[Federal Register: May 10, 2004 (Volume 69, Number 90)]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 2004N-0205]
Furan in Food, Thermal Treatment; Request for Data and
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice; request for data and information.
SUMMARY: The Food and Drug Administration (FDA) is requesting the
submission of data and information on furan, a heat treatment related
byproduct that has been detected in certain thermally treated foods.
FDA is seeking data on the occurrence of furan in food, on sources of
exposure to furan other than food, on mechanisms of formation of furan
in food, and on the toxicology of furan, including mechanisms of
toxicity. FDA will evaluate the available data and will develop an
action plan that will outline FDA's goals and planned activities on the
issue of furan in food. Elsewhere in this issue of the Federal
Register, FDA is announcing a meeting of the agency's Food Advisory
Committee (FAC) on June 7 to 8, 2004.
DATES: Submit data, information, and general comments by July 9, 2004.
Data and information received by June 1, 2004, may be shared with the
FAC before or at that meeting.
ADDRESSES: Submit written comments, data, and information to the
Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic
comments, data, and information to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/dockets/ecomments
FOR FURTHER INFORMATION CONTACT: Lauren Posnick, Center for Food Safety
and Applied Nutrition (HFS-306), Food and Drug Administration, 5100
Paint Branch Pkwy., College Park, MD 20741, 301-436-1639.
During investigations relating to review of a petition for certain
uses of irradiation in food, FDA scientists identified the substance
furan in a number of foods that undergo heat treatment, such as canned
and jarred foods. Furan is a colorless, volatile liquid used in some
segments of the manufacturing industry. The presence of furan is a
potential concern because, based on animal tests, furan is listed in
the Department of Health and Human Services Report on Carcinogens (Ref.
20) and is considered possibly carcinogenic to humans by the
International Agency for Research on Cancer (IARC).
FDA has developed a gas chromatography/mass spectrometry (GC/MS)
method that is capable of detecting and quantitating low levels of
furan in food (Ref. 1). Although furan had previously been reported in
foods, FDA has recently applied this method to a wider variety of food
samples than previously reported in the literature. FDA has analyzed
approximately 120 food samples for furan (including replicates of the
same brand/product) and found furan levels ranging from nondetectable
(within the limits of detection of the method) to approximately 100
parts per billion (ppb). Jarred baby foods and canned infant formulas
are among the foods in which FDA has found measurable furan. FDA has
recently posted these furan data on the agency's Web site at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.cfsan.fda.gov/lrd/pestadd.html
[numsign]furan, along with a
description of its GC/MS method to provide other researchers the
opportunity to review and use the method.
FDA is requesting data on the occurrence of furan in food, on
sources of exposure to furan other than food, on mechanisms of
formation of furan in food, and on the toxicology of furan, including
mechanisms of toxicity. This notice summarizes information currently
available to FDA about the occurrence of furan in food, consumer
exposure to furan, the mechanisms of furan formation in food, and the
toxicology of furan, including the mechanism of toxicity. This notice
also identifies the areas in which additional data would be helpful to
FDA in learning more about furan and evaluating the risk, if any, posed
by the presence of furan in food. These areas are outlined in more
detail in section II of this document.
Finally, FDA will evaluate the available data and will develop an
action plan that will outline FDA's goals and planned activities on the
issue of furan in food. Possible elements of the action plan include an
expanded survey of furan levels in food; studies to address mechanisms
of furan formation in food; possible strategies to reduce furan levels
(if a risk assessment indicates this is necessary); and toxicology
studies to address such issues as mechanisms of furan toxicity and
dose-response. Elsewhere in this issue of the Federal Register, FDA is
announcing plans to seek, from its Food Advisory Committee at a meeting
scheduled for June 7 to 8, 2004, advice about what data are needed to
assess fully the risk to consumers, if any, posed by furan.
B. Occurrence of Furan in Foods
Furan is the parent compound of a class of derivative compounds
collectively known as ``furans.'' These compounds are found in a wide
assortment of foods and may contribute to food's sensory
characteristics (Ref. 2). The nonderivatized furan (i.e., furan) has
been identified previously in a small number of heat-treated foods,
including coffee, canned meat, baked bread, cooked chicken, sodium
caseinate, filberts (hazelnuts), soy
protein isolate, hydrolyzed soy protein, rapeseed protein, fish protein
concentrate, and caramel (Refs. 2, 3, 4, and 5). FDA has identified
very little published quantitative information on furan levels in food.
C. Mechanisms of Formation
Maga reviewed the formation of furan and furan derivatives (furans)
in food (Ref. 2). The primary source of furans in food is thermal
degradation and rearrangement of organic compounds, particularly
carbohydrates (Ref. 2). A variety of experimental systems, including
heating of sugars (eg., glucose, lactose, fructose, xylose, rhamnose),
heating sugars in the presence of amino acids or protein (e.g.,
alanine, cysteine, casein), and thermal degradation of vitamins
(ascorbic acid, dehydroascorbic acid, thiamin), have been used to
produce, isolate, and identify furans in food. In the studies reviewed
by Maga, the nonderivatized furan was found in the following systems:
Thermal degradation of glucose; thermal degradation of glyceraldehydes,
D-Erythrose, pentosans, hexoses, and polysaccharide; and a lactose-
casein browning system (Ref. 2). FDA has not identified any specific
mechanism or mechanisms that produce furan in the samples the agency
has tested to date.
1. Carcinogenic and cytotoxic effects. Furan is classified by IARC
as possibly carcinogenic to humans (Ref. 6). Furan is both carcinogenic
and cytotoxic in rodents. In a bioassay conducted by the National
Toxicology Program (NTP), furan administered by gavage to Fisher 344
rats (2, 4, or 8 milligram per kilogram per body weight (mg/kg/bw)) and
B6C3F1 mice (8 or 15 mg/kg per kg/bw) 5 days a week for up to 2 years
produced hepatic cholangiocarcinoma, hepatocellular adenoma and
carcinoma, and mononuclear cell leukemia in rats, and hepatocellular
adenoma and carcinoma and benign pheochromocytoma of the adrenal gland
in mice (Ref. 7). In both the 2-year NTP bioassay and a 13-week NTP
study, furan also caused cell proliferation, inflammation, biliary
tract fibrosis, hyperplasia, hepatocellular cytomegaly, degeneration,
necrosis, and vacuolization in rats and mice (Ref. 7). A preliminary
report from a second 2-year bioassay in female mice found increased
incidence and multiplicity of hepatic tumors and decreased tumor
latency in mice dosed with 4 or 8 mg/kg bw furan, but not in mice dosed
with 0.5, 1.0, or 2.0 mg/kg bw furan (Ref. 8). Furan has also been
shown to induce apoptosis in mice at hepatocarcinogenic doses (8 and 15
mg/kg bw), perhaps in response to an increased number of DNA
(deoxyribonucleic acid)-altered cells (Ref. 9). In addition, cytotoxic
doses of furan were shown in vivo and in vitro to cause irreversible
uncoupling of hepatic mitochondrial oxidative phosphorylation, leading
to adenosine triphosphate (ATP) depletion (Ref. 10).
2. Metabolism. Experiments in rats with [\14\C] furan show that
furan is rapidly absorbed and extensively metabolized and eliminated
after ingestion; the highest concentration of the absorbed dose was
retained in the liver (Ref. 11). A number of urinary metabolites of
furan have been observed but not identified (Ref. 11). cis-2-butene-
1,4-dial has been identified as a key reactive and cytotoxic metabolite
of furan (Ref. 12), which has been found to bind to protein (Ref. 11)
and nucleosides (Ref. 13). Both in vitro and in vivo studies show that
metabolic activation by cytochrome P450 enzymes is involved in furan-
induced toxicity. Glutathione inhibited the covalent binding of
reactive furan metabolites to microsomal protein in vitro (Ref. 14),
presumably by forming less reactive, water-soluble conjugates with the
3. Mutagenicity and genotoxicity. Furan tested negative for
mutagenicity in the Ames Salmonella test (with and without S9
activation) in the NTP study (Ref. 7), but was weakly positive in one
test strain (TA100) in another study (Ref. 15). The furan metabolite
cis-2-butene-1,4-dial was mutagenic at nontoxic levels in Ames assay
strain TA104, but was not mutagenic in strains TA97, TA98, TA100, and
TA102 (Ref. 16). Furan also tested negative for mutagenicity in germ
cells of male Drosophila melanogaster (Ref. 17). Furan is positive in
mammalian systems in vitro, such as in mouse lymphoma cells, and caused
sister chromatid exchanges and chromosomal aberrations in Chinese
hamster ovary cells, with and without S9 activation (Ref. 7). Furan
also induced DNA double-strand breaks in isolated rat hepatocytes at
doses of 100 micromolar (Ref. 18). In in vivo mammalian systems, furan
induced chromosomal aberrations, but not sister chromatid exchanges, in
mice bone marrow cells and in hepatocytes in mice and rats (Ref. 19).
It did not cause unscheduled DNA synthesis in mouse or rat hepatocytes
4. Mechanism of action of carcinogenesis. As noted previously, cis-
2-butene-1,4-dial is believed to be a key metabolite involved in furan
toxicity and carcinogenesis. cis-2-butene-1,4-dial has been shown to
form both protein and nucleoside adducts (Refs. 11 and 13); it acts as
a mutagen in the Ames assay, and its acute toxic and genotoxic effects
are mitigated by glutathione in vitro (Ref. 16). One hypothesis for
furan carcinogenicity is that cis-2-butene-1,4-dial stimulates cell
proliferation, increasing the likelihood of tumor induction (Ref. 20).
Another hypothesis is that cis-2-butene-1,4-dial activity uncouples
mitochondrial oxidative phosphorylation, thereby depleting ATP
supplies, and leading to activation of DNA double-strand endonucleases,
with the DNA double-strand breaks in surviving cells ultimately
resulting in mutagenesis (Ref. 21).
5. Additional toxicology information. No human studies are
available on the effects of furan. No data were found on the
reproductive and developmental toxicology of furan.
II. Request for Data and Information
FDA has identified a number of areas in which additional data and
information would be helpful to the agency in evaluating the risk, if
any, posed by the presence of furan in food. These areas are outlined
in more detail below. Accordingly, FDA invites all interested persons
to submit data and information on the topics identified.
Interested persons should submit comments on the information in
this notice and responsive data and information to the Division of
Dockets Management (see ADDRESSES) by July 9, 2004. Three copies of all
comments, data, and information are to be submitted. Individuals
submitting written information or anyone submitting electronic comments
may submit a single copy. Submissions should be identified with the
docket number found in brackets in the heading of this document.
Received submissions may be seen in the Division of Dockets Management
between 9 a.m. and 4 p.m., Monday through Friday.
FDA requests data and other information that responds to the
A. Concerning the occurrence of furan in foods and consumer
exposure to furan, FDA has identified the following data needs:
1. Data and information on the particular foods in which furan
2. Data on levels of furan in these foods.
3. Data on the formation and occurrence of furan in home-prepared
foods, as opposed to manufactured foods.
4. Data on environmental sources of furan to which a typical
consumer is likely to be exposed.
B. Concerning the mechanisms of the formation of furan in food, FDA
has identified the following data needs:
1. Data and information on possible mechanisms of furan formation.
2. Data and information on variables that enhance or mitigate furan
formation in foods.
3. Data on the stability or dissipation of furan in foods.
4. Data about the effect of post-production practices, such as
consumer heating of canned foods, on furan levels in foods.
C. Concerning the toxicology of furan, FDA has identified the
following data needs:
1. Data and information on mechanism(s) of furan toxicity,
mutagenicity, and carcinogenesis.
2. Data and information on the reproductive and developmental
toxicology of furan.
3. Data and information on the metabolism of furan in vivo,
including characterization of any reactive furan metabolites in
addition to cis-2-butene-1,4-dial, and data on the role of such
metabolites in producing furan's adverse effects, including
4. Data and information on the diversity of furan pharmacokinetics
in humans or the alteration of furan metabolism as a result of dietary,
medical, or environmental interactions.
5. Data and information on whether sub-cytotoxic furan doses
produce any adverse effect, such as a change in enzyme activities or
6. In the NTP furan study, Cytotoxic and carcinogenic effects were
seen at all doses, and a no adverse effect level (NOAEL) was not
identified. A preliminary report by Goldsworthy et al. showed an NOAEL
dose of 2.0 mg/kg bw in female mice, but data from this study are not
yet available (Ref. 12). FDA would like to acquire data on the effects
of furan doses lower than those used in the NTP study in order to
accomplish the following objectives: (a) Establish a dose-response
curve for the various toxicological endpoints, (b) Determine whether
furan toxicity, including carcinogenesis, is a threshold-dependent
event; and (c) determine whether the carcinogenic activity of furan is
secondary to its hepatotoxic effects.
7. Additional data on the mutagenicity of furan in the TA100 strain
in the Ames test, given the two existing contradictory reports.
8. Additional data and information on the behavior of furan in
other in vivo assays for mutagenicity or toxicity.
The following references are on display in the Division of Dockets
Management (see ADDRESSES) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
1. FDA, ``Determination of Furan in Foods,'' 2004, http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.cfsan.fda.gov/lrd/pestadd.html
2. Maga, J. A., CRC Critical Reviews in Food Science and
Nutrition, ``Furans in foods,'' pp. 355-400, 1979.
3. NRC (National Research Council), Spacecraft Maximum Allowable
Concentrations for Selected Airborne Contaminants, vol. 4., appendix
B14, ``Furan,'' pp. 307-329, National Academy Press, Washington, DC,
4. Persson, T. and E. von Sydow, ``Aroma of canned beef: Gas
chromatographic and mass spectrometric analysis of the volatiles,''
Journal of Food Science, 38: 377-385, 1973.
5. Stoffelsma, J., G. Sipma, D. K. Kettenes, and J. Pypker,
``Volatile components of roasted coffee,'' Journal of Agricultural
Food Chemistry, 16(6): 1000-1004, 1968.
6. IARC, IARC Monographs on the Evaluation of Carcinogenic Risks
to Humans, Volume 63: ``Dry Cleaning, Some Chlorinated Solvents and
Other Industrial Chemicals,'' pp. 394-407, Lyon, France, 1995.
7. NTP, ``Toxicology and carcinogenesis studies of furan (CAS
No. 110-00-9) in F344/N rats and B6C3F1 mice (gavage
studies),'' NTP Technical Report No. 402., U.S. Department of Health
and Human Services, Public Health Service, National Institutes of
Health, Research Triangle Park, NC, 1993.
8. Goldsworthy, T. L., R. Goodwin, R. M. Burnett, P. King, H.
El-Sourady, G. Moser, J. Foley, and R. R. Maronpot, ``Dose Response
Relationships Between Furan Induced Cytotoxicity and Liver Cancer,''
Society of Toxicologic Pathology Annual Conference, Orlando, FL,
9. Fransson-Steen, R., T. L. Goldsworthy, G. L. Kedderis, and R.
R. Maronpot, ``Furan-induced liver cell proliferation and apoptosis
in female B6C3F1 mice,'' Toxicology, 118(2-3): 195-204, 1997.
10. Mugford, C. A., M. A. Carfagna, and G. L. Kedderis, ``Furan-
mediated uncoupling of hepatic oxidative phosphorylation in Fischer-
344 rats--an early event in cell death,'' Toxicology Applied
Pharmacology, 144(1):1-11, 1997.
11. Burka, L. T., K. D. Washburn, and R. D. Irwin, ``Disposition
of [\14\C]furan in the male F344 rat,'' Journal of Toxicology and
Environonmental Health, 34(2): 245-257, 1991.
12. Chen L.-J., S. S. Hecht , and L. A. Peterson,
``Identification of cis-2-butene-1,4-dial as a microsomal metabolite
of furan,'' Chemical Research in Toxicology 8(7): 903-906, 1995.
13. Byrns, M. C., D. P. Predecki, and L. A. Peterson,
``Characterization of nucleoside adducts of cis-2-butene-1,4-dial, a
reactive metabolite of furan,'' Chemical Research in Toxicology
14. Parmar, D. and L. T. Burka. ``Studies on the interaction of
furan with hepatic cytochrome P-450,'' Journal of Biochemical
Toxicology, 8: 1-9, 1993.
15. Lee, H., S. S. Bian, and Y. L. Chen, ``Genotoxicity of 1,3-
dithiane and 1,4-dithiane in the CHO/SCE assay and the Salmonella/
microsomal test,'' Mutation Research, 321(4): 213-218, 1994.
16. Peterson, L. A., K. C. Naruko, and D. P. Predercki, ``A
reactive metabolite of furan, cis-2-butene-1,4-dial, is mutagenic in
the Ames assay,'' Chemical Research in Toxicology, 13(7): 531-534,
17. Foureman, P., J. M. Mason, R. Valencia, and S. Zimmering,
``Chemical mutagenesis testing in Drosophila, IX. Results of 50
coded compounds tested for the National Toxicology Program,''
Environmental and Molecular Mutagenesis, 23(1): 51-63,1994
18. Mugford, C.A. and G. L. Kedderis, ``Furan-mediated DNA
double strand breaks in isolated rat hepatocytes,'' Fundamental
Applied Toxicology, 30(1, Part 2):128, 1996.
19. Wilson, D. M., T. L. Goldsworthy, J. A. Popp, and B. E.
Butterworth, ``Evaluation of genotoxicity, pathological lesions, and
cell proliferation in livers of rats and mice treated with furan,''
Environmental and Molecular Mutagenesis, 19(3): 209-222, 1992.
20. National Toxicology Program (NTP), Report on Carcinogens,
10th ed., U.S. Department of Health and Human Services, Public
Health Service, 2002.
21. Kedderis G. L. and S. A. Ploch, ``The Biochemical Toxicology
of Furan,'' CIIT Activities 19(12), 1999.
Dated: May 4, 2004.
Assistant Commissioner for Policy.
[FR Doc. 04-10588 Filed 5-7-04; 8:45 am]
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