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## Furan CAS No. 110-00-9

Reasonably anticipated to be a human carcinogen First Listed in the Eighth Report on Carcinogens (1998)



### Carcinogenicity

Furan is reasonably anticipated to be a human carcinogen based on sufficient evidence of malignant tumor formation at multiple tissue sites in multiple species of experimental animals (IARC 1995). When administered by gavage, furan induced an increase in the incidence of hepatic cholangiocarcinoma, hepatocellular adenoma, hepatocellular carcinoma, and mononuclear cell leukemia in male and female F344/N rats treated for up to 2 years (NTP 1993). Gavage administration of furan to male F344 rats for 9, 12, or 13 months resulted in high incidences of cholangiocarcinoma by 16 months after cessation of treatment (Maronpot et al. 1991, Elmore and Sirica 1993). When administered by gavage, furan induced a dose-dependent increase in the incidence of hepatocellular adenoma and carcinoma and benign pheochromocytoma in male and female B6C3F 1 mice treated up to 2 years (NTP 1993). No adequate human studies of the relationship between exposure to furan and human cancer have been reported. 

### Additional Information Relevant to Carcinogenicity

In bacteria, furan induced gene mutations in Salmonella typhimurium strain TA100 (Lee et al. 1994) and in E

. coli containing bacteriophage T7 (Ronto et al. 1992), but not in S

. typhimurium strains TA98 (Lee et al. 1994), TA1535, or TA1537 (Mortelmans et al. 1986). In Drosophila melanogaster , it did not induce gene mutations (Foureman et al. 1994). In mammalian in vitro systems, it induced gene mutations in mouse lymphoma cells (McGregor et al. 1988), DNA damage in Chinese hamster ovary (CHO) cells (NTP 1993), and chromosomal damage in CHO cells with an exogenous metabolic activation system (NTP 1993, IARC 1995), but it did not induce DNA damage in mouse or rat hepatocytes (Wilson et al. 1992, NTP 1993). In mammalian in vivo systems, furan induced chromosomal aberrations in bone marrow of B6C3F1 mice (NTP 1993), but did not induce DNA damage in bone marrow or hepatocytes of B6C3F 1 mice (Wilson et al. 1992, NTP 1993) or hepatocytes of F344/CrIBr rats (Wilson et al. 1992). A current hypothesis for the mechanism of furan-induced carcinogenesis is metabolic activation of furan by cytochrome P450 to a reactive and cytotoxic intermediate that stimulates cell replication, increasing the likelihood of tumor induction (Chen et al. 1995, Kedderis et al. 1993). The postulated reactive metabolite is cis -2- butene-1,4-dial, which was recently characterized as a furan metabolite by Chen et al. (1995). This reactive metabolite probably explains furan’s binding reactivity with proteins both in vitro (uninduced and induced F344 male rat liver microsomes) and in vivo (F344 male rat liver protein) in biological systems (Burka et al. 1991, Parmar and Burka 1993). Furan metabolites may react with DNA, but Burka et al. (1991) did not detect any radiotracer in DNA from livers of rats treated with [14C]furan. No data were available that would suggest that the mechanisms thought to account for tumor induction by furan in experimental animals would not also operate in humans.


### Properties

Furan, which is classified as a cyclic, dienic ether, is a clear, colorless, flammable liquid with an ethereal odor. Furan forms explosive peroxides on exposure to air. It is stable to alkalis but forms resins on evaporation or in contact with mineral acids. It is insoluble in water, but is soluble in alcohol, acetone, benzene and ether (IARC 1995, HSDB 2001).



### Use

Furan is used primarily as an intermediate in the synthesis and production of tetrahydrofuran, pyrrole, and thiophene. Hydrogenation of furan over a nickel catalyst produces high yields of tetrahydrofuran and is a source of commercial tetrahydrofuran (NTP 1993, IARC 1995). Furan is also used in the formation of lacquers, as a solvent for resins, and in the production of agricultural chemicals (insecticides), stabilizers, and pharmaceuticals (IARC 1995, HSDB 2001).



### Production

One company in the United States produces furan. Commercial production of furan involves decarbonylation of furfural over a palladium/charcoal catalyst. The minimal purity of the commercial product is 99% (IARC 1995). Approximately 9.7 million lb of furan resins were imported in 1986 (HSDB 2001). Chem Sources (2001) identified 18 U.S. suppliers.


### Exposure

The primary route of potential human exposure to furan is inhalation. Since the industrial processes in which furan is used are conducted in closed systems and its volatility requires that furan be handled in closed containers, occupational exposure is limited (NTP l993). However, furan may be released in the effluent from oil refining, coal mining, and coal gasification (HSDB 2001). It has been detected in cigarette smoke, wood smoke, and automobile exhausts, and it occurs naturally in pine rosin and sorb trees (IARC 1995, HSDB 2001). The National Occupational Hazard Survey, conducted by NIOSH from 1972 to 1974, estimated that 244 workers were potentially exposed to furan in the workplace (NIOSH 1976). The National Occupational Exposure Survey (1981-1983) indicated that 35 workers, including 7 women, were potentially exposed to furan (NIOSH 1984, HSDB 2001). The pattern of commercial use suggests that minimal exposure to the general public would be expected through contact with products contaminated with furan (NTP 1993). Furan has been detected in surface water, industrial effluents, ambient air, foods, human milk samples, and in the breath of both smokers and nonsmokers; however, in most cases, the frequency of detection and concentrations were low. Furan was detected in the indoor air of homes in the Chicago and Washington D.C. metropolitan areas (Jarke et al. 1981); in 1 of 63 industrial effluents at a concentration of <10 μg/L; at 7 μg/L in aqueous condensate samples from low-temperature gasification of rosebud coal; and in one of 12 milk samples obtained from women in four different urban areas (IARC 1995, HSDB 2001). In one study in Texas, furan was detected in the exhaled breath of two out of three male smokers and four out of five male nonsmokers (Conkle et al. 1975, HSDB 2001). Smokers exhaled between 0.25 to 98 μg/h of furan and nonsmokers exhaled between 0.33 and 28 μg/h. In another study in Chicago, 15 of 387 samples collected from 54 male and female nonsmokers had detectable levels of furan in their breath. The mean concentration in breath samples was 0.55 ng/L (HSDB 2001).


### Regulations

DOT Furan is considered a hazardous material and special requirements have been set for

marking, labeling, and transporting this material
EPA Clean Air Act

Prevention of Accidental Release: Threshold Quantity (TQ) = 5,000 lb Comprehensive Environmental Response, Compensation, and Liability Act

Reportable Quantity (RQ) = 100 lb Emergency Planning and Community Right-To-Know Act

Reportable Quantity (RQ) = 100 lb O**S UBSTANCE**  **P ROFILES**  RUNNING

Threshold Planning Quantity (TPQ) = 500 lb Resource Conservation and Recovery Act

Listed Hazardous Waste: Waste codes in which listing is based wholly or partly on

substance - U124

REFERENCES

Burka, L. T., K. D. Washburn and R. D. Irwin. 1991. Disposition of [14C]furan in the male F344 rat. J Toxicol Environ Health 34(2): 245-57. ChemSources. 2001. Chemical Sources International, Inc. http://www.chemsources.com. Chen, L. J., S. S. Hecht and L. A. Peterson. 1995. Identification of cis-2-butene-1,4-dial as a microsomal metabolite of furan. Chem Res Toxicol 8(7): 903-6. Conkle, J. P., B. J. Camp and B. E. Welch. 1975. Trace composition of human respiratory gas. Arch Environ Health 30(6): 290-5. Elmore, L. W. and A. E. Sirica. 1993. "Intestinal-type" of adenocarcinoma preferentially induced in right/caudate liver lobes of rats treated with furan. Cancer Res 53(2): 254-9. Foureman, P., J. M. Mason, R. Valencia and S. Zimmering. 1994. Chemical mutagenesis testing in Drosophila. IX. Results of 50 coded compounds tested for the National Toxicology Program. Environ Mol Mutagen 23(1): 51-63. HSDB. 2000. Hazardous Substances Data Base. National Library of Medicine. http://toxnet.nlm.nih.gov/ cgi-bin/sis/htmlgen?HSDB. HSDB. 2001. Hazardous Substances Data Base. National Library of Medicine. http://toxnet.nlm.nih.gov/ cgi-bin/sis/htmlgen?HSDB. IARC. 1995. Dry Cleaning, Some Chlorinated Solvents and Other Industrial Chemicals. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, vol. 63. Lyon, France: International Agency for Research on Cancer. 558 pp. Jarke, F. H., A. Dravnieks and S. M. Gordon. 1981. Organic contaminants in indoor air and their relation to outdoor contaminants. ASHRAE Trans 87(1): 153-166. Kedderis, G. L., M. A. Carfagna, S. D. Held, R. Batra, J. E. Murphy and M. L. Gargas. 1993. Kinetic analysis of furan biotransformation by F-344 rats in vivo and in vitro. Toxicol Appl Pharmacol 123(2): 274-82. Lee, H., S. S. Bian and Y. L. Chen. 1994. Genotoxicity of 1,3-dithiane and 1,4-dithiane in the CHO/SCE assay and the Salmonella /microsomal test. Mutat Res 321(4): 213-8. Maronpot, R. R., H. D. Giles, D. J. Dykes and R. D. Irwin. 1991. Furan-induced hepatic cholangiocarcinomas in Fischer 344 rats. Toxicol Pathol 19(4 Pt 2): 561-70. McGregor, D. B., A. Brown, P. Cattanach, I. Edwards, D. McBride, C. Riach and W. J. Caspary. 1988.Responses of the L5178Y tk+/tk- mouse lymphoma cell forward mutation assay: III. 72 coded chemicals. Environ Mol Mutagen 12(1): 85-154. Mortelmans, K., S. Haworth, T. Lawlor, W. Speck, B. Tainer and E. Zeiger. 1986. Salmonella mutagenicity tests: II. Results from the testing of 270 chemicals. Environ Mutagen 8 Suppl 7: 1-119. NIOSH. 1976. National Occupational Hazard Survey (1972-74). Cincinnati, OH: Department of Health,
Education and Welfare. NIOSH. 1984. National Occupational Exposure Survey (1981-83). Cincinnati, OH: U. S. Department of Health and Human Services. http://www.cdc.gov/noes/noes3/empl0003.html. NTP. 1993. Toxicology and Carcinogenesis Studies of Furan (CAS No. 110-00-9) in F344 Rats and B6C3F1 Mice(Gavage Studies). Technical Report Series No 402. NIH Publication No. 93-2857. Research Triangle Park, NC: National toxicology Program. 286 pp. Parmar, D. and L. T. Burka. 1993. Studies on the interaction of furan with hepatic cytochrome P-450. J Biochem Toxicol 8(1): 1-9. Ronto, G., P. Grof, J. P. Buisson, J. Einhorn and P. Demerseman. 1992. Genotoxic effectivity--comparison of 36 nitrated furan and arenofuran derivatives on a quantitative scale. Statistical comparison of T7 and other short-term tests. Mutagenesis 7(4): 243-9.Wilson, D. M., T. L. Goldsworthy, J. A. Popp and B. E. Butterworth. 1992. Evaluation of genotoxicity, pathological lesions, and cell proliferation in livers of rats and mice treated with furan. Environ Mol Mutagen 19(3): 209-22.

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