[Federal Register Volume 69, Number 90 (Monday, May 10, 2004)]
[Notices]
[Pages 25911-25913]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-10588]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2004N-0205]


Furan in Food, Thermal Treatment; Request for Data and 
Information

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://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.

SUPPLEMENTARY INFORMATION:

I. Background

A. General

    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://
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

[[Page 25912]]

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.

D. Toxicology

    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 
activated furans.
    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 
(Ref. 19).
    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 
following questions:
    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 
occurs.
    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.

[[Page 25913]]

    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 
carcinogenesis.
    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 
ATP levels.
    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.

III. References

    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://
www.cfsan.fda.gov/lrd/pestadd.html[numsign]furan.
    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, 
1994.
    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, 
2001.
    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 
15(3):373-9, 2002.
    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, 
2000.
    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.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 04-10588 Filed 5-7-04; 8:45 am]
BILLING CODE 4160-01-S