January 31, 2013
Dr. Dennis Keefe
Director, Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
U.S. Food and Drug Administration
CPK-2 Bldg. Room 3044
4300 River Road
College Park, MD 20740
Dear Dr. Keefe:
We are writing to share both our experience and the experience of another scientist with
the Flavor and Extract Manufacturers Association’s (FEMA) GRAS (generally recognized as
safe) program that we believe illustrate an important failure of the current GRAS system.
We urge the Food and Drug Administration (FDA) to consider ways to increase the rigor,
availability, transparency, and acceptance of GRAS reviews.
FDA has essentially delegated GRAS-review authority for flavors, flavor enhancers, and
related substances to FEMA. The FEMA GRAS program exists only with the oversight and
participation of the FDA, as noted by FEMA.1
FDA has noted that the Federal Food, Drug, and Cosmetic Act has several criteria that must
be met before the intended use of a substance in food can be considered GRAS: that its
safety be established scientifically (or by common use prior to 1958), and that the basis for
concluding it is safe must be generally accepted, publicly available, and transparent to
experts (emphasis added).2 FDA has further stated that a GRAS substance is distinguished
from a food additive on the basis of the “common knowledge” about the safety of the

1

Page 269 in Hallagan, John B. and Richard L. Hall. “Under the conditions of intended use – New
developments in the FEMA GRAS program and the safety assessment of flavor ingredients.” Food
and Chemical Toxicology 47: 267-278, 2009. Also personal communication with John B. Hallagan,
November 30, 2012. The qualifications and objectivity of FEMA’s expert panels is a separate
matter.
2
General Comments of the Department of Health and Human Services (HHS) on the Government
Accountability Office’s (GAO) Draft Report Entitled, “Food Safety: FDA Should Strengthen Its
Oversight of Food Ingredients Determined to be Generally Recognized As Safe (GRAS)” (GAO-10246), included in Appendix IV of GAO-10-246, February 2010.

 Page 2
substance for its intended use, and the “widespread awareness of the data and information
about the substance.”3
However, our experience shows that those criteria are not being met. The criterion of
public availability is particularly important when dealing with novel substances such as
sweetness-enhancing compounds, since without it, safety cannot be considered to be
generally accepted.
In a recent interview, Marianna Naum, in the Office of the Deputy Commissioner for Foods
and Veterinary Medicine, said, “Since you’re talking about general recognition of safety,
you have to be talking about familiarity with the ingredient in the scientific community. I
do think it is important for us to keep in mind that these ingredients aren’t necessarily new
ingredients. We are just finding a new use for it. I think it is a misconception of
the GRAS program. These are mostly old ingredients used in new ways.”4
Obviously, familiarity with the ingredient in the scientific community cannot exist when
dealing with a new ingredient, for which the information underlying the GRAS
determination is not publicly available.
CSPI has been attempting for over one year to obtain the scientific information that forms
the basis for the FEMA’s determination that compounds developed by Senomyx are GRAS.5
Unfortunately we have not been able to obtain the information despite our best efforts,
including:
 filing a Freedom of Information Act (FOIA) request (1/18/12, FOIA request number
2012-485) with the FDA
 providing clarifying information (the CAS, FEMA, and JECFA numbers and chemical
names for the substances of interest) to FDA as FDA requested (4/16/12)
 meeting in person with FEMA representatives (11/30/12)
 sending numerous emails and making numerous phone calls to FEMA
representatives (1/3/12 – 1/22/13)
“Guidance for Industry: Frequently Asked Questions About GRAS, December 2004, at
http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/Food
IngredientsandPackaging/ucm061846.htm. The answer to question 4 states, “GRAS substance is
distinguished from a food additive on the basis of the common knowledge about the safety of the
substance for its intended use. As FDA discussed in a proposed rule to establish a voluntary
notification program for GRAS substances (62 Fed. Reg. 18938; April 17, 1997), the data and
information relied on to establish the safety of the use of a GRAS substance must be generally
available (e.g., through publication in the scientific literature) and there must be a basis to conclude
that there is consensus among qualified experts about the safety of the substance for its intended
use. Thus, the difference between use of a food additive and use of a GRAS substance relates to the
widespread awareness of the data and information about the substance, i.e., who has access to the
data and information and who has reviewed those data and information.”
4
Food Safety News, December 18, 2012.
5
Senomyx Inc. develops taste modifiers that may enable food manufacturers to reduce levels of salt,
sugar, artificial sweeteners, and monosodium glutamate (MSG). CSPI wanted to review the safety
information on Senomyx’s sweetness-enhancing substances.
3

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A summary documenting our correspondence with FEMA in an attempt to obtain the
information is attached to this letter.
We recently learned that another scientist, Dr. Susan Schiffman, retired director of the
Duke University Taste and Smell Lab and former Professor of Medical Psychology in the
Department of Psychiatry at Duke University Medical School, currently a consultant, also
asked FEMA for the scientific information underlying the GRAS determination on a
sweetness-enhancing compound developed by Senomyx, but FEMA declined to send her
the information.
Information on the identity and safety of substances in the food supply should not be a
secret and should not require Herculean efforts to obtain. Even the FDA apparently does
not have any information on eight flavor-enhancing compounds developed by Senomyx,
other than rough exposure estimates for four of the compounds.6 FEMA’s delays in
releasing the information foil our ability to evaluate and inform the public about the safety
of those substances. Meanwhile, FEMA touts the transparency of its GRAS program.7
This inability to obtain information in a timely way about the safety of GRAS substances
means that the basis for the GRAS status is not common knowledge and that there is not
widespread awareness of or familiarity with the data and information about the substance.
Hence, there cannot be a general recognition of safety. We urge FDA to reconsider the
GRAS status of any such substance. We call on FDA to publish all FEMA notices pursuant to
the proactive disclosure provisions of the Freedom of Information Act as described by the
Department of Justice and encouraged by the Attorney General and the President.8
Furthermore, we urge the FDA to seriously review its acceptance of the current FEMA
GRAS-review process and consider instituting major reforms.
Thank you for considering these comments.
Sincerely,

Michael Jacobson, Ph.D.
Executive Director

Lisa Y. Lefferts, M.S.P.H.
Senior Scientist

Email from Sharon R. Dodson of FDA to Alison Brown of CSPI on August 10, 2012, attaching letter
to Alison Brown from Sharon R. Dodson dated February 21, 2012 re: FOIA request 2012-485 and
an enclosure with exposure information on 4 compounds.
7 Page 267 in Hallagan, John B. and Richard L. Hall. “Under the conditions of intended use – New
developments in the FEMA GRAS program and the safety assessment of flavor ingredients.” Food
and Chemical Toxicology 47: 267-278, 2009. Also personal communication with John B. Hallagan,
November 30, 2012.
8 Department of Justice Guide to the Freedom of Information Act: Proactive Disclosures. Available
at http://www.justice.gov/oip/foia_guide09/proactive-disclosures.pdf
6

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Attachment: Correspondence between FEMA and CSPI regarding Senomyx’s flavor
enhancers
KEY:
AB: Alison Brown, CSPI (Research Associate)
CG: Christie Gavin, FEMA (Owner and Managing Director of Verto Solutions, which
manages FEMA)
JH: John Hallagan, FEMA (General Counsel, former Science Director)
LL: Lisa Lefferts, CSPI (Senior Scientist)
CSPI: Center for Science in the Public Interest
FEMA: Flavor and Extracts Manufacturers Association
RIFM: Research Institute for Fragrance Materials
Correspondence is via email unless otherwise noted
1/3/12 CSPI's Alison Brown (AB) emails FEMA's Christie Gavin (CG) about gaining access
to the RIFM-FEMA database, asks about fee.
1/10 CG replies to AB that CSPI does not meet the criteria for access to the database, and
would be pleased to talk about what is being sought
notes in files (undated) titled "Christie Gavin FEMA" about CSPI interested in knowing
about Senomyx compounds deemed GRAS.
1/10 AB emails FEMA's John Hallagan (JH) inquiring about status of Senomyx GRAS
approvals by FEMA
1/11 JH: will get back to you by end of week
1/17 JH refers to phone conversation that morning w/AB and sends 2 publications
w/background on FEMA GRAS program. Says will get back shortly w/other info discussed.
1/24 AB thanks JH, says she is checking on the status of the other information requested,
i.e., more details of Senomyx’s GRAS approvals by FEMA, including the scientific data upon
which approvals were based. She notes that GRAS 24 and 25 reports published in Food
Technology don't provide information being sought.
3/5 AB email to JH following up and getting info discussed. Notes that FDA responded that
it could find no information to fulfill our FOIA request
3/17 JH says he'd like to meet to share the information, and can provide a detailed
explanation of the evaluation process and a description of the scientific information used to
establish GRAS status. Suggested 2 dates in March
3/21 AB notes that FEMA says it provides its safety assessment information "for inclusion
in its publicly available databases." Says after reading documents, would like to meet to
discuss any questions
4/5 AB tells JH that, per phone conversation, we are waiting to receive a list of the Senomyx
compounds along with the corresponding FEMA codes
4/5 JH apologizes for the delay, kids are on spring break, will get back once back at work

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4/11 AB says understood, we look forward to receiving the list of compounds along with
corresponding FEMA codes. Also came across another flavor enhancer compound and
asked for info on that (PureCircle and Prinova, called NSF-02)
4/11 JH says a letter containing the info we discussed is attached. (Letter identifies
chemical name, FEMA number, JECFA number, CAS number for 8 compounds, and provides
other information about FEMA and the FEMA GRAS program generally)
4/12 AB thanks JH, asks about the other flavor enhancer she mentioned (NSF-02), is that in
the compounds listed in your letter? Also would like the names of the sponsors of each of
the chemicals listed and information on conflicting interests of each of the members of
FEMA's current Expert Panel. Also what is your availability in upcoming weeks for our
meeting to discuss the scientific evidence evaluating the first flavor enhancer compound on
the list you provide.
4/17 JH: the other substance that AP asked about is not in the list in the letter that he sent
her. FEMA does not identify FEMA GRAS substances by the applicant for GRAS status or the
manufacturer/marketer. He is going on travel and will contact AB in early May to set up a
time to meet. At that time we can discuss the other substance that AB asked about and
begin the process of sharing the information on the substances on the list in his letter.
8/8 AB: Although quite a bit of time has gone by, we would still like to discuss details of the
Senomyx research for the following 8 compounds (lists)
8/8 AB tells her supervisor (Michael Jacobson) that JH was agreeable to speak over the
phone about each Senomyx compound but, to his strong advisement, he preferred to go
over each compound step-by-step. At this point, she says we need to set up a meeting for
him to go over the scientific data of each Senomyx compound.
CSPI's Lisa Lefferts (LL) begins contacting FEMA
10/17 I LL asks JH for a meeting if that is only way to get the information
10/18 JH says he is currently traveling and will call after gets back to the US on Monday to
set up a time, will be in DC next month and can compare calendars
10/31 LL emails JH asking if 11/19 will work to meet
10/31 JH proposes 11/28-30, LL confirms a time on 11/30
11/28 LL reconfirms and says "I trust that at the meeting you will be able to provide me
with the documentation supporting the GRAS determination for each of the Senomyx
substances."
11/30 LL meets with JH, CG, and also Sean Taylor (Scientific Director of FEMA and
Scientific Secretary to the FEMA Expert Panel) and Kelly Poole (Director of Government
Relations for Verto Solutions, which manages FEMA). Provide background information on
organizational structure and GRAS and explain how each Senomyx compound is used. LL
asks for toxicological information for two of the compounds which are sweetness
enhancers. JH says they would provide FEMA's summaries for those 2 compounds in the
“next couple of weeks.”
12/3 JH sends Codex flavor guideline as discussed at meeting, but not FEMA's GRAS
reviews.
12/5 LL requests original studies in addition to FEMA summaries. Also asks for advice on
how to word FOIA to obtain info from FDA (in response to JH's comment during meeting
about importance of wording). Confirms that he will be sending a group safety assessment
document.

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12/7 LL asks questions about FEMA’s poundage survey provided at meeting
12/12 JH responds to Qs about FEMA poundage survey, says will provide info on 2
Senomyx compounds as soon as they can
12/21 LL asks if any progress retrieving summaries, noting it has been 3 weeks since
meeting
12/27 JH sends summary JECFA report and says is going through process to get study
reports and will provide be in touch after first of year
1/7/13 LL thanks JH for JECFA report and asks about status of FEMA summaries and
underlying studies
1/7 JH says he will check on the status today, he thinks the copying is done but needs to
check.
1/8 LL: Thanks JH and asks what he found out about the copying.
1/17 JH sends more detailed JECFA report and says he will be in touch soon to set up a
meeting to give me the studies
1/22 LL thanks JH for the report, says making another special trip to meet with you prior
to receiving the information is unnecessary, please mail the information
1/30 JH apologizes for delay, is traveling, will ask FEMA office to box up studies and send
them, and will let LL know when can expect them
(current as of 1/30/13)