘‘common knowledge element” of GRAS (i.e., scientific evidence
supporting safety under the conditions of use) still must
be satisfied. Moreover, the requirement for the knowledge to be
widely known and accepted by scientists is itself a significant additional
requirement.34 Normally, the mechanism used to establish
that the necessary scientific information is generally available is to
show that the information is published in a peer-reviewed scientific
journal. The agency points out, however, that,
‘‘publication in a peer-reviewed scientific journal of data (such
as toxicity studies) on a test substance has been used to establish
expert consensus in addition to general availability. In other
cases, such publication of data and information in the primary
scientific literature has been supplemented by: (1) publication
of data and information in the secondary scientific literature,
such as scientific review articles, textbooks, and compendia;
(2) documentation of the opinion in an ‘‘expert panel” that is
specifically convened for this purpose; or (3) the opinion or recommendation
of an authoritative body such as the National
Academy of Sciences (NAS). . ..”
These distinctions are discussed in FDA’s 1997 Federal Register
notice (Federal Register, 1997). The FDA also accepts, as part of a
GRAS notification, unpublished studies as providing additional
support for or corroboration of the published scientific findings,
but the critical data and information forming the essential basis
of a GRAS determination must be in the public domain.
ThisGRAS notification program has operated for more than a decade.
During this time the agency has received and responded to well
over 200 GRAS exemption claims on a wide range of food ingredients,
many within the agency’s target time frame of 180 days (Gaynor
et al., 2006). As a technical matter, when FDA responds
affirmatively to a GRAS notice, it summarizes the data relied upon
by the notifier and states that the agency has ‘‘no questions at this
time about (the notifier’s) conclusions that the material is GRAS under
the intended conditions use,” and further states that the agency
has, ‘‘not made its own determination regarding the GRAS status of
the subject use.” This format was adopted because, under the law,
it is the notifier’s burden of proof to establish the GRAS status of
the compound. The agency does not officially ‘‘approve” a GRAS notice
like the agency does for a food additive petition. This distinction
is due to the nature of the GRAS exemption. Implicit in the agency’s
response that it has no further questions is the point that the agency
believes the notifier has made a sufficiently strong case that the use
of the substance in food: (a) satisfies the reasonable certainty of no
harm safety standard, and (b) that the knowledge base concerning
that safety is generally available and generally accepted by a consensus
among qualified experts. In practical terms, when FDA does not
disagree with the notifier’s GRAS determination, it is in effect saying
that it is comfortable that the case has been made that the proposed
use of the substance in food as described by the notifier poses no
safety issues,and that the general scientificcommunity would agree.
The existence of some controversy does not disqualify a GRAS
conclusion. A GRAS claimant, however, should fully address in a
GRAS notice any controversies and differences of scientific opinion
and interpretation that might exist and be prepared to respond to
these later in detail should they arise. The concept of a consensus
among qualified experts does not mean there must be unanimity of
opinion about the safety of the use of a GRAS substance. What interests
FDA and the general food safety community is that, in the written
basis for the GRAS conclusion, the notifier should be able to
demonstrate satisfactorily that the points of controversy that do exist
have been addressed with specificity, and neither any one separately,
nor all collectively, pose a credible challenge to the GRAS
conclusion. When substantial credible criticisms of a GRAS claim
go unanswered by those asserting GRAS status for an ingredient
use, it has the potential to cast a cloud over the GRAS claim because
the claim is, by definition, based on general awareness and general
acceptance by qualified expert consensus. Moreover, if there is a ‘‘severe
conflict” 35 among qualified experts on the safety of the ingredient for
its intended use, that would preclude a finding of GRAS.
Although many GRAS notices receive a positive response from
FDA, the agency has not been reluctant to conclude, when appropriate,
that the notifier has not adequately established the safety
and/or the general recognition of the safety of an intended use. Unless
a deficient GRAS notification is withdrawn, the Agency completes
that process with a publicly available letter to the notifier
indicating that the notification has deficiencies so that the agency’s
rejection of the notifier’s GRAS claim is documented and fully
transparent.
10. When does FDA consult with experts from other FDA centers
or from outside FDA?
Occasionally, FDA finds that it must call upon knowledgeable