I. INTRODUCTION 



o 



0?N~ 



,CH^N- 



NITKOFURANTOIN 



CASNo. 67 20-9 



NH 



\ 



O 



C8H6N4O5 



Molecular weight 238.2 



Synonyms: l-(((5-nitro-2-furanyl) methylene )amino-2, 4- imidazolidinedione); 

 l-(5-nitro-2-furfurylideneamino)-hydantoin; jV-(5-nitro-2-furfurylidene)-l-aminohydantoin; 

 l-((5-nitrofurfurylidene)amino)hydantoin 



Trade names: fienkfuran; Bcrkfurin; Cheiiiiofiiran; Cyantin; Dantafur; Furadanlin; Furadant ine, 

 F^uradantoin; Furadonin, Furadonine, Furantoin; Furatoin; Furobactina; Itiiran; Macrodantin; 

 Nifurantin, NSC 21U7; N Toin, Orafuran, Parafuran, Urizept; USAF RA-2, Welfurin; ZooCurin 



Use, Production, and Exposure 



Nitrofurantoin is used extensively in the treat- 

 ment of urinary tract infections in humans 

 (D'Arcy, 1985) A derivative of 5-nitrofuran, ni- 

 trofurantoin is structurally related to furan and 

 to nitrofurazone, the first 5-nitrofuran described 

 by Dodd and Slillman (1944) to be an effective 

 broad-spectrum antibiotic, as well as to many 

 other nitrofurans (Bryan, 1978) The 5-nitro- 

 furan derivatives have been used extensively in 

 topically and parenterally administered antisep- 

 tics in humans and animals and as antitumor 

 agents, food preservatives, and feed additives for 

 food production animals. 



The starting material for synthesis of 5-nitrofu 

 rans with antimicrobial properties is 2-furalde- 

 hyde (Ichikawa, 1978). 2-Furaldehyde is con- 

 verted by air oxidation and metal catalysts to 

 furoic acid and is thermally decarboxyiated to 

 furan. Preferential eiectrophilic substitution of 

 the furan ring occurs at the 2-position How 

 ever, nitration of the furan nucleus in the 2 and 

 5 positions is favored under conditions of fuming 

 nitric acid and acetic anhydride (containing the 

 active species CH3C02"N02"^). The 2,5-dini- 

 trofuran is converted to 5-nitrofuran by weak 

 bases, which eliminate acetic acid. 



Clinical use of nitrofurantoin began after World 

 War II, between 1953 and 1984, an estimated 

 121,430,000 courses of therapy were given, ac- 

 cording to data from one manufacturer (D'Arcy, 

 1985). Nitrofurantoin treatment for infections 

 may occur over periods of up to 30 months 

 (Simonian et al., 1977) Recent production fig- 

 ures are not available, but in 1974, commercial 

 production was reported to the International 

 Trade Commission (USITC, 1976) (implying 

 that production was greater than 1,000 lb/year) 

 and was listed with the U.S. Environmental 

 Protection Agency TSCA in 1980 (NIOSH, 

 1983). In 1986, 9,300 kg of nitrofurantoin in 

 various preparations was purchased by drug- 

 stores and hospitals (U.S. Pharmaceutical Mar- 

 ket Data Base, 1986). Exposure to nitrofuran- 

 toin in the United States has been estimated at 

 8,900 kg/year (NCI/SRI, 1978). 



Absorption, Metabolism, and Excretion 



After oral or parenteral administration, nitrofu- 

 rantoin is rapidly absorbed and is excreted pri- 

 marily unchanged in the urine and bile of hu- 

 mans (Conklin and Ilailey, 1969; Conklin, 

 1972a,b), rats (Paul, HE., et al., 1960; Buzard et 

 al., 1961; Veronese et al., 1974; Wierzba et al., 

 1982), mice (Maiti and Banerjee, 1978), and dogs 



Nitrofurantoin, NTP TR 341 



16 



