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Chapter 11 FURAZOLIDONE O2NN\N~o H \~/ Furazolidone occurs as an odorless, yellow crystals that melt at 275C. The crystals will darken under strong light and are decomposed by alkali. Furazolidone ' s volubility in water (pH 6 ~ is approx ima te ly 4 0 mg/1 . I t is a lso known by the following synonyms and trade names: 3-[ [~5-nitro-2-furanyl~methylenelamino]- 2-oxazolidinone, 3-~5-nitrofurfurylideneamino)-2-oxazolidinone, _-(S-nitro-2-furfurylidene)-3-amino-2-oxazolidone, NF 180, Furovag, Furoxane, Furoxone, Giarlam, Giardil, Medaron, Neftin, Nicolen, Nifulidone, Ortazol, Roptazol, Tikofuran, and Topazone. Furazolidone is produced synthetically from furfural, hydroxyethylhydrazine, and d iethyl carbonate . PRODUCTI ON The sole U. S . producer of furazol idone is the Norwich Pharmaceutical Company in Norwich, N.Y. (Stanford Researab Institute International 1979 ~ . The compound is prepared according to procedures described in U.S. patents 2,759,931 and 2,927,110 to Norwich Pharmaceutical Co. It was first produced in 1953 as a veterinary medicinal and feed additive, and in 1957 as a human 288

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systemic medicine! for U.S. and worldwide use (Federal Register, 1976a,b; Bryan, 19783. The U.S. International Trade Commission (1976-1978) reports furazolidone data obtained on group of 20 pher~ceutical chemicals whose combined production totals approximately 3.2 million kg/year. The fact that production is reported to and by the commission indicates that annual production is 450 kg or ore. USES Furazol idone is one of f ive S-nitrofurans currently approved for use as systemic veterinary medicines in the United States (Federal Register, 1976a,b; Bryan, 1978) . Its use was approved in 1953 to treat turkeys and chickens for fowl typhoid, paratyphoid, and pullorum; blackhead (histomoniasis); nonspecific enteritis (blue comb, mud fearers , ulcerative enteritis (quail disease), and synovitis (ar thr itis due to f Alterable virus); and paracolon infection (Paracolobactrum). Furazolidone use is permitted in chickens for infectious hepatitis and coccidiosis, in turkeys for hexamitiasis, and in swine for bacterial enteritis (necrotic enteritis, black scours) or vibrionic (bloody) dysentery (Federal Register, 1976a) . Furazol idone is one of two 5-nitrofurans that have been approved in the United States as veterinary feed additives (Federal Register, 1976a,b), and it accounts for approximately 97% of the 5-nitrofurans administered to food-producing animals (Federal Register, 1976b) . As a feed additive, the compound has been approved 289

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for use in chickens and turkeys to prevent fowl typhoid, paratyphoid, pullorum, air-sac infection and paracolon infection, and to enhance growth and feed ef f iciency. In swine, it is approved for the prevention of bacterial enteritis and vibrionic dysentery, and for growth promotion and enhanced feed eff iciency (Federal Register, 1976a) . In 1976, the Food and Drug Administration (FDA} pub' ished proposals to withdraw approval of furazolidone for the Deter inary purposes for which it is now used (Federal Register, 1976a ,b) . To date, no f inal action on these proposals has been taken. Furazol idone has been used in humans to treat bacillary dysentery, typhoid and paratyphoid fevers, giardiasis, brucellosis, and intestinal infections of undetermined etiology {Bryan, 1978; Miura and Reckendorf, 1967: Paul and Paul, 1964, 1966~. EXPOSURE Furazolidone has been the subject of controversy in recent years. The chemical has been determined to cause cancer when ingested by rats and mice, although the producer has challenged this finding. In 1976, the FDA proposed to withdraw approval for use of the drug in food-producing animals (Federal Register, 1976a} . At that time, the agency ruled that data were not adequate to determine the total drug-related residues that can occur, that the analytic techniques for measuring the drug were not reliable for the lower concentrations found in food, that the drug was present in edible tissue following medication when no withdrawal period was observed, 290

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and that a reliable withdrawal period could not be established from the information ava ilable. The results of testing for furazolidone in controlled exper iments a re shown in Table 11-1 . As ind icated, each study concluded the t residues were undetectable (usually with a detection limit of 1 to 5 mg/g) after a 2- to 19-day withdrawal period. The 1976 proposal to ban the use of furazolidone in food-product ng an imals was withdrawn because of problems in obta in ing supportive data, but another proposal is being issued in 1980 (Moy, Food An ima 1 Add i t ive Bra nch, FDA, per sona 1 conm~un ice t ion, 1980 ~ . Although FDA requ ires that food products con ta in no res idue, compliance is handled by the U. S. Department of Agriculture. Because analytic techniques for sampling at low concentrations are unreliable, the existing regulations have not been enforced. It is not possible to estimate the degree to which humans are exposed to this drug. The largest potential for exposure occurs from its presence in food. However, the residue disappears or, at the very least, becomes undetectable, within 20 days after the withdrawal of medication . Thus, the concentrations expected in furazolidone-treated food products cannot be estimated. Moreover, there is no information concerning the percentage of the total poultry and swine treated with the drug. Minute quantities may be released to the air, water, and solid waste in the vicinity of the plant. 291

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Table 11-1 Results of Testing for Furazol idone in Food Food Hype Dose Res idue Reference Chicken ~Excessive. None after 2 days Krieg and Loeliger, 1973 Eggs 100 mg/100 ml water 8 mg/g on 3rd day; Krieg, 1972 for 3 days, and none after 10 S mg/100 mg for 2 days days Eggs 40 mg/100 g water 23 micrograms/9 Krieg, 1972 for 15 days on 6th day; none after 19th day Vea 1 Unknown None found Nouws, 1973 292

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ANALYTIC METHODS Most of the analytic methods for furazolidone are based on thin-layer chromatography (TLC), high-pressure liquid chromatography IMPLY), W absorption spectrophoto~netry, or comb ina t ion s of the se techn ique s . A general procedure using TLC to identify 18 drugs, including furazolidone, in animal feed was reported by Williams (1978~. The sample was extracted with acetonitrile-chloroform (4:1), and an aliquot of the extract was cleaned on a column of aluminum oxide. The concentrated eluate was then subjected to TLC on silica gel G by using chloroform-methanol (9:1) to develop the plate. Spots were made visible on the plates by spraying with 1,2-diaminoethane or with Dragendorff's reagent. Cieri (1978) also reported a method for determining furazolidone in animal feed. The sample was extracted with acetone and cleaned on TLC plates of silica gel H by using chloroform-methanol (9 :1) to develop the plates. The appropriate zone was scraped from the plate, eluted with ethyl alcohol, and quantitated at its absorption maximum near 360 nm. The method was reported not to be applicable at levels below 0.005%. Moreta in et al . (1979 ~ described a procedure for determining furs zol idone and furaltadone in admixture at the levels expected in animal feed ~ i.e., SO to 200 ppm) . The sample was extracted 293

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with dimethylformamide (DMF) and subjected to TLC on silica gel plates developed with chloroform-acetone (7:31. The appropriate zones were then scraped from the plates, extracted with DMF, and determined spectrophotometr ically at 370 nm. Methods reported recently have all been based on HPLC. Lefeb~re (1979 ~ demonstrated that furazolidone could be assayed by HPLC, using a glassy carbon or carbon paste electrode, coupled with a voltametr ic-amperometric detector. Detection limits were reported to be in the low nanogram range; however, no actual residue assays were performed. Using HPLC Jones et al. (1978) determined furazolidone levels in swine and poultry feed at levels as low as 5ppm, with a silica column and a mobile phase of water-saturated dichloromethone. The W-visible detector was set at 360 nm. The sample preparation consisted only of extracting the feed with methanol and 2 N hydrochloric acid (1:1), partitioning the residue into dichloromethane, and concentrating the solvent for a 20 pi injection into the HPLC system. Again using HPLC, Cieri (1979) determined residues of furazolidone and nitrofurazone in feeds at levels as low as 0.5 ppm. The sample was extracted with DMF-acetone (1:1), cleaned on a column of silica gel, and analyzed on a reverse-phase column with 30% acetonitrile as the mobile phase. The detector was set at 365 nm. Hoener et al. (1979) recently reported an HPLC procedure for determining residues of furazolidone in turkey tissue at levels as low as 2 ppb. The tissue was ground with methanol and centrifuged. 294

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The extract then was either injected directly or concentrated be fore be ing in jec ted into the HPLC system. A Bondapak Cue column was used with a mobile phase consisting of methanol and 0.01 mol sodium acetate (1:47. We W absorption detector was set at 365 nm. Recoveries from muscle and liver spiked at the 2 ppb level were 103 + 19% and 112 + 12%, respectively. Bagon { 1979 ~ used a Spher isorb S5-ODS column for HPLC separations of several antibiotics and nitrofurans in pharmaceutical preparations. Furazolidone was separated from nitrofurazone by using a mobile phase of water-methanol (11:9) with the absorption detector set at 375 nm. Although no sables other than pharmaceutical preparations were analyzed, the procedure is sa id to be generally capable of distinguishing the parent compounds from decomposition products and likely congeners. Problems associated with the analysis of furazolidone in edible tissues of at levels of 0.5 to 4.0 ppb with methods ava liable prior to 1976 are well documented (Federal Register, 1976~. Various spectrophotometric and TLC procedures failed to yield satisfactory and reproducible recoveries at these levels. 295

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HEALTH EFFECTS Metabol Sam Furazolidone is biotransformed In Vito in mammals to a variable but major extent (Swaminathan and Lower, 1978~. Two to five metabolites have been suggested from In vitro or in viva analyses (Federal Register, 1976a; Tatsumi et al., 1978~. One biotransformation product, 3-~4-cyano-2-oxobutylideneamino)-2- oxazolidone, was characterized by mass-, ultraviolet-, and nuclear-magnetic-resonance-spectroscopic methods following furazol idone incubation In vitro with milk xanthine oxidase or administration in viva to rabbits, when it was identif fed in urine. In contrast to furazolidone, this metabolite was not an active mutagen in Salmonella typhimurium TA 100 (Tatsumi et al., 1978) . Acute Toxicity Humans. Reported symptons of acute toxicity of furazolidone in humans include nausea, emesis, occasional diarrhea, abdominal pain, and bleeding (Cohen, 1978~. Infrequently, there have been reports of an Antabuse-like reaction to alcohol (Cohen, 1978) or, rarely, idiosyncratic or hypersensitivity reactions such as pneumonitis (Cohen, 1978; Collins and Thomas, 1973; Cortez and Pankey, 1972; Jira sek and Kalensky, 1975 ~ . Hemolytic anemia due to glucose-6-phosphate- dehydrogenase def iciency has been reported with furazo' idone (Cohen, 1978) . Furazolidone demonstrated monoamine-oxidase inhibition (Pettinger and Gates, 1968 ~ and 296

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required precautions when coadministered with other moneamine-oxidase inhibitors, sympathomimetic amines, or tyramine-containing foods. No data have been reported concerning chronic toxic effects of f u ra zol idone in humans . Animals. Furazolidone induced emesis and necrologic changes in dogs (Miura and Rekkendorf, 1967; Rogers et al., 1956) . No published oral LD50 data exist for manunals. The drug also induced cardiomyopathy in turkeys (Czarnecki et al. , 1978; Staley et al.. 1978 ) . Ch ron ic Tox ic i ty Care inogenic ity Humans. No furazolidone-associated carcinogenicity in humans teas been repor ted . An ima Is . Fura zol idone wa s eve lusted for ca rc inogen ic activity in six studies in rats and one study in mice (Federal Register, 1976a,b; Cohen, 1978), but no review of these studies teas yet appeared. However, the FDA has summarized the statistically signif icant ef fects resulting from its analyses of the data submitted (Federal Register, 1976a,b) and has used these evaluations as the basis for proposed regulatory action (Federal Register, 1976a,b). Statistical comparisons of significant effects in rats and mice of both sexes exposed to varying dose levels of furazolidone administered orally for 18 or more months are presented in Tables 11-2 through 11-5. 297

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dose-dependent SCE in the Cohen and Sagi study (1979 ~ and that this type of chromosomal damage was not reported by ]'omomura and Sasaki (1973 ~ suggests that this compound is capable of inducing chromosomal damage in human cells. Further studies are needed to clarify this point. Bacterial DNA. Furazolidone inhibits DNA synthesis in V. cholerae cells while stimulating RNA and protein synthesis and causing filamentation of these cells (Chatterjee and Haiti, 19737. Chatterjee et al. (1977) reported that interstrand cross-linking in DNA takes place with in the furazol idone-treated V. cholerae cells, which therefore might explain the actual mechanism of inhibition of DNA biosynthesis by this drug. The In vivo action of furazolidone has considerable similar ity to that of miton~cin C (Iyer and Szybalsk i, 1964 ~ . Both agents induce interstrand cross-linking in DNA, inhibit DNA synthesis, and cause filamentation of the cells at the appropr late dose level by inhibiting cell division. Te ratogen ic ity No data were ava liable to evaluate the teratogenicity or embryotoxicity of furazolidone. CONCLUS IONS Furazol idone has exhibited carcinogenic effects in male and female rats and mice in a variety of tissues. Susceptible tissues are dif ferent for the two species. Furazolidone, in common with 309

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most 5-nitrofurans studied, is a significant carcinogen in rodents (Cohen, 1978~. Furazolidone is highly mutagenic in both microbial (E. coli) and insect (D. melanogaster) test systems, produces chromosomal damage (breakage, SCE, mitotic suppression) in human lymphocytes, and forms interstrand cross-linking in bacterial (V. cholere) DNA. It is for the above reasons that the use of furazolidone is now being reviewed by the FDA. Resolution of this matter awaits the development of a sufficiently sensitive and reliable analytic method. If risk to human health does exist, it most certainly would be associated with the use of furazolidone for veterinary purposes. A ~solution" may involve the substitution of an efficacious product that could be demonstrated not to have the mutagenic and carcinogenic potential of furazolidone. 310

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REFERENCES Production, Uses, Exposure Federal Register. 1976a. E'urazolidone (NF-180~- Notice of opportunity for hearing on proposal to withdraw approval of certain new animal drug applications. Fed. Reg. 41 :19907-19921. Federal Reg ister . 1976b. Furazolidone, nihydrazone, furaltadone, nitrofurazone withdrawal of proposals and notice of proposed rule making. Fed. Reg. 41~160~:34884-34921, August 17, 1980. Bryan, G.T. 1978. Occurrence, production, and uses of nitrofurans. Pp. 1-11 in G.T. Bryan, ed. Carcinogenesis--A Comprehensive Survey. Volume 4. Nitrofurans: Chemistry, Metabolism, Mutagenesis and Carcinogenesis. Raven Prens, New York. Krieg, R., and H.C. Loeliger. 1973. Determination of furazolidone in blood and tissues of broilers and laying hens after therapeutic application. Arch. Gefluegelkd. 37:93-97. [Chem. Abs. 79:124809w, 19731. Krieg, R. 1972. Passage of furazolidone into eggs with therapeutical application. Arch. Gefluegelkd. 36: 171-174. [Chem. Abs. 78 :105962d, 1973. ~ 311

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Miura, K., and H. K. Reckendorf . Med . Chem. 5: 3 20-381 . Nouws, J.F.M. 1913. 1967. file nitrofurans. Prog. Antibiotic residues detected after slaughter in calves fattened with milk replacers. Tiidsctir. Diergeneeskd. 98: 229-240 ~ in Dutch; English summary] . Paul, H.E., and M.F. Paul. 1964. Ime nitrofurans-- chemotherapeutic properties. Pp. 307-370 in R.J. Schnitzer and F. Hawk ing, eds. Experimental Chemotherapy, Volume 2: Chemotherapy of Bacter ial Infections, Part I . Academic Press, New York. Paul, H.E., and M.F.Paul. 1966. The nitrofurans-- chemotherapeutic properties. Pp. 521-S36 in R. J. Schnitzer and F. Hawking, eds. Exper imental Chemotherapy, Volume 4: Chemotherapy of Neoplastic Diseases, Part I. Academic Press, New York. SRI International. 1979. 1979 Directory of Chemical Producers: United States of America. Stanford Research Institute, International, Menlo Park, Calif. 1122 pp. U. S. International Trade Commission. 1976. Synthetic Organ ic Chemicals. United States Production and Sales, 1974. USITC Publication 776. U.S. Government Printing Office, Washington, D.C. 256 pp. 312

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U.S. International Trade Commission. 1977. Synthetic Organic Chemicals. United States Production and Sales, 197S. USITC Publication 804. U.S. Government Printing Office, Washington, D.C. 246 pp. U. S. International Trade Commission. 1977. Synthetic Organic Chemicals. United States Production and Sales, 1976. USITC Publication 833. U.S. Government Printing Office, Washington, D.C. 357 pp . . 313

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Analytic Methods Bagon, K. R. 1979 . The assay of antibiotics in pharmaceutical preparations using reverse-phase HP=. ARC CC, J. High Resolut. Chromatogr . Chroma tog r . Commun. 2: 211-215 . Cier i, U. R. 1978. Quantitative thin layer chromatographic determination of furazolidone and nitrofurazone in animal feeds . J . Assoc. Of f . Anal. Chem. 61: 92-95 . Cier i, U. R. 1979. High-pressure liquid chromatographic detection and estimation of furazolidone and nitrofurazone in animal feeds. J. Assoc. Off. Anal. Chem. 62:168-170. Federal Register. 1976. Furazolidone, nihydrazone, furaltadone, nitrafurazone withdrawal of proposals and notice of proposed rU1e making. Fed. Re9. 41~160~:34884-34921 (August 17, 19761. Hoener, B., G. Lee, and W. Lundergan. 1979. High-pressure liquid cbromatographic determination of furazolidone in turkey tissue. J . Assoc . Of f . Anal . Chem. 62: 257-261. Jones, A.D., E.C. Smith, S.G. Sellings, and I.W. Burns. 1978. Determination of furazolidone in pig and poultry feeds by high-performance liquid chromatography. Analyst (London) 103:1262-1266. 314

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Lefebvre, J.C. 1979. {ln detecteur voltametrique/amperometrique pour des ni~reaux nano- et sub-nanogranoniques en chromatographie 1 iqu ide a hau te pre ss ion . Feu ill. Biol. 20 :105-109 . Moretain, J.P., J. Boisseau, and G. Gayot. 1979. Thin-layer chromatographic analysis of nitrofurans in feed premixes. J. Agric. Food Chem. 27:454-456. Will iams, D. R. 1978. Identif ication of prophylactic and growth-promoting drugs in anima1 feedingstuffs. Report prepared by the Medicinal Additives in Animal Feeds Sub-comm i t tee n B. . n Ana lys t (London ~ 10 3: S13-520 315

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Bea Ith Ef feats Bli jleveh, W.G.H., M.J.H. Kortseluis, and P.G.N. Kramers. 1977. Mutagenicity testing of H-193, AF-2 and furazolidone in Drosophila melanogaster. Mutat. Res. 56: 95-100 . Chatter jee, S.N., S. Chose, and M. Maiti. 1977. Cross linking of deoxyribonucleic acid in furazolidone treated Vibrio cholerae cell. Biochem. Pharmacol. 26: 1453-1454. Chatter See, S.~., and M. Maiti. 1973. Effects of furazolidone on the reproduct ion of cholera phase . 11: 134-136. Ted fan J . Exp. 8iol . Cohen, S.M. 1978. Toxicity and carcinogenicity of nitrofurans. Pp. 171-231 in G.T. Bryan, ed. Carcinogenesis--A Comprehensive Survey, Volume 4. Nitrofurans: Chemistry, Metabolism, Mutagenesis, and Carcinogenesis. Raven Press, New York. Cohen, M. M., and M. Sag i. 1979. The effects of nitrofurans on mitosis, chromosome breakage and sister-ct~romatid exchanges in human per iphera1 lymphocytes. Mutat. Res. 59 :139-142 . Collins, J.V., and A.L. Thomas. 1973. Pulmonary reaction to Furoxone. Postgrad. Med. J. 49: 518-S20 . 316

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Cortez, L.M., and G.A. Pankey. 1972. hypersensitivity to furazolidone. 105:823-826. Acute pulmonary Am. Rev. Respir. Dis. Czarnecki, C.M., A. Jegers, and E.F. Jankus. 1978. Characterization of glycogen in selected tissues of turkey poults with spontaneous round heart disease and furazolidone-induced cardio~yopa tiny. A`:ta Anat. 102: 33-39. Federal Reg ister . 1976a . Furazol idone {NF-180 ): Notice of opportunity for hearing on proposal to withdraw approval of certain new animal drug applications. Fed. Regist. 41:19907-19921. Federal Register. 1976b. Furazolidone, nihydrazone, furaltadone, nitrofurazone : Withdrawal of proposals and notice of proposed rule making. Fed. Regist. 41:34884-34921. Iyer, V.N., and w. Szybalski. 1964. Mito~ycins and porfiromycin: Chemical mechanism of activation and cross-linking of DNA. Science 145:55-58. Jirasek, L., and J. Kalenaky. 1975. Allergic contact eczema from feeding mixtures in animal production. Cesk. Dermatol. 50:217-225 [in Czecb; English summary]. 317

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Lu, C., D.R. McCalla, and D.W. Bryant. 1979. Action of nitrofurans on E. colt: Mutation and induction and repair of daughter-strand gaps in DNA. Mutat. Res. 67 :133-144. McCalla , D. R., A. Reuvers, and C. Kaiser . 1971. Breakage of bacterial DNA by nitrofuran derivatives. Cancer Res. 31: 2184-2188. McCalla , D. R., and D. Voutsinos. 1974 . On the mutagenicity of nitrofurans. Mutat. Res. 26: 3-16. McCann, J., E. Choi, E. Yamasaki, and B.N. Ames. 1915. Detection of carcinogens as mutagens in the Salmonella microsome test: Assay of 300 chemicals. Proc. Nat. Acad. Sci. USA 72: 5135-5139. Micra, K., and H.K. Reckendorf . 1967. The nitrofurans. Prog. Med. Chem. 5:320-381. Pettinger, W.A., and J.A. Dates. 1968. Supersensitivity to tyramine during monoamine oxidase inhibition in man. Mechanism a t the level of the adrenerg id neuron. C1 in. Pharmacol . Ther . 9: 341-344 . Pagers, G.S., G.B. Belloff, M.F. Paul, J.A. Yurchenco, and 5. Gever. 1956. Furazolidone, a new antimicrobial nitrofuran. A review of laboratory and clinical data. Antibiot. Chemother. (Washington, D.C. ~ 6:231-242. 318

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Staley, N.A., G.R. Noren, C.M. Elandt, and H.L. Sharp. 1978. Furazol idone-induced cardiomyopathy in turkeys: with a relative 1-antitrypsin deficiency. 91:5 31-544 . ~ . Association Am. J. Pathol. Swaminathan, S., and G.M. Lower , Jr . 1978. Biotransforeations and excretion of nitrofurans. Pp. 59-97 in G.T. Bryan, ed. Carcinogenesis~A Comprehensive Survey, volume 4. tlitrofurans: Chemistry, Metabolism, Mutagenesis, and Carcinogenesis. Raven Press, New York. Tatsumi , K., T. Ou, H. Yamada , H. Yoshimura , H. Rosa , and T. Horiochi. 1978. Isolation and identification of the metabolite of N-~5-nitro-2-fur furylidene ~ -3-amino-2-oxazolidone (furazolidone). J. Pharmacobio-Dyn. 1:256-261. [Chem. Abs. 90: 80648p, 1979. ~ Tonomura, A., and M.S. Sasaki. 1973. Chromosomal aberrations and DNA reps ir synthes is in cultured human cells exposed to nitrofurans . Japan J. Genet. 48: 291-294 319 . 1