FINAL DRAFT
United States
Env.ronmema, Protect on 500ECAOCING01 6
SEPA Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR SELECTED NITROFURANS
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: DO NOT CITE OR QUOTE Region VU^"13' Prฐtect!on
230 south Dearborn Street
NOTICE Chlca^ ป"m>ls 6060ซ
This document Is a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It Is being circulated for comments"
on Us technical accuracy and policy Implications.
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DISCLAIMER
This report Is an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Waste and Emergency Response (OSWER). This document series
Is Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). Both published literature and
Information obtained from Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for In this document
and the dates searched are Included In "Appendix: Literature Searched."
Literature search material Is current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document Is sent to the Program Officer (OSWER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses (RfDs)
for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfD, is an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time interval, for example, one that does
not constitute a significant portion of the Hfespan. This type of exposure
estimate has not been extensively used, or rigorously defined as previous
risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfDs is the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfDs are not estimated. A
carcinogenic potency factor, or q-j* (U.S. EPA, 1980), is provided Instead.
These potency estimates are derived for both oral and Inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxicity and carcino-
genldty are derived. The RQ is used to determine the quantity of a hazar-
dous substance for which notification Is required 1n the event of a release
as specified under the CERCLA. These two RQs (chronic toxicity and cardno-
genlclty) represent two of six scores developed (the remaining four reflect
IgnHabllUy, reactivity, aquatic toxldty, and acute mammalian toxicity).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxicity and cancer-based RQs are defined in U.S.
EPA, 1983a and 1986a, respectively.
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EXECUTIVE SUMMARY
The selected nltrofurans are a class of synthetic compounds character-
ized by the presence of the 5-n1tro-2-furanyl functional group. With the
exception of 5-n1tro-2-furancarboxaldehyde and nltrofurfuryl methyl ether,
the nltrofurans are solids with high melting points. They are, 1n general,
sparingly soluble to Insoluble 1n water and darken on exposure to light.
The nltrofurans are used either as antibacterial agents (for oral or topical
applications to humans or animals) or as Intermediates In the synthesis of
other nltrofurans (Ebetino, 1978; IARC, 1974, 1983; Wlndholz, 1983; Bateman,
1980). Currently, one U.S. manufacturer - produces at least four of the
selected nltrofurans (SRI, 1986).
Because of the lack of experimental data, most of the conclusions
reached about the environmental fate and transport of nltrofurans are specu-
lative. Photolysis 1s expected to.be a major environmental fate process for
the nltrofurans because they absorb light very strongly 1ii the sunlight
region of the spectra (Sadtler, 1962, 1963a,b,c, 1965, 1966; Wlndholz, 1983)
and darken on exposure to sunlight (Wlndholz, 1983; Ebetino, 1978). In
water, photodecomposltlon 1s expected to be the major removal mechanism.
Exposure of an aqueous solution of nltrofurazone to sunlight has been shown
to result 1n photodecomposltlon (Shahjahan, 1979; Shahjahan and Enever,
1979). Aquatic volatilization, adsorption to sediments and bloconcentratlon
are not expected to be significant. In the atmosphere, the nltrofurans can
undergo photolysis and oxidation by photochemically produced OH radicals and
ozone. The half-life for the vapor phase reaction of nltrofurfuryl methyl
ether and 5-n1tro-2-furancarboxaldehyde with hydroxyl radicals and ozone 1n
1v
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the atmosphere has been estimated to be -16 minutes (U.S. EPA, 1987). In
soil, the nltrofurans appear to be susceptible to leaching and surflcial
photolysis.
*
Pertinent water, food, air or dermal monitoring data could not be
located In the available literature as cited In Appendix A. A National
Occupational Hazard Survey conducted between 1972 and 1974 estimated that
24,802 U.S. workers may be exposed to furazolldone and 3805 workers may be
exposed to nltrofurazone (NIOSH, 1984).
The lowest reported nltrofuran concentration that was toxic to fish and
Invertebrates other than protozoa was 10 mg/8, nltrofurazone, which was a
24-hour LCrn for striped bass larvae. A large volume of Information was
provided by McCalla (1965) and McCalla and Reuvers (1970) who Investigated
toxldty of several nltrofurans to Euqlena gradlls cultures. The most
toxic compounds 1n these studies were 2-n1trofuran, nltrofurfural, 5-n1tro-
2-methylfuran, furalazlne and 5,5-d1n1tro-2,2-d1furan, all of which were
lethal or caused bleaching at 2-3 mg/i. Limited data for aquatic plants
and bacteria Indicated that concentrations of 1 mg/i nltrofurazone,
furazolldone or AF-2 Inhibited growth of Selenastrum caprlcornutum.
Chlorella pyrenoldosa and Achromobacter aquamaMnus. respectively.
Experiments with animals (Veronese et al., 1974; ConkHn et al., 1969)
and humans (Conklln, 1978; Hoener and Patterson, 1981) Indicate that
nltrofurantoln Is rapidly and nearly completely absorbed from the
gastrointestinal tract, predominantly from the small Intestine rather than
from the stomach or colon (Veronese et al., 1974). In humans, the rate of
gastrointestinal absorption Is Increased by decreasing the size of the
crystalline structure (Hoolenaar et al., 1976; Forn and P1no, 1974;
Mannlsto, 1978; Conklln and Halley, 1969; Rosenberg and Bates, 1976) or
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administration with food rather than during a fasting period (Hannlsto,
1978; Rosenberg and Bates, 1976; Hoener and Patterson, 1981). Increasing
the viscosity of a suspension of nltrofurantoln decreases the rate of
absorption (Sod and Parrot, 1980; Seager, 1968). In laboratory animals,
gastrointestinal absorption of nltrofurazone 1s -88% (Tatsuml et al., 1971),
of furazolldone Is -80-90% (Tatsuml and Takahashl, 1982; Tennent and Ray,
1971), of furalazlne Is -40-50% and acetyl furatrlzlne Is -20% (Takai et
al., 1974). Furazolldone may be absorbed poorly In humans (IARC, 1983). A
minimum estimate for gastrointestinal absorption of fuMum Is -42% of an
administered dose (Cohen and Bryan, 1978).
Although data were not located for absorption following Inhalation
exposure, Intratracheal administration of nltrofurantoln to dogs led to
plasma levels and urinary excretion Identical to that noted with Intravenous
treatment, which suggests that absorption may be more rapid following
Inhalation compared with oral exposure (Conklin, 1978)..
Following Intravenous treatment with nltrofurantoln, blood levels drop
rapidly, suggesting rapid distribution (Conklin, 1978). Reversible binding
to plasma protein Influences movement Into other extracellular fluid
compartments such as cerebrospinal fluid and aqueous humor. Nltrofurantoln
appears 1n human seminal fluid at concentrations greater than those In
plasma {Conklin, 1978) and, at least In some animal species, crosses the
placental barrier (Buzard and Conklin, 1964). Tissue levels of radio-
activity after treatment with 14C-nitrofurantoin (Statham et al., 1985),
14C-furazoHdone (Tennent and Ray, 1971) and l4C-fur1um (Wang et al.,
1975) are highest in the liver or kidney, organs associated with elimina-
tion. No single tissue appears to retain nltrofuran-associated radio-
activity following a single dose, but bloaccumulatlon following chronic
dosing has not been investigated.
v1
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Pathways for the metabolism of the nltrofurans Include nltroreductlon
(Conklin, 1978; Hoener and Patterson, 1981; Boyd et al., 1979; Hoener and
Krueger, 1984; H1nch1n et al., 1984, 1986; Holtzman et al., 1981; Yeung et
al., 1983; Tatsuml et al., 1973b, 1975, 1981, 1984; Akao et al., 1971a;
Tennent and Ray, 1971; Tatsuml and Takahashl, 1982; Abraham et al., 1984;
Wang et al., 1975; Skarka, 1981), which Is sometimes accompanied by opening
of the furan ring, hydroxylatlon of the furan ring (Conklln, 1978; OHvard
et al., 1976; Jonen et al., 1980), side chain modifications (Conklln, 1978;
Skarka, 1981) and hydrolytlc removal of the side chain (Conklin, 1978;
Tatsuml et al., 1984). Generally, metabolism by nltroreductlon predominates
and appears to occur by two separate mechanisms: one that is NADPH-dependent
and associated with liver mlcrosomes (Holtzman et al., 1981; Boyd et al.,
1979; Abraham et al., 1984; Tatsuml et al., 1981; Wang et al., 1975) and one
similar to xanthlne oxldase, associated with supernatant fractions of tissue
homogenates (Boyd et al., 1979; Mlnchin et al., 1986; Akao et al., 1971a;
Tatsuml et al., 1981). The extent of nltroreductlon has been directly
correlated to the extent of binding of metabolites to tissue macromolecules.
The nltrofurans and their metabolites are excreted principally and
rapidly through the urine (Hoener and Patterson, 1981; Veronese et al.,
1974; Braeunllch et al., 1978; Wlerzba et al., 1982, 1984; WataM et al.,
1985), with both tubular secretion (Braeunllch et al., 1978; Akerblom, 1974)
and glomerular filtration (Veronese et al., 1974) contributing. Renal
excretion appears to be a rate-saturable process (Veronese et al., 1974;
Watarl et al., 1985). Tubular resorptlon has been observed for nltrofuran-
toln and has been shown to be pH-dependent, since the drug Is a weak organic
acid with a pKa of 7.2 (Braeunllch et al., 1978).
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Biliary excretion of the nltrofurans and their metabolites appears to be
a less Important phenomenon, which accounts for -20% of an Intravenous or
oral dose of nltrofurantoln In the dog (Conklln, 1978) and -14.8% of an oral
dose of furazolldone 1n the rat (Tatsuml and Takahashl, 1982).
Data regarding the toxldty of the nltrofurans by relevant routes of
exposure are restricted to oral exposure. Most of the nltrofurans tested
have been shown to be oncogenlc In animals. Furazolldone (U.S. DHEW,
1976a,b), fuMum (Erturk et a!., 1970c; Cohen et a!., 1975) and nitrofura-
zone (Morris et al., 1969; Erturk et al., 1970c; U.S. DHEW, 1976b) have been
shown to Increase the Incidence of mammary tumors In female rats. Furazoll-
done has also been associated with the Induction of lung tumors 1n mice
(U.S. DHEW, 1976a). Furlum 1s also carcinogenic In mice and 1s associated
with leukemlas (Cohen et al., 1970, 1973a,b; Cohen and Bryan, 1978; Headley
et al., 1977). In hamsters, fuMum 1s associated with tumors of the urinary
bladder (Croft and Bryan, 1973); 1n dogs, 1t Is associated with tumors of
the .mammary gland and gall bladder (Erturk et al., 1970b). Nltrofurantoln
was associated with an Increased Incidence of mammary tumors In germ-free
(Wang et al., 1984) but not 1n conventionally-maintained rats (Morris et
al., 1969; Cohen et al., 1973c). Negative results for carclnogenlclty were
reported for 5-n1tro-2-furancarboxaldehyde dlacetate In rats (Morris et al.,
1969) and for nltrovln In rats (Erturk et al., 1980, 1983).
All the nltrofurans that have been tested for mutagenlclty were positive
1n reverse mutation and other tests In prokaryotes (Rosenkranz and Speck,
1977). Exogenous metabolic activation was not always required, but
bacterial strains with n1troreducta-se activity did seem to be necessary for
a positive result. Generally positive results were observed 1n yeasts (Ong,
1978; B1gnam1 et al., 1982; Knapp et al., 1983) and mixed results were noted
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1n ]). melanoqaster (Kramers, 1978, 1982; ZlmmeMng et al., 1985) and various
in vitro and in vivo mammalian systems (Probst and Hill, 1980; Probst et
al., 1981; Cohen and Sagi, 1979; Tonomura and Sasaki, 1974; Lee et al.,
1980).
The most sensitive target organ to the systemic toxldty of the
nltrofurans appears to be the testls. Furazolldone (Konno et al., 1977;
Hernandez et al., 1985), nltrofurantoln (Nelson and Bunge, 1957; Nelson and
Stelnberger, 1953; Southern Research Institute, 1980) and nltrofurazone
(Nelson and Stelnberger, 1953; Formanek et al., 1971; Hagenas et al., 1978;
Hershberger et al., 1969; Physiological Research Laboratories, 1980a) all
have adverse effects on the testes of rats, 'mice and/or man. Nltrofurantoln
was associated with ovarlon degeneration (Southern Research Institute, 1980)
and nltrofurazone with uterine hypoplasla (Physiological Research Labora-
tories, 1980a) In rats.
Furazolldone given orally to female mice can Interrupt pregnancy
(Jackson and Robson, 1957). Nltrofurantoln was negative for developmental
toxldty In oral studies 1n rats and rabbits and had no effect on male and
female reproduction In rats at dosages of 10, 20 or 30 mg/kg/day (Prytherch
et al., 1983, 1984; Sutton et al., 1983). These dosages, however, were
relatively low. Nltrofurazone given orally at 200 mg/kg/day during organo-
genesls was associated with fetotoxldty In rats (U.S. EPA, 1983b). When
administered parenterally to mice, nltrofurantoln and nltrofurazone were
associated with fetal toxlclty and fetal malformations (Nomura et al., 1975,
1976, 1984). Nlfuroxlme, furazolldone, nltrofurazone and nltrofurantoln
Induced right-sided hypoplasla and other malformations In. cultured rat
embryos (Greenaway et al., 1986).
Ix
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In humans, therapeutic doses of nltrofurans have been associated with
adverse effects. Nltrofurazone, used as a topical antibacterial, was deter-
mined to be a common sensltlzer among many agents tested In the patch test
(Bajaj and Gupta, 1986). Cavanagh (1973) described a dying back peripheral
neuropathy In humans treated for trypanosomlasls with large doses of
nltrofurans.
Data were sufficient to derive risk assessment values only for four of
the chemicals that are the subject of this document: furazolldone, furlum,
nltrofurazone and nltrofurantoln.
Data for the carclnogenlclty of furazolldone were considered sufficient
to classify 1t as an EPA Group 82 chemical, a probable human carcinogen.
Human q,*s of 3.8 (mg/kg/day)'1 for oral exposure and 1.9 (mg/kg/
day)"1 for Inhalation exposure were calculated based on the Induction of
mammary tumors In female rats In the dietary study reported by U.S. DHEW
(1976a,b). The concentrations 1n drinking water that are associated with
Increased lifetime risk of cancer at levels of 10~5, 10~ซ and 10~7 are
9.2xlO~5, 9.2xlO~* and 9.2xlO~7 mg/l, respectively. The concen-
trations In air that are associated with Increased lifetime risk of cancer
at risk levels of 10~5, 10~ซ and 10~7 are l.SxlCT5, l.SxlO"6 and
1.8xlO~7 mg/m3, respectively. An F factor of 22 (mg/kg/day)"1 was
also derived for furazolldone, placing It 1n Potency Group 2. A Potency
Group 2 and an EPA Group B2 chemical has a MEDIUM Hazard Ranking under
CERCLA, and therefore, an RQ of 10 based on carclnogenlclty. An RQ of 100
based on chronic toxldty was also derived for furazolldone, based on In-
creased mortality of rats 1n the dietary study reported by U.S. DHEW (1976a).
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Data for the cardnogenlcHy of furlum were also considered sufficient
to classify It as an EPA 82 chemical. Human q *s of 50.4 (nig/kg/day)"1
for oral exposure and 25.2 (mg/kg/day)"1 for Inhalation exposure were
derived based on the Induction of leukemia In mice 1n the dietary study by
Cohen et a "I. (1970). The concentrations 1n drinking water that are
associated with Increased lifetime risk of cancer at risk levels of 10~5,
10~* and 10~7 are 7.0xlO~6, 7.0xlO"7 and 7.0xlO"8 mg/1,
respectively. The concentrations In air that are associated with Increased
lifetime risk of cancer at risk levels of 10~5, 10~6 and 10~7 are
1.4xlO~6, 1.4xlO~7 and 1.4xlO~8 mg/m3, respectively. An F factor of
347 (mg/kg/day)"1 was also derived for furl'um, placing It In Potency Group
2. A Potency Group 2 and an EPA Group B2 chemical has a MEDIUM Hazard
Ranking under CERCLA, which corresponds to an RQ of 10 based on
cardnogenldty. An RQ of 1000 based on chronic toxldty was also derived
based on depressed Immune function In a subchronlc dietary study" In mice by
Headley et al. (1977).
Sufficient data were available to classify nltrofurazone as an EPA Group
B2 chemical. Human q,*s of 1.5 (mg/kg/day)"1 for oral exposure and
7.6X10"1 (mg/kg/day)"1 for Inhalation exposure were derived based on the
Induction of mammary tumors 1n rats In the dietary study by Erturk et al.
(1970a). The concentrations In water that are associated with Increased
lifetime risk of cancer at risk levels of 10~5, 10~6 and 10~7 are
2.3xlO"4, 2.3xlO~5 and 2.3xlO~6 mg/l, respectively. The
concentrations In air that are associated with Increased lifetime risk of
cancer at risk levels of 10~5, 10"6 and 10~7 are 4.6xlO~5,
4.6xlO~6 and 4.6xlO~7 mg/m3, respectively. An F factor of 10
(mg/kg/day)"1 was also derived for nltrofurazone, placing 1t 1n Potency
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Group 2, which with an EPA classification of 82 results in a MEDIUM Hazard
Ranking under CERCLA and an RQ of 10 based on carclnogenlcity. The RQ based
on chronic toxldty for nltrofurazone 1s 100 based on Impaired fertility In
male mice 1n an oral study by Hershberger et al. (1969).
Data regarding the carclnogenlcity of nltrofurantoln are Inadequate
pending the results of the NTP study; therefore, nltrofurantoln Is tempo-
rarily classified as an EPA Group D chemical. RfDs of 0.9 mg/kg/day or 63
mg/day for a 70 kg human for subchronlc oral exposure and of 0.09 mg/kg/day
or 6 mg/day for a 70 kg human for chronic oral exposure were derived based
on a NOAEL of 90.2 mg/kg/day in female mice 1n a subchronlc dietary study by
Southern Research Institute (1980). Uncertainty factors of 100 (10 for
Interspecies extrapolation and 10 to protect the most sensitive Individuals)
for the subchronic RfD and of 1000 (an additional factor of 10 for use of
subchronlc NOAEL) for the chronic RfO were used. The LOAEL was 135.4
mg/kg/day, at which male mice had testlcular degeneration and reduced
spermatogenesls In the study by Southern Research Institute (1980). An RQ
of 100 was derived based on reduced spermatogenesls in humans in the study
by Nelson and Bunge (1957).
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TABLE OF CONTENTS
Page
1. INTRODUCTION 1-1
1.1. STRUCTURE AND CAS REGISTRY NUMBER 1-1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1-1
1.3. PRODUCTION DATA 1-1
1.4. USE DATA 1-8
1.5. SUMMARY 1-8
2. ENVIRONMENTAL FATE AND TRANSPORT 2-1
2.1. AIR 2-1
2.1.1. Reaction with Hydroxyl Radicals 2-1
2.1.2. Photolysis 2-1
2.2. WATER .-r- 2-1
2.2.1. Hydrolysis 2-1
2.2.2. Photolysis 2-2
2.2.3. M1crob1al Degradation 2-2
2.2.4. Volatilization 2-2
2.2.5. Adsorption 2-2
2.2.6. B1oconcentrat1on 2-3
2.3. SOIL 2-3
2.3.1. Adsorption 2-3
2.3.2. Photolysis 2-3
2.4. SUMMARY 2-3
3. EXPOSURE 3-1
4. AQUATIC TOXICITY 4-1
4.1. ACUTE TOXICITY 4-1
4.2. CHRONIC EFFECTS 4-6
4.3. PLANT EFFECTS 4-6
4.4. SUMMARY 4-8
5. PHARMACOKINETCS 5-1
5.1. ABSORPTION 5-1
5.1.1. Gastrointestinal 5-1
5.1.2. Pulmonary 5-5
5.2. DISTRIBUTION 5-6
5.3. METABOLISM 5-8
5.4. EXCRETION 5-17
5.5. SUMMARY 5-20
X111
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i
TABLE OF CONTENTS (cont.)
Page
6. EFFECTS 6-1
6.1. SYSTEMIC TOXICITY . 6-1
6.1.1. Inhalation Exposures 6-1
6.1.2. Oral Exposures 6-1
6.1.3. Other Relevant Information 6-8
6.2. CARCINOGENICITY 6-11
6.2.1. Inhalation 6-11
6.2.2. Oral 6-11
6.2.3. Other Relevant Information 6-37
6.3. MUTAGENICITY 6-40
6.4. TERATOGENICITY 6-59
6.5. OTHER REPRODUCTIVE EFFECTS ...._. 6-63
6.6. SUMMARY 6-65
7. EXISTING GUIDELINES AND STANDARDS 7-1
7.1. HUMAN 7-1
7.2. AQUATIC 7-1
8. RISK ASSESSMENT 8-1
8.1. CARCINOGENICITY 8-1
8.1.1. Inhalation 8-1
8.1.2. Oral 8-1
8.1.3. Other Routes 8-4
8.1.4. Weight of Evidence 8-4
8.1.5. Quantitative Risk Estimates 8-6
8.2. SYSTEMIC TOXICITY 8-13
8.2.1. Inhalation Exposure 8-13
8.2.2. Oral Exposure 8-13
9. REPORTABLE QUANTITIES 9-1
9.1. BASED ON SYSTEMIC TOXICITY 9-1
9.2. BASED ON CARCINOGENICITY 9-16
10. REFERENCES 10-1
APPENDIX A: LITERATURE SEARCHED A-l
APPENDIX B: CANCER DATA SHEETS FOR DERIVATION OF q-j*s B-l
APPENDIX C: SUMMARY TABLES FOR SELECTED NITROFURANS C-l
xlv
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LIST OF TABLES
No. TUIe Page
1-1 NHrofuran Synonyms, CAS Numbers, Empirical Formula
and Structures ........................ 1-2
1-2 Selected Physical Properties of the NHrofurans ....... 1.-4
1-3 NHrofuran Production Data for 1977 ............. 1-6
1-4 Use Data for NHrofurans ................... 1-9
4-1 Acute Toxlclty of NHrofurans to Aquatic Organisms ...... 4-2
4-2 Toxldty of NHrofurans to Flagellate Protozoans
(Euglena gradHs) ...................... 4-3
4-3 Toxlclty of NHrofurans to Aquatic Plants and Bacteria. . . . 4-7
6-1 Oral LD Values for NHrofurans ............... 6-9
6-2 Incidence of Mammary Tumors 1n Female Rats fed Diets
Containing Furazolldone ................... 6-13
6-3 Incidence of Tumors 1n Female Sprague-Dawley Rats fed
Diets Containing Furlum .................. . 6-16
6-4 Incidence of Benign Mammary Flbroadenomas 1n Female
Sprague-Dawley Rats Fed Diets Containing Furlum ....... 6-17
6-5 Incidence of Tumors 1n Female Mice fed Diets Containing
Furlum ............................ 6-19
6-6 Incidence of Leukemia 1n Female Swiss Mice fed Diets
Containing Furlum ...................... 6-22
6-7 Incidence of Leukemia 1n 30 Female Swiss Mice fed Diets
Containing Furlum ...................... 6-24
6-8 Incidence of Urinary Bladder Tumors 1n 24 Weanling Male
Syrian Golden Hamsters fed Diets Containing Furlum ...... 6-26
6-9 Incidence of Mammary Flbroadenomas 1n Germ-Free Female
Sprague-Dawley Rats Fed Diets Containing NHrofurantoln . . . 6-30
6-10 Incidence of Mammary Tumors 1n Female Sprague-Dawley Rats
Given Intragastrlc Doses of NHrofurazone 1n Sesame 011 ... 6-31
6-11 Incidence of Benign Mammary Tumors 1n Female Holtzman
Rats fed Diets Containing NHrofurazone ........... 6-33
6-12 Incidence of Benign Mammary Tumors 1n 30 Female Sprague-
Dawley Rats fed Diets Containing NHrofurazone ........ 6-34
xv
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LIST OF TABLES (cont.)
No. Title Page
6-13 Incidence of Mammary Tumors 1n Female Rats fed Diets
Containing NHrofurazone 6-36
6-14 Genotoxlclty Testing of Furalazlne 6-41
6-15 Genotoxlclty Testing of Furazolldone 6-42
6-16 Genotoxlclty Testing of Furlum 6-45
6-17 Genotoxlclty Testing of 5-NHro-2-furancarboxaldehyde .... 6-46
6-18 Genotoxlclty Testing of 5-N1tro-2-furancarboxaldehyde
Dlacetate 6-47
6-19 Genotoxlclty Testing of Nltrofurantoln 6-48
6-20 Genotoxlclty Testing of NHrofurazone 6-53
6-21 Genotoxlclty Testing of NHrovln. 6-56
6-22 Genotoxlclty Testing of Z-furan 6-57
9-1 Oral Toxldty Summary for Furazolldone 9-2
9-2 Oral Composite Scores for Furazolldone 9-3
9-3 Furazolldone: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 9-4
9-4 Oral Toxldty Summary for FuMum 9-5
9-5 Oral Composite Scores for Furlum 9-6
9-6 Furlum: Minimum Effective Dose (MED) and Reportable
Quantity (RQ) 9-7
9-7 Oral Toxldty Summary for Nltrofurantoln 9-9
9-8 Oral Composite Scores for Nltrofurantoln 9-12
9-9 Nltrofurantoln: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 9-13
9-10 Oral Toxldty Summary for Nltrofurazone 9-14
9-11 Oral Composite Scores for NHrofurazone 9-17
xv1
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LIST OF TABLES (cont.)
No. Title Page
9-12 Nltrofurazone: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 9-18
9-13 Derivation of Potency Factor (F) for Furazolldone 9-20
9-14 Derivation of Potency Factor (F) for Furlum 9-22
9-15 Derivation of Potency Factor (F) for Nltrofurazone 9-24
xv11
-------
LIST OF ABBREVIATIONS
BCF
BUN
bw
CAS
CNS
CS
ow
LD50
LOAEL
MED
MTD
NADPH
NOAEL
ppm
RfD
RQ
RVd
RVe
UV
B1oconcentrat1on factor
Blood urea nitrogen
Body weight
Chemical Abstract Service
Central nervous system
Composite score
Concentration effective to 50% of recipients
(and all other subscripted concentration levels)
Octanol/water partition coefficient
Concentration lethal to 50% of recipients
(and all other subscripted dose levels)
Dose lethal to 50% of recipients
Lowest-observed-adverse-effect level
Minimum effective dose
Maximum tolerated dose
N1cot1nam1de adenlne dlnucleotlde phosphate
(reduced form)
No-observed-adverse-effect level
Parts per million
Reference dose
Reportable quantity
Dose-rating value
Effect-rating value
Ultraviolet
XV111
-------
1. INTRODUCTION
1.1. STRUCTURE AND CAS REGISTRY NUMBER
The selected nltrofurans are a class of 2-subst1tuted synthetic com-
pounds characterized by the presence of the 5-n1tro-2-furanyl group as shown:
The Individual structures, CAS Registry numbers, empirical formulas, and
common synonyms of the selected nltrofurans are presented In Table 1-1.
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Selected physical properties of the nltrofurans are presented In Table
1-2. In general, they are solids at ambient temperatures with relatively
high melting points and low water solubilities; nltrofurfuryl methyl ether
Is an exception, occurring as an oily liquid with a water solubility of 11
g/l (Wlndholz, 1983). Most nltrofurans darken with exposure to strong
alkali or to light (Ebetlno, 1978). Their strong absorption of UV light at
environmental wavelengths (>290 nm) 1s Indicative of photolabUHy.
1.3. PRODUCTION DATA
Production data for the nltrofurans are presented 1n Table 1-3. The
Norwich Eaton Pharmaceutical Division of the Procter & Gamble Company manu-
factures furazolldone, nUrofurantoln, nltrofurazone and 5-n1tro-2-furan-
carboxaldehyde 1n Norwich, NY (SRI, 1986). Current production figures are
not available for any of the nltrofurans. FuMum and nltrovln have never
been produced or used commercially In the United States (IARC, 1974, 1983).
Most of the commercialized nltrofurans are synthesized from either
5-n1tro-2-furancarboxaldehyde or Its dlacetate, which are produced by
nitrating furfural with appropriate nitrating agents (Ebetlno, 1978).
0052d 1-1 07/06/87
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0052d
1-5
06/02/87
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TABLE 1-3
NHrofuran Production Data for 1977*
NHrofuran
Acetylfuratrlzine
Furalazlne
Furazolldone
Producer/Location
NA
NA
Fallek Chemical
Type
NA
NA
Importer
Production Range
(thousands of pounds)
NA
NA
none
Furium
Nlfuroxime
5-N1tro-2-furancar-
boxaldehyde
5-N1tro-2-furancar-
boxaldehyde dlacetate
NHrofurantoln
New York, NY
Norvlch Eaton
Pharmaceutical
Division of P&G
Company, NY
NA
NA
Norvlch Eaton
Pharmaceutical
Division of P&G
Company, NY
Confidential
Napp Chemical
Lod1, NO
ICO Group, Inc.
New York, NY
Norvlch Eaton
Pharmaceltlcal
Division of P&G
Company, NY
producer
NA
NA
producer
Importer
Importer
Importer
producer
NA
NA
NA
NA
confidential
1-10
none
NA
0052d
1-6
07/09/87
-------
TABLE 1-3 (cent.)
NHrofuran
NHrofurfury!
methyl ether
NHrovIn
Z-furan
Producer/Location
Type Production Range
(thousands of pounds)
NHrofurazone
Napp Chemical
Lod1, NJ
ICO Group, Inc.
New York, NY
Norwich Eaton
Importer
importer
producer
<1
none
NA
Pharmaceutical
Division of P&G
Company, NY
NA .NA
NA NA
NA NA
NA
NA
NA
'Source: U.S. EPA, 1977
NA = Not available
0052d
1-7
07/09/87
-------
1.4. USE DATA
In general, the nltrofurans are used either as antibacterial agents or
as Intermediates In the synthesis of other nltrofurans. A description of
the use of each selected nltrofuran 1s presented In Table 1-4.
1.5. SUMMARY
The selected nltrofurans are a class of synthetic compounds character-
ized by the presence of the 5-n1tro-2-furanyl functional group. With the
exception of 5-nitro-2-furancarboxaldehyde and n1trofurfuryl methyl ether,
the nltrofurans are solids with high melting points. They are, In general,
sparingly soluble to Insoluble In water -and they darken on exposure to
light. The nltrofurans are used either as antibacterial agents (for oral or
topical applications to humans or animals) or as Intermediates 1n the
synthesis of other nltrofurans (Ebetino, 1978; -IARC, 1974, 1983; Wlndholz,
1983; Bateman, 1980). Currently, one U.S. manufacturer produces at least
four of the selected nitrofurans (SRI, 1986).
0052d 1-8 07/06/87
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0052d
1-10
07/06/87
-------
2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
Based on the melting points of the selected nltrofurans (see Table 1-2),
only two appear to have a potential for vapor phase emission to the
atmosphere: nltrofurfuryl methyl ether and 5-n1tro-2-furancarboxaldehyde.
2.1.1. Reaction with Hydroxyl Radicals and Ozone. According to U.S. EPA
(1987), the estimated rate constants for the vapor phase reaction of nltro-
furfuryl methyl ether and 5-n1tro-2-furancarboxaldehyde with hydroxyl radi-
cals 1n the atmosphere, at 25ฐC, are ~1.7-1.8xlO~10 cm3/molecule-sec.
The estimated rate constant for the reaction with ozone Is l.OxlO*15
cmVmolecule-sec. Given typical atmospheric concentrations of 8xlOs
hydroxyl radicals/cm3 and 6xl01:L ozone molecules/cm3, an atmospheric
half-life of -16 minutes Is estimated for these chemicals.
2.1.2. Photolysis. As noted 1n Section 2.2.2., the nltrofurans strongly
absorb light 1n the sunlight region of" the spectram (Sadtler, 1962,
1963a,b,c; 1965, 1966; Wlndholz, 1983) and darken on exposure to sunlight
(Wlndholz, 1983; Ebetlno, 1978). Direct photolysis may therefore be
Important for all nltrofurans In the atmosphere, whether In the vapor or
partlculate phase. In the vapor phase, however, reaction with hydroxyl
radicals and ozone 1s likely to be more rapid based on the above estimates.
2.2. WATER
2.2.1. Hydrolysis. In general, the selected nltrofurans do not contain
functional groups that are significantly hydrolyzable under environmental
conditions; however, a few nltrofurans Including 5-n1tro-2-furancarboxalde-
hyde dlacetate may be susceptible to some hydrolysis (Ebetlno, 1978), but no
kinetic data on hydrolysis could be located 1n the available literature as
cited 1n Appendix A.
0053d 2-1 09/08/87
-------
2.2.2. Photolysis. The nltrofurans absorb light very strongly In the
sunlight region of the spectrum (Sadtler, 1962, 1963a,b,c, 1965, 1966;
Wlndholz, 1983) and darken on exposure to light (Wlndholz, 1983; Ebetlno,
1978). This Indicates that the nltrofurans will photolyze 1n sunlight.
Exposure of an aqueous solution of nltrofurazone to sunlight resulted In the
photodecomposHlon of the nltrofurazone, with 5-n1tro-2-furaldehyde produced
as one of seven decomposition products (Shahjahan, 1979; Shahjahan and
Enever, 1979).
2.2.3. M1crob1al Degradation. Pertinent data regarding environmental
mlcrobial degradation were not located. Since the nitrofurans are anti-
bacterial agents, they are likely to be toxic to many microorganisms at or
above critical concentrations. At very low concentrations that may be found
in the environment, the ability of microorganisms to attack the nltrofurans
is not known.
2.2.4. Volatilization. With the exception of nltrofurfuryl methyl ether,
for which melting point data are not available, and 5-n1tro-2-furancarbox-
aldehyde, the nitrofurans have relatively high melting points (indicative of
very low vapor pressures) and sufficient water solubility to suggest that
volatilization from water is unlikely to be important.
Using the bond estimation method of Mine and Mookerjee (1975), the
Henry's Law constants of both nltrofurfuryl methyl ether and 5-nitro-2-
furancarboxaldehyde are estimated to be <10~7 atm-mVmol at 25ฐC. This
value of Henry's Law constant Indicates that the compounds will not
volatilize from water (Lyman et al., 1982).
2.2.5. Adsorption. The log K and water solubilities of the nitro-
furans (see Table 1-2) suggest that adsorption to sediment in the aquatic
environment will not be significant.
0053d 2-2 06/02/87
-------
2.2.6. Bloconcentratlon. The BCF of an organic chemical can be estimated
from the following regression equation (Lyman et al., 1982):
Log BCF = 0.76 Log KQW - 0.23 (2-1)
For the nitrofurans, the BCF values calculated from Equation 2-1 range from
<1 to ~30 using the log K values listed in Table 1-2. These BCF values
a 3 OW
indicate that the nitrofurans are not expected to bioconcentrate signifi-
cantly in aquatic organisms.
2.3. SOIL
2.3.1. Adsorption. The log K values and water solubilities of the
ow
nitrofurans (see Table 1-2) indicate that these compounds will generally be
weakly sorbed onto soils and therefore, will be susceptible to leaching in
soil.
2.3.2. Photolysis. Since the nitrofurans photodegrade in sunlight (see
Section 2.2.1.), photodecomposition on soil surfaces is expected to occur.
2.4. SUMMARY
Because of the lack of experimental data, most of the conclusions
reached about the environmental fate and transport of nitrofurans are specu-
lative. Photolysis is expected to be a major environmental fate process for
the nitrofurans because they absorb light very strongly in the sunlight
region of the spectra (Sadtler, 1962, 1963a,b,c, 1965, 1966; Windholz, 1983)
and darken on exposure to sunlight (Windholz, 1983; Ebetino, 1978). In
water, photodecomposition is expected to be the major removal mechanism.
Exposure of an aqueous solution of nitrofurazone to sunlight has been shown
to result in photodecomposition (Shahjahan, 1979; Shahjahan and Enever,
1979). Aquatic volatilization, adsorption to sediments and bioconcentration
are not expected to be significant. In the atmosphere, the nitrofurans can
undergo photolysis and oxidation by photochemically produced OH radicals and
0053d 2-3 06/02/87
-------
ozone. The half-life for the vapor phase reaction of nltrofurfuryl methyl
ether and 5-nltro-2-furancarboxaldehyde with hydroxyl radicals and ozone In
the atmosphere has been estimated to be ~16 minutes (U.S. EPA, 1987). In
-soil, the nltrofurans appear to be susceptible to leaching and surflclal
photolysis.
0053d 2-4 07/06/87
-------
3. EXPOSURE
Pertinent water, food, air or dermal monitoring data could not be
located 1n the available literature as dted 1n Appendix A. A National
Occupational Hazard Survey conducted between 1972 and 1974 estimated that
24,802 U.S. workers may be exposed to furazolldone and 3805 workers may be
exposed to nitrofurazone (NIOSH, 1984).
0054d 3-1 06/02/87
-------
4. AQUATIC TOXICITY
4.1. ACUTE TOXICITY
Data concerning acute toxldty of nltrofurans to aquatic organisms are
presented 1n Table 4-1. The lowest reported toxic concentration for fresh-
water fishes was 10 mg/l nltrofurazone, a 24-hour LC5Q for striped bass,
Horone saxatlHs. larvae (Hughes, 1973). Most of the data were not useful
for interspecies comparisons, but Wise et al. (1987) noted that channel
catfish, Ictalurus punctatus. were ~4 times more sensitive to nltrofurazone
than goldfish, Carasslus auratus.
There are relatively few data available for invertebrates other than
protozoans. The only freshwater species tested was Daphnla magna. with a
48-hour LCf-n of >30 mg/i furazolldone (Canton and van Esch, 1976) and a
48-hour ECrg of 28.67 mg/l nltrofurazone (Hacrl and Sbardella, 1984).
The only toxic effects reported for marine Invertebrates were decreased
growth and survival of larval hard clams, MercenaMa mercenarla. exposed to
5 and 25 mg/l, respectively (Davis and H1du, 1969).
A large volume of data concerning toxldty of several nltrofurans to the
protozoan, Euglena gracIll's, was provided by McCalla (1965) and McCalla and
Reuvers (1970). This Information 1s summarized In Table 4-2. McCalla
(1965) determined nltrofuran concentrations that were lethal or caused
bleaching of Euglena grac111s cultures. The most toxic of 10 nltrofurans
tested was furallzlne, which was lethal at 5 mg/l and caused bleaching at
2.5 mg/l. The least toxic was nltrofurazone, with a lethal concentration
of 256 mg/l and a bleaching concentration of 64-128 mg/l. McCalla and
Reuvers (1970) conducted similar experiments under both light and dark con-
ditions because several of the nltrofurans tested are converted to compounds
0055d 4-1 06/02/87
-------
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0055d
4-2
06/02/87
-------
TABLE 4-2
Toxlclty of Nitrofurans to Flagellate Protozoan (Euglena qradlis)
Compound
NHrofurfural
Nlfuroxime
NHrofurazone
NHrofurantoin
Furazolidone
Furalazlne
N1hydrazonea
Furamazone'3
Furmethonolc
Thiofuradened
Nltrofurantoin
Furmethonolc
Concentration
(mg/l)
32
8-16
64
16
. 256
64-128
32-64
16
64-128
8-16
5.0
2.5
64
32
32
8
64
16
128
32-64
30
>100
10
>30
30
100
10
>30
Effect
lethal concentration
bleaching concentration
lethal concentration
bleaching concentration
lethal concentration
bleaching concentration
lethal concentration
bleaching concentration
lethal concentration
bleaching concentration
lethal concentration
bleaching concentration
lethal concentration
bleaching concentration
lethal concentration
bleaching concentration
lethal concentration
bleaching concentration
lethal concentration
bleaching concentration
lethal concentration, light
lethal concentration, dark
bleaching concentration, light
bleaching concentration, dark
lethal concentration, light
lethal concentration, dark
bleaching concentration, light
bleaching concentration, dark
Reference
HcCalla, 1965
McCalla and
Reuvers, 1970
0055d
4-3
06/02/87
-------
TABLE 4-2 (cont.)
Compound
Concentration
(mg/l)
Effect
Reference
N1hydrazonea
Furamazoneb
5-NHrofuryl
alcohol
5-NHrofuroic
acid
Nitrofurazone
Nifuroxlme
Thlofuradened
NF-4166
2-NHrofuran
M1 trofurf ural
50
50
10
25
50
50
10
25
30
30
10
10
100
100
100
100
50
50
30
30
20
20
100
100
100
100
30
10
10
3
>iO
4
5
2
lethal concentration, light McCalla and
lethal concentration, dark Reuvers, 1970
bleaching concentration, light
bleaching concentration, dark
lethal concentration, light
lethal concentration, dark
bleaching concentration, light
bleaching concentration, dark
lethal concentration, light
lethal concentration, dark
bleaching concentration, light
bleaching concentration, dark
lethal concentration, light
lethal concentration, dark
lethal concentration, light
lethal concentration, dark
bleaching concentration, light
bleaching concentration, dark
lethal concentration, light
lethal concentration, dark
bleaching concentration, light
bleaching concentration, dark
lethal concentration, light
lethal concentration, dark
lethal concentration, light
lethal concentration, dark
lethal concentration, light
lethal concentration, dark
bleaching concentration, light
bleaching concentration, dark
lethal concentration, lignt
lethal concentration, dark
bleaching concentration, light
bleaching concentration, dark
0055d
4-4
06/02/87
-------
TABLE 4-2 (cont.)
Compound
Concentration
(mg/i)
Effect
Reference
5-N1tro-2-
methylfuran
Furalazlne
5,5-Dinitro-
2,2-dlfuran
30
10
10
3
4.0
2.5
3.5
2.0
10
5
4
2
lethal concentration, light
lethal concentration, dark
bleaching concentration, light
bleaching concentration, dark
lethal concentration, light
lethal concentration, dark
bleaching concentration, light
bleaching concentration, dark
lethal concentration, light
lethal concentration, dark
bleaching concentration, light
bleaching concentration, dark
McCalla and
Reuvers, 1970
a5-N1tro-2-furaldehyde acetyl hydrazone
'35-N1tro-2-furaldehyde semloxamazone
c5-Morpholinomethyl-3-(5-nitro-2-furfuryl1d1ne-am1no)-2-oxazol1d1non'e
d"l-(5-N1tro-2-furfuryl1d1ne-am1no)-2-1m1dazol1d1neth1one
el-[3-(5-N1tro-2-furyl)-N-2-propenylidine amino-hydantoin
0055d
4-5
06/02/87
-------
of different toxlclty under Illumination. NHrofurantoin, furmethonol,
nihydrazone and furamozone liberated 5-nitro-2-furaldehyde under illumina-
tion and were more toxic In light than In the dark. Compounds that were
more toxic In the dark than light were-2-nitrofuran, nltrofurfural, 5-nitro-
2-methylfuran, furalazlne and 5,5-dinitro-2,2-d1furan. Compounds that were
equally toxic in light and dark were nltrofurazone, nlfuroxime, thlofuradene
and NF-416. The most toxic compounds in these experiments were 2-nitro-
fiiran, nltrofurfural, 5-n1tro-2-methylfuran, furalazine and 5,5-dinitro-2,2-
dlfuran, all of which were lethal or caused bleaching at 2-3 mg/9. without
illumination.
4.2. CHRONIC EFFECTS
The only available information concerning chronic or subchronic toxicity
of nitrofurans to aquatic organisms was provided by Aoki et al. (1975), who
exposed medaka, Oryzias latipes, to AF-2 or nltrofurazone for 30 days in the
dark. F1sh exposed to 0, 2, 5 and 10 mg/2. AF-2 had survival rates of 97,
79, 44 and 0%, respectively. Hypophyseal lesions consisting of large
vacuoles occurred In fish exposed to 5 mg/l AF-2. In fish exposed to 10
mg/8, nltrofurazone, survival was unaffected, and no histopathological
effects were observed.
4.3. PLANT EFFECTS
Data concerning toxicity of nitrofurans to aquatic plants and bacteria
are presented In Table 4-3. The lowest reported toxic concentrations were
~1 mg/8. nltrofurazone, furazolldone or AF-2, which inhibited growth of
Selenastrum capricornutum. Chlorella pyrenoidosa and Achromobacter aqua-
marinus, respectively (see Table 4-3).
0055d 4-6 06/02/87
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0055d
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4.4. SUMMARY
The lowest reported nitrofuran concentration that was .toxic to fish and
Invertebrates other than protozoa was 10 mg/l nHrofurazone, which was a
24-hour LC50 for striped bass larvae. A large volume of Information was
provided by McCalla (1965) and McCalla and Reuvers (1970), who investigated
toxicity of several nitrofurans to Euglena gracllis cultures. The most
toxic compounds in those studies were 2-nitrofuran, nitrofurfural, 5-nitro-
2-methylfuran, furalazine and 5,5-dinitro -2,2-difuran, all of which were
lethal or caused bleaching at 2-3 mg/l. Limited data for aquatic plants
and bacteria indicated that concentrations of 1 mg/l nitrofurazone,
furazolidone or AF-2 inhibited growth of Selenastrum capricornutum.
Chlorella pyrenoidosa and Achromobacter aquamarinus, respectively.
0055d 4-8 07/06/87
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Oral treatment consisted of a 13-15.8 mg/kg/day dose (divided into three
doses .of -4-5 mg/kg each, administered at 8 a.m., 12 noon and 4 p.m.) of.a
microcrystalUne veterinary preparation in tablet form. Intravenous treat-
ment consisted of a single bolus dose of the sodium salt of nitrofurantoin
at 3.0 or 6.0 mg/kg. Urinary recovery accounted for 23.8-32.5% of the dose
following oral treatment and 34.5-36.2% following intravenous treatment,
which suggests that the extent of gastrointestinal adsorption of nitrofuran-
toin is great in dogs.
When a macrocrystalline formulation of nitrofurantoin in capsule form
was administered according to the protocol described above, a slight reduc-
tion in total 24-hour urinary recovery (23.5-29.2% of dose) and a notably
prolonged period of urinary excretion resulted. Hence, a slower rate of
absorption might be attributed to the macrocrystalline formulation.
Data suggest that nitrofurantoin is rapidly and extensively absorbed
from the gastrointestinal tract of humans. Conklin (1978) compared urinary
excretion of orally administered nitrofurantoin with urinary excretion of
intravenously injected nitrofurantoin and concluded that a "suitable dosage
form is well absorbed" following oral administration.
Hoener and Patterson (1981) studied 24-hour urinary excretion of nitro-
furantoin following a 50 mg dose to six healthy male subjects weighing 62-80
kg. A crossover technique was used so that each subject was treated orally
and intravenously, with a suitable period between treatments. Intravenous
treatment consisted of a solution of nitrofurantoin in 5% dextrose, and oral
treatment consisted of a commercially available tablet. Urinary nitrofuran-
toin accounted for 47% of the intravenous dose and 34% of the oral dose.
Peak concentrations in plasma and urine occurred 45-240 minutes after oral
administration, indicating rapid gastrointestinal absorption in humans.
0056d 5-2 06/03/87
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Since nltrofurantoln Is a pharmaceutical used to treat urinary Infec-
tions 1n humans, factors regarding administration and formulations of the
compound that may affect absorption (hence, b1oava1lab1l1ty) are among the
subjects of many available studies. The size of the crystals used In
manufacturing nltrofurantoln preparations has been studied by several
Investigators (Conklln and Halley, 1969; Forn and P1no, 1974; Moolenaar et
al., 1976; Rosenberg and Bates, 1976; Mannlsto, 1978). Generally, the rate
of absorption seems to be greater with preparations using mlcrocrystalllne
formulations of nltrofurantoln as compared with macrocrystalline
formulations. The rate of absorption was enhanced (manifested by higher
levels of the drug 1n the urine) when nltrofurantoln was taken with food
rather than during a fasting period (Rosenberg and Bates, 1976; Mannlsto,
1978; Hoener and Patterson, 1981). Increasing the viscosity of a suspension
of nltrofurantoln for oral administration, by adding algln, carbomer, guar
gum or colloidal magnesium aluminum silicate (Sod and Parrott, 1980) or
methyl cellulose (Soc1 and Parrott, 1980; Seager, 1968), slowed the rate of
absorption.
Rat studies suggest that orally administered nltrofurazone also Is
extensively absorbed from the gastrointestinal tract. Tatsum! et al. (1971)
reported 88% gastrointestinal absorption of an oral dose of l4C-n1trofura-
zone, based on total recovery of radioactivity 1n the urine and bile. In
subsequent similar studies with radlolabeled nltrofurazone In portal vein
and thoracic lymph duct-cannulated male Donryu rats, Tatsuml et al. (1975)
determined that gastrointestinal absorption was almost entirely by portal
circulation rather than lymphatic circulation, based on recovery of admin-
istered radioactivity.
0056d 5-3 07/06/87
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Nitrofurazone is partially degraded In the small Intestine of the rat
and the degradation products are absorbed more slowly than unchanged nitro-
furazone (Tatsuml et al., 1973a, 1975).
A rat study by Tatsuml and Takahashi (1982) Indicates that furazolldone
1s absorbed less well than nitrofurantoin and nltrofurazone from the gastro-
intestinal tract. When a single 10 mg/kg dose of 14C-furazoHdone was
administered orally to bile duct-fistulated rats, urine, bile and feces
collected over a 48-hour period contained 59.7, 14.8 and 19.0%, respec-
tively, of the administered dose. When bile duct-fIstulated rats were
administered a 10 mg/kg dose by 1ntraper1toneal injection, intestinal excre-
tion accounted for -5% of the dose of radioactivity. It may be concluded,
therefore, that gastrointestinal absorption accounted for -79.5% of the
radioactivity associated with a 10 mg/kg dose of 14C-furazoHdone.
Tennent and Ray (1971) reported that radioactivity from orally adminis-
tered 14C-furazol1done was recovered from rats as follows: 81.5% of the
dose In urine, 11.0% of the dose 1n feces, 3% of the dose 1n expired air and
8.1% of the dose In the carcass. Total recovery was -103.6%, and the
results of the study Indicate that gastrointestinal absorption accounted for
-90% of the dose.
In the same study, a young castrated male Yorkshire pig was maintained
for 3 weeks on a diet containing 0.033% furazolldone and then given an oral
dose of 14C-furazoHdone. Within 48 hours, 70.49% of the dose of radio-
activity was recovered In the urine, which suggests extensive absorption of
14C-furazoHdone-associated radioactivity.
According to IARC (1983), unchanged furazolldone was poorly absorbed
from the gut and metabolized extensively In the Intestine of volunteers
treated orally with 400 mg/day for 21 days.
0056d 5-4 07/06/87
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Cohen and Bryan (1978) presented the only data from which Inferences
regarding the gastrointestinal absorption of furlum can be made. A single
dose of 0.1 mg 14C-furlum was administered by gavage to female Swiss mice
sacrificed 6 hours later. Of the administered dose of radioactivity, 36.5%
was found in the urine, 5.1% In the carcass, 40.9% 1n the gastrointestinal
tract and 17.4% 1n the feces. It was not clear from the study whether the
40.9% In the gastrointestinal tract was located in the tissue, the contents
or both. The total amount of the dose found in the urine and carcass
(41.6%) may be considered a minimum estimate of gastrointestinal absorption
of 14C-furium associated radioactivity. At the same time, the data
indicate that the rate of gastrointestinal absorption was rapid.
After oral administration of furalazine and furatrizine to rats, the
calculated gastrointestinal absorption rates were 40-50 and 20%, respec-
tively (Takai et al.. 1974)
IARC (1983) reported that only 0.6% of an oral dose of 14C-nitrovin
was absorbed through the intestine of the rat. NHrovin is a large molecule
composed of two 5-nitrofuran rings joined by a 1,4-pentad1ene-3-l-amino-
hydrazone chain.
5.1.2. Pulmonary. Although data specifically regarding absorption
following inhalation exposure to nitrofurans could not be located in the
available literature, Conklin (1978) reported that intratracheal
administration of nltrofurantoin to dogs resulted in plasma drug concentra-
tions and urinary drug excretion Identical to those observed after Intra-
venous injection. These data suggest that for nltrofurantoin, absorption
following inhalation exposure to nitrofurantoin would be extremely rapid and
extensive.
0056d 5-5 07/06/87
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5.2. DISTRIBUTION
Conklin (1978) reported that Intravenously administered nltrofurantoln
remains 1n the blood for only short periods of time, with a half-life of <30
minutes and a concentration time curve that follows first-order kinetics.
Following oral administration, nltrofurantoln concentrations In the blood
are usually low, and often below detection limits. Nltrofurantoln In the
blood stream occurs at slightly higher concentrations 1n the plasma than In
the cellular fraction. Reversible binding to plasma proteins, specifically
to the albumin fraction (Conklln, 1978; Kurz et a!., 1977) was observed In
rats and dogs (Conklin, 1978) and in humans (Conklin, 1978; Mannisto and
Lammlnsivu, 1982). Mannisto and Lammlnsivu (1982) reported that when humans
were given a single 100 mg oral dose of nitrofurantoin, 87.9-95.2% of the
plasma drug concentration was bound to protein during the first 4 hours
following treatment.
Conklin (1969) reported that the blood nltrofuran concentration 10
minutes after Intravenous administration to dogs was only one fifth of the
level anticipated if the total dose was confined to blood. Under these
conditions, a volume of distribution of 0.7 I/kg is estimated for nitro-
furantoin, which suggests that the compound is rapidly distributed to
extracellular and Intracellular fluid compartments.
Nltrofurantoln concentrated in the cerebrospinal fluid and aqueous humor
(Paul et al., 1960), lymph (Buzard et a!., 1961) and prostatic fluid (Scott
and Wade, 1968) of dogs. Concentrations in these compartments, other than
lymph, have been found to be less than the concentration of free drug In the
plasma (Buzard and Conklin, 1965). Buzard et al. (1961) reported that
protein binding is a major factor Influencing the extent of distribution to
the lymph.
0056d 5-6 07/10/87
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In humans, nltrofuran was not detected In prostatlc fluid following oral
treatment (Hadsen et al., 1968); however, it was found to be "highly
concentrated" In the seminal fluid of Individuals taking oral therapeutic
doses (Armstrong et al., 1968). Several studies Indicate that the testes
are a target organ for the toxic effects of the nltrofurans (Section 6.5.).
NHrofurantoln was detected In fetal circulation, but not In amnlotlc
fluid or fetal urine, of guinea pigs and dogs treated Intravenously during
the last trimester of pregnancy (Buzard and Conklin, 1964). It was also
detected 1n milk from animals given oral doses (Paul et al., 1960) and
humans given oral therapeutic doses (Anderson, 1977).
Statham et al. (1985) administered a single, 15 mg/kg subcutaneous dose
of [l4C-formyl]-n1trofuranto1n to adult male Sprague-Dawley rats and
measured the concentrations of unchanged compound and metabolites In blood,
liver, lung and kidney at various time points for 16 hours. After 8 hours,
highest concentrations of nltrofurantoln were located in the kidney,
followed (1n decreasing order) by the liver, blood and lung. At T6 hours,
highest concentrations were located 1n the kidney, followed (In decreasing
order) by the blood, lung and liver. A similar profile was observed for
radioactive metabolites of nltrofurantoln, except that concentrations were
always lowest in the liver.
Tennent and Ray (1971) administered a single 1.25 mg oral dose of
[14C-formyl]-furazolidone to a 57 pound (25.9 kg) castrated male Yorkshire
pig that had been maintained on a diet that contained 0.033% furazolidone
for 3 weeks. WHhin 48 hours, 89.5% of the radioactivity had been recovered
from excreta, and the pig was sacrificed to determine levels of
radioactivity remaining In several tissues. The highest levels of
radioactivity, in decreasing order, were located in the kidney, liver,
thyroid, bile, blood, muscle and fat.
0056d 5-7 - 07/06/87
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Wang et al. (1975) and Chlu et al. (1975) administered a single Intra-
perltoneal dose (not specified) of l4C-fur1um to young female (50 g) and
lactating (300 g) Sprague-Dawley rats and measured the radioactivity 1n
several tissues at selected time points from 2-24 hours posttreatment. The
highest concentrations of radioactivity In all tissues of young rats and
lactating rats were observed at 2 hours. Generally, the highest levels of
radioactivity occurred In the liver, followed by the kidney. Considerably
lower levels were located 1n the lung, thymus, spleen, heart, ovary and
uterus. In the liver, precipitation with hot and cold trlchloroacetic acid
showed that >50% of the radioactivity was closely associated with the
protein and nucleic add fractions. At 24 hours, 10.6% of the dose of
radioactivity remained In the carcass of young rats, and 2.9% remained in
the carcass of the lactating rats.
5.3. METABOLISM
The basic structural uni.t for the class 5-n1trofurans 1s the 5-nitro-2-
furanyl moiety (see Section 1.1.), where R Is any one of a number of side
chain configurations. B1otransformat1on may Include reduction of the
5-n1tro group to form amlnofuran, which might be expected to undergo acetyl-
atlon (Paul and Paul, 1964); reduction of the 5-nltro group followed by a
split of the furan ring and the subsequent formation of a cyano derivative;
opening of the furan ring with loss of the nltro group and hydrolysis of the
side chain to form a-ketoglutarlc acid (Buzard, 1962); hydroxylation of
the furan ring (OHvard et al., 1976) and any of a number of modifications,
Including removal of the side chain R (Pugh et al., 1972),
When nltrofurantoin was administered to humans or rats, unchanged parent
compound and metabolites were recovered 1n the urine (Hoener and Patterson,
1981; Jonen et al., 1980; Ollvard et al., 1976; Hoener and Krueger, 1984).
0056d 5-8 07/06/87
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Hoener and Patterson (1981) administered single 50 mg intravenous doses of
nltrofurantoln to a group of six healthy, 62- to 80-kg men. Cumulative
urinary excretion, measured at 24 hours, contained 47% of the dose as
unchanged compound and 2.1% of the dose as metabolites. When the same
procedure was followed using single 50 mg oral doses, cumulative urinary
excretion, measured at 24 hours, contained 34% of the dose as unchanged
compound and -1.7% of the dose as metabolites.
In the Jonen et al. (1980) study, adult male Sprague-Oawley rats were
given a single 33 mg/kg oral dose of l4C-n1trofurantoin. Cumulative
urinary excretion, measured at 36 hours, accounted for 22.4% of the dose as
unchanged compound and 7.0% of the dose as metabolites. The data from
Hoener and Patterson (1981) and Jonen et al. (1980) indicate that blotrans-
formation plays a relatively minor role in the elimination of nltrofuran-
toln; however, the extent of that role cannot be quantified since excretion
of. the drug by other routes (pulmonary, biliary) was not measured.
In humans treated Intravenously or orally, the major urinary metabolite
was identified as aminofurantoin (1.2-1.4% of the dose) and another metabo-
lite was tentatively Identified as an acetylatlon product of aminofurantoin
(Hoener and Patterson, 1981), which suggests that nitroreduction, possibly
with the production of a series of reactive intermediates, Is a significant
biotransformatlon pathway in humans.
Urinary excretion data suggest that oxidative pathways are significant
in the metabolism of nltrofurantoln In rats. Olivard et al. (1976) adminis-
tered 100 mg/kg orally to rats and Identified tautomeric mixtures of the
4-hydroxy derivative of nitrofurantoin as the major metabolite. Jonen et
al. (1980) observed that pretreatment with B-naphthoflavone or 3-methylchol-
anthrene, known Inducers of cytochromes distinct from cytochrome P-450 and
0056d 5-9 07/06/87
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other phenobarbitol-inducible systems (Jonen, 1980), Increased the ratio of
metabolites to unchanged compounds In the urine of rats given an oral 33
mg/kg/dose of radlolaboled nltrofurantoln. Pretreatment with phenobarbltol
did not increase the proportion of urinary radioactivity that was metabo-
lized. Neither pretreatment protocol altered the total dose of radioactiv-
ity that was excreted 1n the urine. The 3-methylcholanthrene-induced
metabolite was identified as the 4-hydroxylation product of nitrofurantoin.
4-Hydroxylation may be a significant blotransformation pathway for nitro-
furans in rats.
Side effects of nitrofurantoin therapy In humans Include severe pulmo-
nary and hepatic toxicities and polyneuropathies (Hoener and Krueger, 1984;
Boyd et al., 1979; Jonen, 1980; Minchin et al., 1984, 1986). It is
generally believed that these toxic manifestations result from the unstable
nltroreduction intermediates that have been shown to be capable of covalent
binding to macromolec.ules In the liver, lung and kidney (Boyd et al., 1979;
Hoener and Krueger, 1984; Minchin et al., 1986). Although the experiments
in Intact rats by Olivard et al. (1976) and Jonen et al. (1980) suggest that
oxidation of nitrofurantoin is more important than nltroreduction, several
organ perfusion and in vitro experiments clearly indicate that nltro-
reduction can occur in this species. In a rat kidney preparation perfused
with oxygen and nitrofurantoin, the 5-amino and 5-cyano derivatives, both of
which are known end products of nitroreduction, were identified In the urine
(Hoener and Krueger, 1984). The 4-hydroxy product observed In the urine
from Intact rats was not identified. In an experiment using an Isolated rat
liver (Jonen, 1980) and in several |n_ vitro systems using rat liver
preparations (Boyd et al., 1979; Holtzman et al., 1981; Moreno et al., 1984;
Minchin et al., 1986; Aufrere et al., 1978), both nitroreduction and
0056d 5-10 07/06/87
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oxidation reactions (4-hydroxylatlon) have been demonstrated. Generally,
the rate of metabolism of nltrofurantoln was greater In anoxic conditions
during which oxidation reactions are suppressed and full expression of the
nitroreduction reactions is allowed. Nitroroduction has also been
demonstrated in intact perfused rat lung {Minchin et al., 1984) and rat lung
microsomal and soluble fraction in vitro preparations (Boyd et al., 1979).
Few attempts have been made to identify the Intermediate or end products
of nitroreduction. In systems prepared from fractions of rat lung and
liver, Minchin et al. (1986) observed as many as four separate reduction
products of nltrofurantoln. Aufrere et al. (1978) identified l-[[(3-cyano-
l-oxopropyl)-methylene]am1no]-2,4-1midazolid1ned1one, an open-ring nitro-
reduction product, 1n an In vitro rat liver system.
In several in vitro experiments, the extent of binding of nltrofurantoln
metabolites to tissue or macromolecules increased with an Increasing degree
of hypoxia, which resulted in a greater amount of reductive metabolism (Boyd
et al., 1979; Minchin et al., 1984, 1986). This observation suggests that
reduction products may be more likely than oxidation products to mediate
nltrofurantoin-lnduced toxidty. Generally, the reductase activity observed
was associated with the microsomal fraction of tissue preparations (Holtzman
et al., 1981; Moreno et al., 1984; Boyd et al., 1979) and was dependent upon
NADPH (Boyd et al., 1979). Nitrofuran reduction activity is also mediated
by the soluble fractions of rat lung and liver homogenates and, based on Its
requirement for NADH or hypoxanthlne, Is similar to xanthine oxldase
activity (Boyd et al., 1979).
Holtzman et al. (1981) explained the nitroreductase-mediated toxicity
observed In vivo in aerobic conditions. They suggested that the first step
0056d 5-11 07/06/87
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1s the transformation of RNO- to RNOl, by the contribution of an
electron from the reductase enzyme. RNOl then Interacts with 0-,
which Is plentiful 1n aerobic conditions, to regenerate the original
compound and leave the highly reactive superoxlde anlon, Ol, which may
be responsible for the observed toxicity.
Jonen et al. (1980) reported the presence of yellow compounds excreted
1n the urine of the rabbit, rat, guinea pig, dog and calf, but not of
humans, fed nitrofurazone. Spectrophotometrlc similarity to a yellow
metabolite of nltrofurantoln, identified as the 4-hydroxy product, suggests
that metabolism of nitrofurazone in animals 1s primarily an oxldative
process. Yeung et al. (1983) administered a single dose of 0.13 mg/kg
l4C-n1trofurazone by gavage to conventional and germ-free adult male
Sprague-Dawley rats and characterized the radioactivity recovered in urine
over an unspecified collection period. A stable reduction metabolite was
Identified In the urine of both conventional and germ-free rats, but nearly
twice as much was found In the urine from the conventional rats. These data
suggest that microblal reduction of nitrofurazone occurs 1n the gut before
absorption and that enzymatic reduction of nitrofurazone also occurs,
probably in the liver, after absorption. Using rats with cannulated portal
veins and using jn_ vitro preparations made from the mucosal layer of the
small intestine, Tatsumi et al. (1973b, 1975) showed that nitrofurazone Is
metabolized 1n the Intestinal mucosa. Metabolites were not identified.
The metabolic degradation of nitrofurazone by various fractions of liver
homogenate from male Donryu rats was studied by Akao et al. (1971a). When
incubated under anaerobic conditions, nitrofurazone was rapidly metabolized.
The disappearance of nitrofurazone, measured by the Spectrophotometrlc
change In optical absorbance at 300-450 my, paralleled a change In the
0056d 5-12 07/10/87
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maximum absorption wavelength. Since the optical characteristics of nltro-
furazone are thought to be Imparted primarily by the presence of the nltro
group, the disappearance of nUrofurazonc was thought to have occurred
primarily as a result of nitroreduction of the compound. Under aerobic
conditions, the rate of disappearance of nltrofurazone exceeded the rate of
reduction of the nltro group, and It was assumed that another metabolic
pathway accompanied nltroreductlon.
Tennent and Ray (1971) administered an oral dose of [14C-formyl]-
furazolldone to a young castrated male Yorkshire pig and characterized the
radioactivity recovered In the urine. Several metabolites of furazolidone
were Isolated, but few were Identified. A positive response in the
nlnhydrln reaction confirmed that nltroreduction to the amino form had
occurred. An acetylated nltroreduction product, a carbonate and a product
resulting from removal of the methylene am1no-2-bxazo!1done sldechaln were
tentatively identified.
The ^n vivo metabolism of furazolidone in rats has been studied
extensively by Tatsumi and Takahashi (1982) and Tatsuml et al. (1984). Hale
Wlstar rats appear to metabolize furazolidone almost completely. Tatsuml
and Takahashi (1982) administered a single 10 mg/kg oral dose of
[14C-formyl]-furazoHdone to rats and recovered 93.5% of the radioactivity
in urine, bile and fcces by 48 hours. Unchanged furazolidone represented
only 0.05% of the radioactivity in the bile and urine and 0.50% of that in
feces. Two urinary metabolites were identified, N-(5-acetamido-
furfurylidene)-3-am1no-2-oxazol idone, an acetylated amino derivative of
furazolidone and 3-(4-cyano-2-oxobutyl1deneamino) 2-oxazolidone, the result
of nltroreduction and opening of the furan ring. Together these two
metabolites accounted for nearly all of the UpophiHc metabolites In urine,
which constituted -10% of the total urinary radioactivity. These
0056d 5-13 07/06/87
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metabolites were also Isolated from rats treated with N-(5-am1.no-2-
furfuryl1dene)-3-am1no-2-oxazol1done, the amlno (nltroreductlon) product of
furazolldone. The Investigators concluded that metabolism of furazolldone
to the amlno {nltroreductlon) product preceded formation of the acetylamlno
and open-ring cyano derivatives. Of the urinary radioactivity, ~90%
occurred as polar water-soluble metabolites that were not Identified. The
open-ring cyano derivative was also Identified In the urine of orally
treated rabbits (Tatsuml et al., 1978).
In a subsequent experiment, Tatsuml et al. (1984) Identified two addi-
tional metabolites, N-(4-methoxycarbonyl-2-oxobutyl1deneam1no)-2-oxazol1done
and a-ketoglutarlc acid, In the urine of rats. The first of these metabo-
lites was believed to be a methylatlon product of an Intermediate metabo-
lite, N-(4-carboxy-2-oxobutyl1d\aneam1no)-2-oxazol1done, an open-chain
carboxyllc add.
-------
O.N
HOOCCH?CH,CDCH = N-N \
I \
Th* open-chain carboiylic
HOOCCHjCHjCOCOOH
*lpht-Kซtoglulปric acid
FIGURE 5-1
Postulated Metabolic Pathways for Furazolldone 1n Rats
Source: Tatsuml et al., 1984
0056d
5-15
06/03/87
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Furazolldone reducing activity has also been located in the 9000 g
supernatant fraction of rat liver and In milk xanth1.ne oxldase (Tatsuml et
al., 1981). 2,3-D1hydro-3-cyanomethyl-2-hydroxyl-5-nitro-la,2-d1(2-oxo-
oxazol1d1n-3-yl)1minomethylfuro-[2,3-b]furan, a unique furazolldone reduc-
tion product, was Identified, which represents the joining of two molecules
of furazolldone at the furan ring.
The metabolism of furlum 1s similar to that observed for the other
5-n1trofurans discussed In this section. Wang et al. (1975) and Chlu et al.
(1975) administered [1*C-20]-fur1um to young female Sprague-Dawley rats by
IntraperHoneal Injection (0.2 mi, 2 yCl) and collected urine, feces and
expired air for 24 hours. 14CO- accounted for
-------
group occurs at a lesser rate and results In the formation of the
corresponding ketone. In Intact animals, it is postulated that both
processes occur simultaneously and results in nitroreduced hydrolysis
products.
5.4. EXCRETION
Data regarding excretion of the nitrofurans are largely restricted to
nitrofurantoin, and indicate that urinary excretion predominates. When six
men weighing 62-80 kg were given a single 50 mg Intravenous dose of nitro-
furantoin, 47% of the dose was recovered in the urine as unchanged parent
compound within 24 hours (Hoener and Patterson, 1981). Urinary metabolites
collected in the same period accounted for 2.1% of the dose. Oral adminis-
tration of a 50 mg dose to the same subjects resulted in recovery of 34% of
the dose as nitrofurantoin and 1.7% as metabolites in 24 hours.
An experiment using rats suggests that renal excretion 1s a
rate-saturable process. Veronese et al. (1974) administered nitrofurantoin
intravenously to rats in single doses of 5, 10, 20, 40 or 80 mg/kg and
measured cumulative urinary excretion at 3, 6 and 9 hours. Urinary
excretion was complete by 6 hours, and at 5-20 mg/kg accounted for 21-28% of
the dose. At 40 and 80 mg/kg, urinary excretion accounted for 15 and 8.3%
of the dose, respectively. For oral dosages of 10-40 mg/kg and 24-hour
urine collection, excretion accounted for 23.0-29.2% of the dose. ,At 80
mg/kg, recovery was decreased to 15.8% of the dose.
Braeunllch et al. (1978) further Investigated the renal excretion of
nitrofurantoin in rats. In 60 minutes following a 20 mg/kg 1ntraper1toneal
dose, urinary excretion of nitrofurantoin accounted for 14-25% of the dose
in rats >33 days of age, 6.8% of the dose in 15-day-old rats and 2.4% of the
dose in 5-day-old rats. Thus, the rate of renal excretion was age-dependent
0056d 5-17 07/06/87
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In the rat. Wlerzba et al. (1982, 1984) also demonstrated that nltrofuran-
toln excretion rate was age-dependent in rats and children. Braeunllch et
al. (1978) concluded that the apparent age effect on renal excretion In rats
reflected a lower urinary pH In younger rats. Since nltrofurantoln behaves
as a weak organic acid with a pKa of 7.2, tubular resorption 1s enhanced at
lower urinary pH. The administration of sodium bicarbonate effectively
raised urinary pH and Increased urinary excretion of nltrofurantoln.
Renal excretion of nltrofurantoln appears to occur at least partially by
tubular secretion. Concurrent administration of probenedd, a known Inhib-
itor of tubular secretion, decreased urinary excretion of nltrofurantoin in
all ages of rats (Braeunlich et al., 1978). Force feeding water to Increase
the rate of glomerular filtration resulted in significantly increased urine
flow but did not significantly Increase the excretory rate of nltrofurantoin
in' rats at any age. Repeated treatment with nltrofurantoln or pretreatment
with phenobarbltol had no effect on renal excretion.
Tubular secretion of nltrofurantoln has also been demonstrated 1n .the
dog and rabbit. Akerblom (1974) administered 5 mg/kg orally to dogs with or
without probenecid and measured the cumulative 6-hour excretion of nltro-
furantoln. Urinary recovery without and with probenedd accounted for 19
and 7% of the dose of nltrofurantoln, respectively.
Renal excretion of nltrofurantoln in intravenously treated rabbits
appears to be a rate saturable mechanism (Watari et al., 1985), as has been
previously discussed for rats (Veronese et al., 1974). In rabbits, renal
clearance declined from 19.3 mi/mlnute/kg at a dose of 0.5 mg/kg to 14.4
ml/minute/kg at 1.25 mg/kg and to 1.54 ml/minute/kg at 15.0 mg/kg. The
fraction of the dose excreted In urine In 3-4 hours declined from 62.7% at a
dose of 0.5 mg/kg to 16.2% at 15.0 mg/kg. The ratio of renal clearance of
0056d 5-18 07/06/87
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nltrofurantoln to the renal clearance of inulln was plotted against the
plasma concentration of nHrofurantoin after a single 10 mg/kg Intravenous
Injection. As plasma concentration Increased, the clearance ratio decreased
and became <1 at high concentrations. The Investigators suggested that
glomerular filtration and tubular secretion both contribute to urinary
excretion with tubular resorptlon acting to reduce total renal excretion.
Increasing urinary pH Increased the clearance ratio, Indicating a reduction
In tubular resorptlon due to a greater extent of ionization of nHrofuran-
toin in the tubular fluid at higher pH.
Noeschel et al. (1982) observed no change in renal excretion or blood
levels of nHrofurantoin in humans treated orally at 300 mg during normal
pregnancy, gestosls or pyelonephritis. Renal excretion decreased and blood
levels increased during fetal delivery.
After a 100 mg/kg oral dose of [14C-formyl]-nitrofurazone to rats, 66%
of the radioactivity was recovered from the urine within 96 hours (Tatsuml
et al., 1971). Only -1% of the radioactivity recovered represented
unmetabollzed compound.
The biliary route Is important 1n the excretion of the nltrofurans.
Conklin (1978) stated that >20% of an intravenous dose of nHrofurantoin Is
recovered from the bile of dogs; recovery from the bile is <20% after oral
administration. Tatsumi et al. (1971) administered a 100 mg/kg oral dose of
[14C-formylJ-nHrofurazone to rats and recovered 27% of the dose of
radioactivity from the bile within 48 hours. Tatsuml and Takahashl (1982)
administered a single 10 mg/kg oral dose of [l4C-formyl]-furazol1dine to
adult male Wlstar rats with biliary fistula and collected urine, bile and
feces for 48 hours. Radioactivity 1n the urine, bile and feces accounted
0056d 5-19 07/06/87
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for 59.7, 14.8 and 19.0% of the dose, respectively. Of the radioactivity
recovered, only 0.05, . 0.05 and 0.50% In each respective compartment
consisted of unchanged parent compound.
5.5. SUMMARY
experiments using animals (Veronese et a!., 1974; Conklln et al., 1969)
and humans {Conklin, 1978; Hoener and Patterson, 1981) indicate that
nitrofurantoin is rapidly and nearly completely absorbed from the
gastrointestinal tract, predominantly from the small intestine rather than
from the stomach or colon (Veronese et al., 1974). In humans, the rate of
gastrointestinal absorption Is Increased by decreasing the size of the
crystalline -structure (Hoolenaar et al., 1976; Forn and Pino, 1974;
Hannisto, 1978; Conklin and Hailey, 1969; Rosenberg and Bates, 1976) or
administration with food rather than during a fasting period (Mannisto,
1978; Rosenberg and Bates, 1976; Hoener and Patterson, 1981). Increasing
the viscosity of a suspension of nitrofurantoin decreases the rate of
absorption (Sod and Parrot, 1980; Seager, 1968). In laboratory animals,
gastrointestinal absorption of nitrofurazone is -88% (Tatsuml et al., 1971),
of furazolldone 1s -80-90% {Tatsuml and Takahashi, 1982; Tennent and Ray,
1971), of furalazine is -40-50% and acetyl furatrizine is -20% (Takai et
al., 1974). Furazolldone may be absorbed poorly in humans (IARC, 1983). A
minimum estimate for gastrointestinal absorption of furlum is -42% of an
administered dose (Cohen and Bryan, 1978).
Although data were not located for absorption following inhalation
exposure, Intratracheal administration of nitrofurantoin to dogs led to
plasma levels and urinary excretion Identical to that noted with Intravenous
treatment, which suggests that absorption may be more rapid following
inhalation compared with oral exposure (Conklin, 1978).
0056d . 5-20 07/06/87
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Following Intravenous treatment with nHrofurantoin, blood levels drop
rapidly, which suggests rapid distribution (Conklln, 1978). Reversible
binding to plasma protein Influences movement Into other extracellular fluid
compartments such as cerebrosplnal fluid and aqueous humor. NHrofurantoin
appears In human seminal fluid at concentrations greater than those in
plasma (Conklln, 1978) and, at least in some animal species, crosses the
placenta! barrier (Buzard and Conklin, 1964). Tissue levels of radio-
activity after treatment with 14C-nitrofurantoin (Statham et a!., 1985),
14C-furazolidone (Tennent and Ray, 1971) and 14C-fur!um (Wang et a!.,
1975) are highest 1n the liver or kidney, organs associated with elimina-
tion. No single tissue appears to retain nitrofuran-assodated radio-
activity following a single dose, but bloaccumulatlon following chronic
dosing has not been Investigated.
Pathways for the metabolism of the nltrofurans Include nltroreductlon
(Conklln, 1978; Hoener and Patterson, 1981; Boyd et al., 1979; Hoener and
Krueger, 1984; Minchin et al., 1984, 1986; Holtzman et al., 1981; Yeung et
al., 1984; Tatsumi et al., 1973b, 1975, 1981, 1984; Akao, 1971a; Tennent and
Ray, 1971; Tatsumi and Takahashl, 1982; Abraham et al., 1984; Wang et al.,
1975; Skarka, 1981) sometimes accompanied by opening of the furan ring,
hydroxylation of the furan ring (Conklln, 1978; Olivard et al., 1976; Jonen
et al., 1980), side chain modifications (Conklln, 1978; Skarka, 1981) and
hydrolytlc removal of the side chain (Conklln, 1978; Tatsumi et al., 1984).
Generally, metabolism by nltroreductlon predominates and appears to occur by
two separate mechanisms: one that is NADPH-dependent and associated with
liver microsomes (Holtzman et al., 1981; Boyd et al., 1979; Abraham et al.,
1984; Tatsumi et al., 1981; Wang et al., 1975) and one similar to xanthlne
oxldase, associated with supernatant fractions of tissue homogenates (Boyd
0056d 5-21 07/06/87
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et a!., 1979; Mlnchln et al., 1986; Akao et a!., 1971a; Tatsumi et al.,
1981). The extent of nltroreductlon has been directly correlated to the
extent of binding of metabolites to tissue macromolecules.
The nltrofurans and their metabolites are excreted principally and
rapidly In the urine (Hoener and Patterson, 1981; Veronese et al., 1974;
Braeunllch et al., 1978; Wlerzba et al., 1982, 1984; Watarl et al., 1985),
with both tubular secretion (Braeunllch et al., 1978; Akerblom, 1974) and
glomerular filtration (Veronese et al., 1974) contributing. Renal excretion
appears to be a rate-saturable process (Veronese et al., 1974; Watarl et
al., 1985). Tubular resorptlon has been observed for nltrofurantoln and has
been shown to be pH-dependent, since the drug is a weak organic acid with a
pKa of 7.2 (Braeunlich et al., 1978).
Biliary excretion of the nltrofurans and their metabolites appears to be
a less Important phenomenon, which accounts for -20% of an Intravenous or
oral dose of nltrofurantoln In the dog (Conklin, 1976) and -14.8% of an oral
dose of furazolldone In the rat (Tatsumi and Takahashi, 1982).
0056d 5-22 07/10/87
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposures. Pertinent data regarding subchronlc or
chronic toxlclty that Is associated with Inhalation exposure to any of the
nltrofurans could not be located In the available literature as cited In
Appendix A.
6.1.2. Oral Exposures.
6.1.2.1. SUBCHRONIC -- Few data are available regarding the toxlclty
of the nltrofurans after subchronlc oral administration. Minimal toxlclty
data can be derived from the short-term oral cancer studies discussed 1n
more detail In Section 6.2.
Rogers et al. (1956) fed groups of 15 male and 15 female young rats
diets containing 0, 0.033, 0.1 or 0.3% furazolidone (0, 330, 1000 or 3000
ppm) for 35 days. Estimated dosages were 0, 27-28, 76-85 and 256-276
mg/kg/day for the four groups, respectively. One rat on the 1000 ppm and
nine on the 3000 ppm diet died. A marked decrease In growth rate occurred
at >1000 ppm. Hematology and urlnalysls results were unremarkable. On
hlstopathological examination, the testls apppeared to be the most sensitive
organ. Spermatogenic alterations and interstitial changes were noted at
>1000 ppm. No adverse effects were reported at 330 ppm (27 mg/kg/day).
Groups of 5-8 male and female beagle dogs were given furazolidone at
7.5, 25 or 50 mg/kg/day for up to 6 months (Rogers et al., 1956). Dosages
were divided Into three doses/day 1n gelatin capsules. Controls were
maintained. At >25 mg/kg/day, anorexia, weight loss and neurological signs
were noted and were accompanied by hlstopathological lesions in the testes
and CNS. Hlstopathologlcal lesions were also observed at 7.5 mg/kg/day, but
no other signs of toxlclty were noted at this dosage.
0057d 6-1 07/06/87
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In male Nubian goats given 40, 80, 160 or 320 mg/kg/day furazolidone
orally for up to 10 days, severe signs of CNS Impairment and death within
5-7 days, accompanied by histopathological evidence of brain necrosis and
liver and kidney damage occurred at 160 and 320 mg/kg/day (Ali et al.,
1984). Lesser signs were observed at 40 and 80 mg/kg/day.
In experiments with female Sprague-Dawley rats fed diets containing
0.199% (1990 ppm) furium for 46 weeks, there were no apparent effects on
growth (Cohen et al., 1975; Erturk et al., 1970a). Dogs treated with oral
doses of -50 mg/kg/day furium for 30 months followed by a 5-month recovery
period had no effects on growth, hematology or BUN (Erturk et al., 1970b).
No effects on body weight gain were observed in male weanling guinea pigs
fed diets containing 0.1% (1000 ppm) furium for 50 weeks (Croft and Lower,
1981). Hyperplasia of the epithelium of the urinary tract was observed in
female Sprague-Dawley rats fed a diet containing 0.199% (1990 ppm) furium
for 46 weeks (Erturk et al., 1970a) and in weanling male Syrian g9lden
hamsters fed a diet containing 0.1% (1000 ppm) furium for 48 weeks, but
these were considered to be preneoplastic changes.
In female Swiss mice fed a diet containing 0.1% (1000 ppm) furium for 13
weeks, a severe and progressive weight loss was observed starting at 10
weeks (Cohen et al., 1970). This effect appeared to be independent of the
development of leukemia because the latency period for leukemia was 18 weeks.
The development of leukemia in mice has been associated with suppression
of immune function. Headley et al. (1977) fed diets containing 0, 100, 250,
500 or 1000 ppm furium to groups of five 5-week-old female BALB/c mice for
up to 13-14 weeks and measured both antibody-mediated and cell-mediated
immune response. Exposure to furium at 1000 ppm for 6 days suppressed the
number of antibody forming cells in the spleen (measure of antibody-mediated
0057d 6-2 06/04/87
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Immune response) and exposure to 1000 ppm for 70 days suppressed cell-
mediated Immunity. Exposure to furlum for 13-14 weeks suppressed antibody-
mediated Immunity to 86% of that of controls at 100 ppm and to <54% at 250,
500 or 1000 ppm. A dose-related suppression of cell-mediated Immunity
occurred 1n all treated groups of mice.
In a more recent study, Headley et al. (1981) fed groups of 91
five-week-old female BALB/c mice diets containing TOO, 500 or 1000 ppm
furlum for 12 weeks, followed by an observation period of up to 6 weeks. A
control group of 293 mice was maintained. Antibody-mediated Immunity was
suppressed In all treated groups In a dose-related manner. Cell-mediated
Immunity was suppressed In the 500 ppm group at week 14 and in 1000 ppm mice
as early as 7 weeks of treatment.
Morris et al. (1969) fed female Holtzman rats diets containing 0.2%
(2000 ppm) 5-n1tro-2-furancarboxaldehyde dlacetate for 36 or 44.5 weeks.
Although mortality of control and treated rats was high because of concur-
rent Infections, the rats appeared to tolerate the drug with no obvious
signs of toxldty.
Southern Research Institute (1980) fed diets containing nltrofurantoln
at 0, 0.06, 0.13, 0.25, 0.5 or 1% (0, 600, 1300, 2500, 5000 or 10,000 ppm)
to groups of 10 male and 10 female F1scher-344 rats weighing 120-139 g
(males) or 98-117 g (females) for 91 days. Similarly, groups of 10 male and
10 female B6C3F1 mice weighing 22-28 g (males) and 18-21 g (females) were
fed diets containing 0, 0.03, 0.06, 0.13, 0.25 or 0.5% (0, 300, 600, 1300,
2500 or 5000 ppm) nltrofurantoln for 91 days. Both species were sacrificed
for examination on days 92-103. Parameters evaluated Included clinical
observations, body weight, food consumption, gross pathology, relative liver
weight, comprehensive hlstopathology of controls and high-dose rats and mice
0057d 6-3 09/15/87
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and hlstopathology of selected organs and tissues of lower dose groups as
necessary to determine no effect levels for critical target organs. One
female rat at 10,000 ppm died. Clinical signs that are Indicative of a
toxic response to nitrofurantoin Include walking on tiptoe, and ruffled fur;
these occurred at 10,000 ppm in rats of both sexes and at 5000 ppm in
females. Exposure to nitrofurantoin affected the rate of body weight gain.
Body weight changes of the treated groups of males were +11, -3, -15, -54
and -75% of that of controls at 600, 1300, 2500, 5000 and 10,000 ppm,
respectively. For females, these values were -10, -10, -31, -71 and -93%,
respectively. Food consumption appeared to be reduced 1n male rats at 2500
and 5000 ppm and In female rats at 600-5000 ppm, but in neither sex at
10,000 ppm. Relative liver weights were increased In both sexes at >5000
ppm. Pathologic examination revealed testicular and ovarian degeneration at
>2500 ppm. One rat at 1300 ppm had small testes but no other significant
changes.
Among mice, two males at 5000 ppm and one male at 300 ppm died. No
other deaths occurred. Clinical signs associated with toxlclty included
trembling, inactivity, hypothermia and sunken eyes and occurred at >2500 ppm
in both sexes. A noteworthy reduction in rate of body weight gain occurred
in males at >2500 ppm and in females at 5000 ppm. Relative liver weight did
not appear to be affected by dietary nitrofurantoin. Gross and microscopic
pathologic examination revealed that the target organ in females 1s the
ovary, and the target organs in the male are the testis and kidney. Ovarian
follicular necrosis occurred at >2500 ppm but not at 1300 ppm. Epithelial
necrosis of the kidney occurred in males at >2500 ppm and testicular
degeneration and reduced spermatogenesis at >600 ppm. One male at 300 ppm
had small testes, but histopathologic examination was normal.
0057d 6-4 09/15/87
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Morris et al. (1969) fed diets containing n1trofuranto1.n at 0 or 0.3% (0
or 3000 ppm) to groups of twenty 60-day-old female Holtzman rats for 36
weeks or to groups of 30-36 weanling female rats for 44.5 weeks. No overt
signs of toxldty were observed. In a study where weanling female
Sprague-Oawley rats were fed with nltrofurantoln, however, the Initial
dietary level of 0.187% (1870 ppm) was reduced to 0.1% (1000 ppm) after 16
weeks because of slightly Impaired growth (Cohen et al., 1973a).
NHrofurazone appears to be more toxic than nltrofurantoln. Physio-
logical Research Laboratories (1980a) fed diets containing 0, 0.015, 0.031,
0.062, 0.125 or 0.25% (0, 150, 310, 620, 1250 or 2500 ppm) nltrofurazone to
groups of 10 male and 10 female 41- to 56-day-old Fischer 344 rats for 13
weeks. Groups of 10 male and 10 female B6C3F1 mice (56-59 days old) were
fed diets containing 0, 0.007, 0.015, 0.031, 0.062 or 0.125% (0, 70, 150,
310, 620 or 1250 ppm) also for 13 weeks. Rats and mice were sacrificed for
examination on the second day after exposure ended. Parameters of toxldty
evaluated Included clinical signs, body weight gain, food consumption,
relative liver weight and gross pathology on all animals and a comprehensive
microscopic examination of all controls, dead animals and all high concen-
tration rats and mice with >60% survival at termination. In addition, a
comprehensive microscopic examination was performed on all rats and mice
with gross lesions.
No unscheduled deaths occurred 1n rats at any dietary concentration.
The most obvious clinical sign in rats was Increased excitability, which was
noted in both sexes at >1250 ppm. Reduced rate of body weight gain occurred
1n a dose-related manner in both sexes and appeared to be more severe in
males. Compared with the rate of body weight gain In controls, the rate of
body weight gain 1n male rats was reduced by 5, 15, 44 and 78% at 310, 620,
0057d 6-5 09/15/87
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1250 and 2500 ppm, respectively; and In female rats was reduced by 6, 22 and
67% at 620, 1250 and 2500 ppm, respectively. A dose-related reduction In
food Intakes of >13% occurred in males at >620 ppm and 1n females at >1250
ppm. Increased relative Hver weight was observed (p<0.005) In both sexes
of rats at all dietary concentrations. Gross and microscopic examination
revealed atrophy of the skeletal muscles of the rear limbs 1n both sexes at
2500 ppm, osteomalada of the long bones In both sexes at 1250 and 2500 ppm,
testlcular degeneration at >310 ppm, and moderate uterine hypoplasla at
>1250 ppm.
Mice seem to be more sensitive than rats to the toxlclty of nltrofura-
zone. Cumulative mortality was six males and nine females 1n the high-dose
group and three males and five females at 620 ppm, the second highest level.
Deaths occurred as early as the second week of the experiment. Clinical
signs, Including hyperexcHabllHy and seizures occurred at >620 ppm. The
rate of body weight gain was depressed 1n treated mice, but the extent was
variable and did not exhibit a dose-related pattern. The Investigators
concluded that a significant rate of body weight gain depression occurred In
males at >620 ppm and 1n females at >310 ppm. Food consumption appeared to
be reduced at 1250 ppm. Relative liver weights were depressed 1n males at
70 ppm and 1n females at 70 and 150 ppm, and were elevated 1n males at 620
and 1250 ppm. Pathologic examination revealed testlcular hypoplasla and
arrested spermatogenesls at >620 ppm. Significant pathologic lesions were
not observed 1n female mice.
Morris et al. (1969) fed diets containing 0.1% (1000 ppm) nltrofurazone
to female Holtzman rats for 36 or 44.5 weeks. Irritability was noted within
2 days of the beginning of the feeding period. HyperexcHabllHy, hyper-
Irritability, a tendency to resist handling, to squeal and attack when
0057d 6-6 06/04/87
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handled, and to have generalized seizures persisted throughout the exposure
period. The Investigators noted that hyperlrrltablllty was a part of the
acute toxldty associated with nHrofurazone.
PUsek et al. (1975) reported that nHrovIn was not toxic when male
Wlstar rats weighing -0.140 kg at the start were fed diets containing
nltrovln at 0.001, 0.002 or 0.004% (10, 20 or 40 ppm) of the diet for 60
days. Control rats were maintained. Parameters of toxlclty evaluated
Included general condition, body weight and growth rate, food consumption,
hematology, clinical chemistry and necropsy examination. It is not clear if
hlstopathologlcal examination was performed. There were no adverse effects
reported at any dietary concentration.
6.1.2.2. CHRONIC Chronic toxldty data are limited to cancer
studies that report Increased mortality In rats and mice fed dietary
furazolldone and decreased growth 1n rats fed nltrofurantoln. U.S. DHEW
(1976a) reported four long-term feeding experiments with furazolldone: a
high-dose Sprague-Dawley rat study, a Fischer rat study, a low level
Sprague-Oawley rat study and a mouse study. Groups of 50 male and 50 female
Sprague-Oawley rats were fed diets that contained 0, 1, 5 or 15 mg/kg/day
furazolldone for 2 years; increased mortality In the female rats occurred at
the 5 mg/kg/day level. In the other rat studies 1n which Sprague-Dawley or
Fischer rats were fed diets containing 0, 250, 500 or 1000 ppm for 18 or 20
months, respectively, Increased mortality occurred in males at 500 ppm.
Assuming a food factor for rats of 0.05 (U.S. EPA, 1980), a corresponding
dosage of 25 mg/kg/day 1s estimated. In groups of 50 male and 50 female
Swiss MBR/ICR mice fed diets containing 0, 75, 150 or 300 ppm furazolldone
for 18 months followed by a 10-month observation period, increased mortality
occurred In middle- and high-dose males and high-dose females. Assuming a
0057d 6-7 09/15/87
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food factor for mice of 0.13 (U.S. EPA, 1980), 150 ppm corresponds to an
estimated dosage of 19.5 mg/kg/day.
Wang et al. (1984) fed a group of 12 young adult female germ-free
Sprague-Dawley rats a diet containing nltrofurantoln at 0.188% (1880 ppm)
for 2 years. A slight reduction 1n growth rate compared with controls was
observed. Ito et al. (1983) fed diets containing 0, 0.075 or 0.3% (0, 750
or 3000 ppm) nltrofurantoln to groups of -50 male and -50 female BDF1 mice
for 24 months. There were no effects on survival but body weights of high-
dose group mice were consistently less than controls throughout the study.
6.1.3. Other Relevant Information. Oral LD5_ data for various nltro-
furans are presented 1n Table 6-1. Nltrofurantoln and nltrofurazone appear
to be the more acutely toxic members of the class and furazolldone and
nltrovln appear to be somewhat less toxic. Physiological Research Labora-
tories (1980b) fed groups of five male and five female Fischer 344 rats and
five male and five female B6C3F1 mice diets containing 0, 0.063, 0.125,
0.25, 0.5 or 1.0% (0, 630, 1250, 2500, 5000 or 10,000 ppm) nltrofurazone for
14 days. Clinical signs associated with nltrofurazone occurred 1n all
treated groups of rats. Mortality occurred 1n male rats at >2500 ppm and In
females at >5000 ppm. Marked reduction 1n rate of body weight gain occurred
1n both sexes of rats at >1250 ppm. H1stopatholog1cal lesions associated
with treatment occurred In both sexes of rats at >2500 ppm and Included
pertbronchlal lymphold Infiltration, bone marrow hypoplasla, ovarian degen-
eration and aspermatogenesls. All treated groups of mice exhibited hyper-
excltabllHy and convulsions. All male and female mice at >2500 ppm and 3/5
males at 1250 ppm died. Enlarged adrenals were observed in all treated
groups. Hlstopathologlc examination was unremarkable.
0057d 6-8 09/15/87
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TABLE 6-1
Oral 1050 Values for NHrofurans
Chemical
Furazolidone
Nitrofurantoin
NHrofurazone
Nitrovin
Species
rats
mice
rats
mice
rats
mice
mice
LDso Value
(rag/kg)
2336
4098-4543
604
360
590
380
5330
Reference
NIOSH, 1987a
Rogers et al. , 1956
NIOSH, 1987b;
Sax, 1984
NIOSH, 1987b;
Sax, 1984
NIOSH, 1987c;
Sax, 1984
NIOSH, 1987c;
Sax, 1984
NIOSH, 1987d
0057d
6-9
06/04/87
-------
An English- abstract of a Czechoslovak^ study reported that young male
H strain mice were able to withstand an oral dose of nltrovln of 9000 mg/kg
without signs of toxlclty (PUsek et a!., 1975). This dosage 1s substan-
tially above the LD5 for mice reported by NIOSH (1987d).
The nltrofurans have been associated with various health problems In
humans. Bajaj and Gupta (1986) applied the patch test with several topical
antibacterial agents to 390 patients with suspected contact dermatitis.
NHrofurazone was listed as a common sensltlzer. Cavanagh (1973) described
a dying-back type of peripheral neuropathy In humans treated with nltro-
furans. Generally, peripheral neuropathies were not observed 1n patients
given moderate therapeutic dosages (not specified) to treat urinary tract
Infection but were observed 1n patients given heroic dosages (1.5 g/day) to
treat trypanosomlasls. Severe symptoms of neuropathy appeared 1n 10-14 days
after starting treatment. Bone et al. (1976) reported the development of
debilitating desquamatlve Interstitial pneumonia In two men who had been
taking nltrofurantoln orally dally for 2 years (dosage not specified).
Gradual reversal of symptoms was obtained by discontinuing nltrofurantoln
*
therapy and using cortlcosterolds.
Alcohol ingestlon has been shown to modify the action and toxlclty of
concurrently used therapeutic agents. Alcohol 1n combination with nltro-
furantoln has been associated with toxic effects (not otherwise specified)
(Anonymous, 1985). In a metabolism study, furazolldone decreased the
breakdown of ethanol 1n rabbits; nltrofurantoln or nltrofurazone had no
effect (Cholsy and Potron, 1971).
Nltrofurantoln Is used to treat urinary tract Infections 1n humans.
Mueller et al. (1976) observed that concurrent administration of vitamin 86
with nltrofurantoln Increased the concentration of the drug 1n the urine.
0057d 6-10 09/15/87
-------
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the cardnogenlclty of the
nltrofurans by Inhalation exposure could not be located 1n the available
literature as cited In Appendix A.
6.2.2. Oral. Data were not located regarding the cardnogenlclty of the
nltrofurans to humans; however, the cardnogenlclty of several of the
nltrofurans has been tested by oral administration to laboratory animals.
Several studies that used rats and mice, available only from secondary
sources, establish furazolldone as an animal carcinogen. In 1971, Norwich
submitted, to FDA four chronic oral studies on the effects of several
nltrofurans In rats and mice, which are summarized 1n the Federal Register
(U.S. DHEW, 1976a,b). In the first Norwich study (1965-1967) [as reported
1n the Federal Register (U.S. DHEW, 1976a,b)], furazolldlne, furaltadone,
nltrofurazone and nlhydrazone were administered 1n a diet containing 0.19%
of a tested compound to female Sprague-Dawley rats (Holtzman strain) In
seven test groups of 35 animals each for 45 weeks followed by an 8-week
drug-free observation period. This study suggested that the rats fed
nltrofurans had a significantly higher Incidence of mammary tumors compared
with the control. It was also suggested that the tumor-Inducing potency was
In the following orders for these compounds: furaltadone, furazolldone,
nltrofurazone and nlhydrazone.
In the follow-up Norwich study, 280 Carworth Farm (CFE strain) rats 1n
seven groups of 20 males and 20 females were fed diets containing 0.1% of
nltrofurans for 45 weeks followed by a 5-week drug-free .observation period.
Results from this experiment Indicated that the two strains of rats had
similar responses toward the compound. U.S. DHEW (1976a,b) reported
0057d 6-11 09/17/87
-------
markedly Increased Incidences of mammary tumors (Norwich Pharmacol Co.
studies) 1n female Sprague-Dawley and Carworth Farms rats fed diets
containing 0.1% (1000 ppm) furazolldone (Table 6-2).
Hess and Clark (1967) performed a 2-year chronic study of furazolldone
1n rats. There were three dose groups of 10 males and 10 females each fed
0, 0.05 and 0.1% of furazolldone. The results Indicated 3 times as many
tumors In rats fed 0.1% furazolldone 1n the diet compared with the control.
U.S. DHEW (1976a) also presented the protocol and generalized results of
four larger and longer-term studies using both sexes of rats and mice. In
the first study, groups of 50 male and 50 female Sprague-Dawley rats were
fed diets containing 0, 250, 500 or 1000 ppm of furazolldone for 18 months
and observed for 2.5 years or until death. Control diets were then fed to
all groups until mortality for each group reached 90%, at which time the
survivors 1n that group were sacrificed. The predominant tumor site In
female rats was the mammary gland. The Increased Incidence of malignant
tumors was statistically significant (p<0.01) In the high-dose group, the
Increased Incidence of benign tumors was significant 1n the middle-dose
group and the Increased Incidence of total mammary tumors was significant
(p<0.05) 1n all treated groups. A significant Increase (p<0.05) in total
tumors observed 1n the high-dose males Included squamous cell carcinoma,
dermal fibroma, pituitary neoplasms and lymphoretlcular neoplasms. No tumor
type predominated In males, but mammary tumors were not observed. A
significant Increase In mortality was observed in middle- and high-dose
group males and high-dose group females.
U.S. DHEW (1976a) also reported a second study in which groups of 40
male and 40 female Sprague-Dawley rats were fed diets that provided
furazolldone at 0, 1, 5 or 15 mg/kg/day for 2 years (731 days).
Furazolldone appeared to decrease the time to onset of mammary tumors in
0057d 6-12 09/15/87
-------
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female rats. When data from all tumor sites and types were combined, a
higher Incidence occurred In high-dose females than In controls (p<0.05). A
linear dose-related trend 1n the Incidence of total tumors 1n all treated
groups of females (p<0.05) was also detected. No Increase In tumor
Incidence was observed 1n male rats. Mortality was also accelerated 1n
middle- and high-dose female rats (p<0.05).
In the third study, Fischer rats were treated by the same protocol as In
the first Sprague-Oawley rat study, except that furazolldone was fed for 20
months {U.S. DHEW, 1976a) and observed for an additional 11 months. Both
the Incidence and multiplicity of mammary tumors In female rats were
significantly (p<0.01) greater In all treated groups than 1n controls.
Malignant mammary tumors were noted only 1n high-dose group females. The
Incidence of thyroid adenomas was Increased In rats of both sexes 1n the
middle- and high-dose groups (p<0.05), and the Incidence of sebaceous gland
adenomas was Increased In middle- and high-dose males and high-dose females
(p<0.05). In addition, testlcular mesothelloma and basal cell epHhellomas
were significantly Increased In males at the 0.1% dose level. Mortality was
*
Increased In middle- and high-dose males and high-dose females. It was
concluded by the Director of FDA that furazolldone 1s "a demonstrated
carcinogen In Fischer rat."
In the fourth study reported by U.S. DHEW (1976a), groups of 50 male and
50 female Swiss MBR/ICR mice were fed diets containing furazolldone at 0,
75, 150 or 300 ppm for 18 months followed by a 10-month observation period.
An Increased Incidence of bronchial adenocarclnomas of the lung was observed
1n males In the middle- and high-dose groups and In high-dose group females
(p values not reported). The response was dose-related In both sexes. The
0057d 6-14 09/15/87
-------
Incidence of total malignant tumors and total tumors of all types was
elevated (p<0.05) In middle- and high-dose males and high-dose females.
Survival was reduced In high-dose males and middle- and high-dose females.
From the results of these four chronic studies, the director of FDA made
the following conclusions:
1. Furazolldone Induced malignancies In rats and mice.
2. There Is some evidence for a dose-response trend.
3. There are sex differences In the response.
4. Mammary tumors were found In female rats while In mice the
target organ was the lung.
5. In addition to, the Increased Incidence of tumors among the
treated animals, there 1s an Increase in the frequencies of
multiple primary tumors In the affected animals.
Furlum has been shown to be carcinogenic In rats, mice, hamsters and
dogs. In two similar studies at the same laboratory (using female
Sprague-Dawley rats), furlum at 0.199% (1990 ppm) of the diet produced a
highly significant Incidence of malignant and benign mammary tumors and
malignant salivary gland tumors (Erturk et al., 1970a) (Table 6-3) and
benign mammary tumors (Cohen et al., 1975) (Table 6-4). In both
experiments, duration of exposure was 46 weeks and the duration of the
experiment was 66 weeks. Survival was not compromised by treatment
(penicillin was given concurrently In the first experiment to control
Infections), and the growth rate of treated rats appeared to be comparable
with controls. NFTA (furlum) was given to 70 female Sprague-Dawley weanling
rats at a dose of 0.199% (1990 ppm) by weight in the diet for 46 weeks
followed by 20 additional weeks of control diet. Of 56 rats that survived
16 or more weeks, 52 had tumors in the following organs: 47 mammary tumors,
24 fIbroadenomas of the breast, 23 adenocardnomas of the breast, 6 salivary
gland adenocardnomas, 7 alveolar cell carcinomas of the lung, 2
0057d ' 6-15 09/15/87
-------
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TABLE 6-4
Incidence of Benign Mammary Flbroadenomas In Female
Sprague-Dawley Rats fed Diets Containing Fur1umaปb
Number/Group0
67
70
Dietary
Concentration
(%)
0
0.1996
Duration of
Exposure
(weeks)
NA
46
Duration of
Experiment
(weeks )d
66
66
Incidence
of Tumors^
5/67
37/70
(p<0.001)
Strengths of study:
WEIGHT OF EVIDENCE
purity of test material verified, given by relevant
route of exposure, study of adequate duration, excel-
lent survival, group sizes sufficient, pathological
examination was sufficiently comprehensive
Weaknesses of study:
Overall adequacy: adequate
only one sex of rat was used, only one dosage level
used
aSource: Cohen et a!.. 1975
bPur1ty was verified by testing.
GWeanl1ng rats weighed 0.040-0.078 kg at start. Results from two experi-
ments were combined.
Denominator represents starting numbers. Survival to time to first
tumor, 30 weeks 1n controls, 42 weeks 1n treated rats, was not reported.
6Cumulat1ve dose was 9.5-10.3 g/rat.
NA = Not applicable
0057d
6-17
09/09/87
-------
transitional cell carcinomas of the kidney pelvis, 3 skin tumors, 1 small
Intestinal adenocarclnoma and 1 splenic lymphosarcoma .with hepatic
metastasis. They further demonstrated that many of these tumors were either
transplantable or have the ability to metastaslze to other foreign organs
(Erturk et al., 1970b).
Cohen et al. (1975) reported their studies of eight 5-n1trofurans with
heterocycllc substitutions at the 2 position In the comparative
cardnogenlcHy studies (Including NFTA) In female Sprague-Dawley rats.
Weanling Sprague-Dawley rats (Initially at 40-78 g) were given the chemical
1n the diet at 0.2%. The animals were weighed; food and chemical
consumption were determined at weeks 0, 1, 3, 6, 10 and monthly thereafter.
The growth curve of the treated animal and the control were reported to be
the same. The animals were also palpated biweekly for tumors beginning at
the 6th week. The final sacrifice was undertaken at 64 weeks. FuMum
(NFTA) was reported to be associated with Inducing tumors at an Incidence
rate of 40-60%. An attempt was also made 1n this paper to correlate the
chemical structures of various. Isomer cogeners with target organ
cardnogenlcHy. This report confirmed earlier reports of furlum
cardnogenlcHy from the same laboratory. Treated rats 1n both studies had
hyperplasla of the transitional cell epithelium of the renal pelvis. These
lesions were considered to be preneoplastlc because transitional cell
carcinomas were found 1n two treated rats 1n the first study and 1n three
treated rats 1n the second study.
Data Indicate that furlum causes leukemia 1n mice. Cohen et al. (1970)
(Table 6-5) demonstrated that exposure of female Swiss mice to 0.1% (1000
ppm) furlum 1n the diet for 13 weeks resulted 1n a high Incidence of
lymphocytlc leukemia (15/16) and a low Incidence of squamous cell tumors 1n
the forestomach (3/16). Furlum was fed to female 5-week-old Swiss mice at
0057d 6-18 09/15/87
-------
TABLE 6-5
Incidence of Lymphocytlc Leukemia 1n Female Mice
fed Diets Containing Fur1umaปb
Strain
Swiss
RF
BALB/c
C3H
No. /Group
56
50
35
30
30
30
30
37
30
16
20
30
30
32
36
Dietary
Concentration
(%)
0
0.1
0
0.01
0.025
0.05
0.1
0
0.1 .
0
0.1
0
0.1
0
0.1
Duration of
Exposure
(weeks)
NA
13
NA
14
14
14
14
NA
14
NA
14
NA
14
NA
14
Duration of
Experiment
(weeks)
27
27
28
28
28
28
28
28
28
28
28
28
28
28
28
Incidence of
Lymphocytlc
Leukemia
0/51C
15/16d-e
0/15f
7/10f
8/12f
9/139
8/99
0/35C
22/22h
3/151
12/16.3
0/29C
21/29*
0/26C
12/24k
0057d
6-19
09/09/87
-------
TABLE 6-5 (cont.)
WEIGHT OF EVIDENCE
Strengths of study: relevant route of exposure, purity of compound measured,
experiment of sufficient duration to establish the
carcinogenlcity of the compound, group sizes adequate
Weaknesses of study: only female mice were examined, mortality was high In
the first experiment
Overall adequacy: adequate
aSource: Cohen et a!., 1970
bPur1ty was verified
Denominator represents number surviving to T4th week.
^Heavy mortality accompanied by cannibalism reduced numbers available for
examination. Denominator represents mice available for necropsy.
eThree mice also had papillary tumors of the forestomach.
^Denominator represents numbers surviving to 18.th week, time to first tumor
1n 0.01 and 0.02554 diet groups.
90enom1nator represents numbers surviving to 14 weeks, the first time point
for which data are reported. Time to first tumor was 12 weeks.
"Denominator represents number surviving to 14th week; time to first tumor
was 13 weeks.
^Denominator represents number surviving to 18th week, the time to first
tumor.
^Denominator represents number surviving to 14th week, the time to first
tumor.
^Denominator represents number surviving to 14th week; time to first tumor
was 15 weeks.
NA = Not applicable
0057d 6-20 09/09/87
-------
0.1% (weight of diet) for 13 weeks with a cumulative dose of 490 mg/mouse.
The mice were observed for 14 more weeks while being fed control diet.
Itwas reported that "leukemia" appeared suddenly at week 13 and cannlball-
zatlon of moribund mice drastically reduced the survivor numbers from the
Initial 30 mice to 9 at 14 weeks and 1 at 18 weeks.
In a follow-up study, reported 1n the same paper, the effect of dose on
furlum cardnogenldty 1n mice was studied (Cohen et a!., 1970). Groups of
30 female 5-week-old Swiss mice were fed 0.1, 0.05, 0.025 and 0.01% dose for
14 weeks. The leukemia Incidence for the respective doses were 8/9, 9/13,
8/16 and 7/14. The latent periods for the detection of leukemia In these
groups were 12 weeks, 12 weeks, 18 weeks and 18 weeks. Stomach tumors were
also detected In 12/52 of the treated animals. In contrast, the control
animals developed 1/35 pulmonary adenoma, but no leukemia or forestomach
tumors.
In the same report, RF, BALB/c and C3H female mice were noted as
susceptible to the leukemogenlc effect. It was observed that these mice
strains were regarded as having a low Incidence of spontaneous leukemia.
While being fed a diet, of 0.1% NFTA, RF, BALB/c, C3H and Swiss mice
developed leukemia In 12/16, 21/29, 12/24 and 22/22 1n comparison with the
control (RF) 3/16.
In a subsequent report (Cohen et al.t 1973a), furlum was fed at 0, 0.05
and 0.1% (0, 500 and 1000 ppm) of the diet to groups of female Swiss mice
for 14 weeks followed by a 16-week observation period. A dose-related
Increase occurred In the Incidence of lymphocytlc leukemia (Table 6-6). In
addition, squamous cell paplllomas of the forestomach occurred in 1/25
low-dose, 2/27 high-dose and 0/28 control mice. Cohen et al. (1973a)
reported a correlation of structural activity relationship of furlum related
compounds and target organ carclnogenldty In the Swiss mice. It was
0057d 6-21 ' 09/15/87
-------
TABLE 6-6
Incidence of Leukemia 1n Female Swiss Mice fed
Diets Containing Fur1umaป^
Number/Group
30
30
30
Dietary
Concentration
(X)
0
0.05d
0.10e
Duration of
Exposure
(weeks)
NA
14
14
WEIGHT OF EVIDENCE
Duration of
Experiment
(weeks)
NA
30
30
Incidence
of Tumors0
1/28
18/25
26/27
Strengths of study:
Weaknesses of study:
Overall adequacy:
relevant route of exposure, purity of compound
measured, group sizes and duration of experiment
sufficient to establish the carclnogenldty of the
compound
only female mice were examined
adequate
aSource: Cohen et al., 1973a
bPur1ty was verified.
Denominator represents number surviving to week 10, the time to first
tumor.
^Cumulative dose/mouse was 0.29 g.
Cumulative dose/mouse was 0.59 g.
NA = Not applicable
0057d
6-22
09/09/87
-------
reported that the Incidences of leukemia for furlum were 26/27, 18/25 and
1/28 for the 0.1%, 0.05% and 0% doses, respectively. The average latent
periods were 15^2.4, 22.2^5.0 and 66 weeks, respectively. Furlum and
related compounds can be divided Into three groups: the first acts on the
urinary bladder and causes leukemia and low Incidence of forestomach tumor;
the second Induces high Incidence of forestomach tumor; the third group
Induced lymphocyte leukemia.
As part of a study Investigating the effects of thymectomy and splenec-
tomy (Cohen et a!., 1973b) and as part of another study on the effects of
selected chemicals (Cohen and Bryan, 1978) on the Incidence of furlum-
Induced leukemia and stomach tumors 1n mice, groups of 30 female Swiss mice
were fed various dietary levels of furlum for 14 weeks followed by a 16-week
observation period. Because the protocol and results were very similar,
these studies are presented together 1n Table 6-7. An apparent dose-related
Increase 1n the Incidence of leukemia occurred 1n the experiment reported by
Cohen and Bryan (1978). Without thymectomy and splenectomy, the Incidence
of lymphocytlc leukemia was 26/27. In partially thymectomlzed Swiss mice,
the Incidence was 4/4 and In total thymectomlzed mice, 0/15. In contrast
with the leukemia, the Incidence of forestomach paplllomas In these groups
was 1/27, 0/7 and 12/15, respectively. They concluded that "splenectomy and
thymectomy appear to prevent the appearance of lymphocytlc leukemia but
allows for a greater Incidence and degree of malignancy of the forestomach
neoplasms."
Cohen and Bryan (1978) reported studies on the effects of p-hydroxy-
acetanlllde on NFTA leukemogenlc activity. This chemical can block the NFTA
leukemogenlc activity 1n mice. The Inhibitory effect, however, can be
lifted by the action of chemicals such as sodium sulfate and L-meth1on1ne.
0057d 6-23 09/15/87
-------
TABLE 6-7
Incidence of Leukemia In 30 Female Swiss Mice fed Diets
Containing Furlum3
Dietary
Concentration
(%)
0
0.1
0
0.05d
0
0.0256
0.05f
0.19
Duration of
Exposure
(weeks)
NA
14
NA
14
NA
14
14
14
Duration of
Experiment
(weeks)
30
20C
30
30
30
30
30
30 .
WEIGHT OF EVIDENCE
Incidence
of Tumors^ Reference
1/27 Cohen et al.,
1973b
26/27
0/27 Cohen and
Bryan, 1978
19/25
0/27
8/22
17/22
23/25
Strengths of study:
Weaknesses of study:
Overall adequacy:
relevant route of exposure, purity of compound checked,
group size and duration of experiment sufficient to
elicit an unequivocally positive response
only females were examined
adequate
Purity was checked
Denominator represents number surviving to 10 weeks
CA11 mice had died by 20 weeks
Cumulative dose was 0.29 g/mouse
Cumulative dose was 0.15 g/mouse
Cumulative dose was 0.34 g/mouse
^Cumulative dose was 0.69 g/mouse
NA = Not applicable
0057d
6-24
09/09/87
-------
In contrast with the effect on the Inhibition of leukemia, p-hydroxyace-
tanlUde has no effects on forestomach papllloma Incidence. Headley et al.
(1977) administered furlum at 0.01-0.1% (100-1000 ppm) of the diet for
periods ranging from 1-98 days to groups of female BALB/c mice to study the
effects of furlum on the Immune response (see Section 6.1.2.1.). Leukemia
developed In 8/18 mice fed 0.05% furlum for 14 weeks.
Hamsters exposed to furlum In the diet developed tumors of the urinary
bladder (Table 6-8). Croft and Bryan (1973) fed diets containing 0 or 0.1%
(0 or 1000 ppm) furlum to groups of 24 male weanling Syrian golden hamsters
for 48 weeks followed by control diet for 22 weeks. A variety of tumors
derived from the transitional cells of the bladder and squamous ' cell
carcinomas of the bladder were Induced in 0/24 controls and 16/24 treated
hamsters. Squamous papHlomas of the forestomach, similar to those observed
1n mice (see above), were observed in 0/24 control and 6/24 treated hamsters.
Furlum has also been shown to be an oncogen in dogs. Erturk et al.
(1970b) fed two female mongrel dogs food containing furlum that supplied ~50
mg/kg/day for 30 months and then observed them for a 5-month period. One
female mongrel dog was maintained as a control. Both treated dogs developed
benign fIbroadenomas of the mammary gland, adenomas of the gall bladder and
hyperplasia of the transitional cells of the renal pelvis, but malignant
tumors were not found. The control dog did not develop benign or malignant
tumors.
In contrast with the results In rats, mice, hamsters and dogs, a study
of furium In guinea pigs was negative. Croft and Lower (1981) fed groups of
30 male weanling guinea pigs diets containing 0 or 0.1% (0 or 1000 ppm)
furlum for 50 weeks followed by control diet for an additional 70 weeks.
All guinea pigs were killed and thoroughly examined at 124 weeks. No tumors
were located 1n any of the tissues of treated or control guinea pl.gs.
0057d 6-25 09/15/87
-------
TABLE 6-8
Incidence of Urinary Bladder Tumors 1n 24 Weanling Male
Syrian Golden Hamsters fed Diets Containing Furiumaปb
Dietary
Concentration
(X)
0
O.lc
Duration of
Exposure
(weeks)
NA
48
Duration of
Experiment
(weeks)
70
70
Incidence
of Tumors
0/24
16/24d
Strengths of study:
Weaknesses of study:
Overall adequacy:
WEIGHT OF EVIDENCE
relevant route of exposure, purity of compound verified,
group size and study duration sufficient to elicit an
unequivocally positive response
only male hamsters were used, only one dose level tested
adequate
aSource: Croft and Bryan, 1973
bPur1ty was verified.
Cumulative dosage was 12.6 mmol (3191 mg)/hamster
^Diverse sizes and types of transitional cell tumors or squamous cell car-
cinomas, occasionally metastatlc
NA = Not applicable
0057d
6-26
09/09/87
-------
In the only cancer study located regarding 5-n1tro-2-furancarboxaldehyde
dlacetate, Morris et al. (1969) fed diets containing 0 or 0.2% (0 or 2000
ppm) of the compound to groups of 20 female Holtzman rats (60 days of age,
weighing 0.170-0.175 kg) for 36 weeks, and observed them for an additional
17-19 weeks. In a second experiment, groups of 30-36 rats (22 days old,
weighing 0.055-0.58 kg) were fed diets containing 0 or 0.2% (0 or 2000 ppm)
for 44.5 weeks followed, and observed for an additional 15-17 weeks. In
both experiments concurrent respiratory infection resulted in heavy mortal-
ity and required therapy first with tetracycl.lne and then with penicillin.
In addition, piperazlne citrate was given to control pinworm infestation.
Tumors were found only in the mammary gland and were histopathologically
benign. The incidences, based on numbers of rats surviving to 36 weeks
(time of first tumor), were 0/5 and 0/5 at 0 and 0.2% (0 and 2000 ppm) in
the diet 1n the first experiment, and 3/16 and 4/13 at 0 and 0.2% in the
diet 1n the second experiment. The Investigators concluded that 5-n1tro-2-
furancarboxaldehyde dlacetate was not carcinogenic 1n these experiments.
CarclnogenlcHy studies of nltrofurantoln administered to animals are
Inconclusive. Three dietary studies using rats (Morris et al., 1969; Cohen
et al., 1973c) and one using mice (Ito et al., 1983) yielded negative
results. In the first report, groups of 20 female Holtzman rats, 60 days of
age and weighing 0.270-0.175 kg were fed diets containing 0, 0.3 or 0.3% (0,
3000 or 3000 ppm) nltrofurantoin for 36 weeks followed by a 17- to 19-week
observation period (Morris et al., 1969). The two groups treated at 0.3%
differed only in the nature of the basal diet to which the nltrofurantoln
was added, but there appeared to be no impact on the Integrity or results of
the experiment. In another experiment (Morris et al., 1969), nltrofurantoln
was fed at 0 or 0.3% (0 or 3000 ppm) of the diet to groups of 30-36 female
Holtzman rats at 22 days of age and weighing 0.055-0.058 kg. Treatment was
0057d 6-27 09/15/87
-------
for 44.5 weeks followed by a 15- to 17-week observation period. Concurrent
respiratory Infection caused high mortality In control and treated rats 1n
the first experiment and In controls In the second experiment. Concurrent
therapy Included tetracycllne and penicillin to control Infection, and
plperazlne citrate to control a plnworm Infestation. Based on numbers of
rats surviving to 36 weeks of age, the age at which the first tumor was
observed, the Incidences of mammary tumors was 0/5, 1/9 and 1/7 1n the first
experiment at 0, 0.3 and 0.3% of the diet, respectively. In the second
experiment, the Incidences of mammary tumors were 3/16 at 0% nltrofurantoln
and 5/18 at 0.3%. In neither experiment was the Incidence of mammary tumors
significantly greater 1n treated groups than 1n controls.
Cohen et al. (1973c) fed a diet containing nltrofurantoln to a group of
weanling female Sprague-Dawley rats Initially weighing 0.040-0.072 kg. The
diet contained 0.187% (1870 ppm) for the first 16 weeks and was reduced to
0.1% (1000 ppm) from weeks 16-75. Control diet was fed from week 75 to week
80, at which time the rats were sacrificed and subjected to a thorough
examination. A group of 30 control rats were fed the basal diet for 80
weeks and then were sacrificed and examined. Controls were treated with
penicillin on weeks 15 and 26 to control a respiratory Infection. Although
the number of rats starting In the treatment group was not reported, 36 were
alive at 10 weeks, 19 of which had tumors. The Incidence of total tumors 1n
controls was 14/30. The most common tumors 1n controls and treated rats
were mammary Hbroadenomas and adenocarclnomas. The Incidences of these
tumors were 6/30 and 6/30 In controls and 13/36 and 6/36 In the treated
rats, respectively. These Incidences were not statistically different.
A significant decrease 1n the total number of male mice with tumors and
In the Incidence of hepatomas 1n male mice was observed In treated mice In a
dietary study with nltrofurantoln ~(Ito et al., 1983). Groups of -50 male
0057d 6-28 09/15-/87
-------
and -50 female BDF1 mice, 9 weeks old at Initiation, were fed diets contain-
ing 0, 0.075 or 0.3% (0, 750 or 3000 ppm) for 24 months, at which time they
were sacrificed and examined. Treatment with nltrofurantoln had no effect
on survival, but a definite depression of average body weight was observed
at 0.3% (3000 ppm) of the diet In both sexes. No tumor type appeared to be
Increased In Incidence 1n either sex of treated mice compared with control
mice.
The only experiment that suggested a carcinogenic role for
nltrofurantoln was a 2-year dietary study In which 12 female germ-free
Sprague-Dawley rats, Initially weighing 0.085-0.110 kg, were fed diets
containing 0.188% (1880 ppm) nltrofurantoln for 2 years (Wang et al., 1984)
(Table 6-9). A control group of 11 female rats was maintained. The
Incidence of mammary fIbroadenomas was Increased In treated (9/12) compared
with control (2/11) rats (p<0.01). Although the Incidence of mammary
fIbroadenomas was Increased In the treated rats, very small group sizes were
used. Furthermore, the occurrence of mammary flbroadenomas 1n aging female
rats 1s common, and the Incidence can be highly variable. The germ-free
manner 1n which these rats were maintained represents an unnatural
condition. The biological significance of this apparently positive response
to nltrofurantoin 1s unclear, particularly 1n light of the negative results
where female rats were used 1n studies with larger numbers of animals
(Morris et al., 1969; Cohen et al., 1973c).
Nltrofurantoln has been tested by the National Toxicology Program for
carclnogenlclty In dietary studies 1n which rats and mice were used (NTP,
1987), but results are not yet available.
Three oral exposure studies suggest that nltrofurazone Induces mammary
tumors In female rats (Grlswold et al., 1968; Morris et al., 1969; Erturk et
0057d 6-29 09/15/87
-------
TABLE 6-9
Incidence of Mammary Flbroadenomas In Germ-Free Female Sprague-Dawley
Rats fed Diets Containing N1trofuranto1naปb
Number/Group
11
12
Dietary
Concentration
(X)
0
0.188 .
Duration of
Exposure
(weeks)
NA
2
Duration of
Experiment
(weeks)
2
2
Incidence of
Tumor s0'^
2/11
9/1 2e
Strengths of study:
WEIGHT OF EVIDENCE
relevant route of exposure, satisfactory duration of
exposure, statistical analysis was performed, adequate
necropsy and hlstologlcal examination
Weaknesses of study:
Overall adequacy: limited
group sizes were small, only one dosage level, only
one sex studied, germ-free conditions are unnatural
aSource: Wang et aV.. 1984
bMacrodant1n, a drug form of nltrofurantoln; purity not reported.
cWean!1ngs weighed 0.085-0.110 kg at start.
dRats were maintained In Isolation; all diets and drinking water was auto-
claved to maintain germ-free conditions.
ep<0.01
NA = Not applicable
0057d
6-30
09/15/87
-------
al., 1970c). Grlswold et al. (1968) treated groups of 10 or 20 female
Sprague-Oawley rats with nitrofurazone by gavage every 3 days over a 30-day
period (10 doses given) and observed them for an additional 9 months (Table
6-10). Carcinoma of the mammary gland was observed In 1/5 of the high-dose
rats surviving to termination. Tumors observed in 1/10 and 1/9 rats at
lower doses were benign. The investigators described the response to nitro-
furazone as borderline; however, treated groups were too small to properly
evaluate these results.
Morris et al. (1969) observed a highly significant increased Incidence
of mammary tumors in female rats treated with nitrofurazone in the diet at
0.1% (1000 ppm) for 36 or 44.5 weeks (Tatrre 6-11). All mammary tumors were
described as "histologically benign." These tumors, however, were trans-
plantable to other male and female rats of the same strain with a greater
degree of successful transplant in the females (Erturk et al., 1970c). The
transplanted tumors reached 4-100 g in mass and histologically demonstrated
an Increased glandular component, increased mitoses and disruption of the
basement membrane, changes that suggest a tendency toward developing
malignancy. One transplanted tumor was described as an adenocardnoma.
Metastases were not observed in donor or recipient rats.
Because the nitrofurazone used by Morris et al. (1969) was contaminated
with -3% 5-nitro-2-furaldehyde azine, the feeding experiment was modified
slightly and repeated with pure nitrofurazone (Erturk et al., 1970c) (Table
6-12). A highly significant Increase In mammary tumors was observed. All
tumors were histologically benign. The Investigators reported that accord-
ing to Foulds (1951), the mammary fibroadenoma of the rat is an Incompletely
developed tumor, which may become malignant.
0057d 6-31 , 09/15/87
-------
TABLE 6-10
Incidence of Mammary Tumors in Female Sprague-Dawley Rats Given
IntragastMc Doses of NHrofurazon In Sesame Oilaปb
Number/Group0
140
20
10
10
Total Dosaged
(mg/rat)
of
500h
350
200
Surviving to
9 Months6
127
5
10
9
Tumor
Incidence
5/1329
1/51
1/103
1/9J
WEIGHT OF EVIDENCE
Strengths of study: relevant route of exposure, adequate number of controls
Weaknesses of study: small size of treated groups, experiment too short in
duration
Overall adequacy: Inadequate
aSource: GMswold et a!., 1968
DPur1ty was tested by appropriate methods.
C40 days old at start
^Divided into 10 doses with 1 dose given every 3 days over 30-day period.
Observation period of 9 months
^Vehicle control
9lt 1s not clear what animals the denominator represents, but It appears
to be those surviving to sacrifice and any that had grossly visible
mammary tumors.
"Determined as the MTD in a 60-day experiment
1 Carcinoma
^Benign
0057d 6-32 09/15/87
-------
TABLE 6-11
Incidence of Benign Mammary Tumors 1n Female Holtzman Rats fed Diets
Containing N1trofurazoneaปb
Dietary Duration of Duration of Tumor
Number/Group Concentration Exposure Experiment Incidence p Value0
(%) (weeks) (weeks)
20d
20d
30-36f
30-36f
0
0.1
0
0.1
NA
36
NA
44.5
53-55
53-55
59.5-61.5
59.5-61.5
0/5e
11/186
3/1 6e
24/24e
NA
0.001
NA
0.001
Strengths of study:
Weaknesses of study:
Overall adequacy:
WEIGHT OF EVIDENCE
Test material was administered by a relevant route of
exposure and adequate necropsy .and hlstopathologlcal
examination were performed. In spite of poor
survival, a statistically significant response was
observed.
Survival was poor; a small number of only one sex were
used; concurrent therapy was performed; duration of
exposure and experiment too short; test material
Impure; only one dosage tested.
limited
aSource: Morris et al., 1969
bConta1ned -3% 5-n1tro-2-furaldehyde azlne, an Impurity.
cProbabH1ty that the observed result might have occurred by chance, as
calculated by the exact method for 2x2 tables.
d60 days of age, 0.170-0.175 kg body weight at start of experiment
eNumber In denominator represents survivors to at least 36 weeks of age,
the age at which the first tumor was observed; respiratory Infection
troubled the experiment, causing heavy mortality. Concurrent therapy con-
sisted of tetracycllne and penicillin, and plperazlne citrate for plnworms.
f22 days old, 0.055-0.058 kg body weight at start of experiment
NA = Not applicable
0057d
6-33
09/15/87
-------
TABLE 6-12
Incidence of Benign Mammary Tumors 1n 30 Female Sprague-Dawley
Rats fed Diets Containing N1trofurazoneaซb
Dietary
Concentration
(%)
0
0.100d
Duration of
Exposure
(weeks)
NA
46
Duration of
Experiment
(weeks)
66
66
Incidence
of Tumors0
2/29
22/29
Strengths of study:
Weaknesses of study:
Overall adequacy:
HEIGHT OF EVIDENCE
Test material was pure and given by a relevant route
of exposure; study was of adequate duration and survi-
val was excellent
only one sex tested, only one dosage used
adequate
aSource: Erturk et a!., 1970c
bPure material
Denominator represents rats surviving >22 weeks.
Investigators estimated dosage at 10-20 mg/rat/day with a total cumula-
tive dosage of 4800 mg/rat.
NA = Not applicable
0057d
6-34
09/15/87
-------
U.S. DHEW (1976b) reported a Norwich Pharmacol Co. study with nltrofura-
zone where female Sprague-Dawley rats and male and female Carworth Farms
rats were used (Table 6-13). Mammary tumors occurred 1n treated females of
both strains, but not 1n treated males or control rats of either sex. In
female Sprague-Dawley rats, no significant difference In Incidence was
observed between 0.05 and 0.1% of the diet.
Nltrofurazone has been tested by the National Toxicology Program for
cardnogenlclty In dietary studies that used rats and mice (NTP, 1987), but
results are not yet available.
In the only studies of the cardnogenlclty of nltrovln located, Erturk
et ITI. (1980, 1983) treated 28 female Sprague-Dawley rats with a diet
containing 1000 ppm nltrovln hydrochlorlde for 46 weeks followed by a
22-week observation period. A group of 40 female rats served as controls.
The Incidence of single mammary fIbroadenomas was 6/37 1n controls and 3/26
In the treated group. Additional details were not available.
6.2.3. Other Relevant Information. Studies with nltrofurazone 1n rats
Indicate that this compound Induces benign mammary tumors 1n a large propor-
tion of exposed females (see Section 6.2.2.). Akao et al. (1971b) Investi-
gated the ability of nltrofurazone to modify the hepatic response of male
Donryu rats to 4-(d1methylam1no)azobenzene. Rats were fed a diet containing
0.06% 4-(d1methylam1no)azobenzene with or without nltrofurazone at 0.2%
(2000 ppm) for ~3.5 months, followed by basal diet for an additional month.
Preneoplastlc lesions such as nodular growth of regenerative cells, atypical
cells, fibrous proliferation, cholanglof1bros1s and bile duct proliferation
(all clearly evident In rats fed 4-(d1methylam1no)azobenzene) were markedly
reduced 1n rats receiving 4-(d1methylam1no)azobenzene) plus nHrofurazone.
Taklzawa et al. (1975) noted a correlation between the cardnogenlclty
of certain polyaromatlc hydrocarbons and their ability to destroy the
0057d - 6-35 09/15/87
-------
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6-36
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sebaceous glands of the skin, and tested nHrofuran derivatives to determine
1f a similar correlation exists for this class of chemicals. Groups of five
young ICR Swiss mice were treated by dorsal skin painting twice dally for 3
days with the test compound 1n dimethyl sulfoxlde and were killed 4 days
after the last application so that the condition of the sebaceous glands
could be observed. Dimethyl sulfoxlde-treated negative controls and
7,l2-d1methylbenz[a]anthracene-treated positive controls were similarly
handled and examined. Positive controls had 99.5% sebaceous gland
destruction and negative controls had 0.2% sebaceous gland destruction.
Nitrofurazone yielded 1.9, 7.7 and 98.3% sebaceous gland destruction at
cumulative doses of 0.20, 1.00 and .5.00 mg/mouse, respectively.
NHrofurantoln resulted in 1.1 and 0.7% sebaceous gland destruction at 1.00
and 5.00 mg/mouse, respectively. Although nitrofurazone is a potent animal
oncogen (see Section 6.2.2.), nltrofurantoin gave largely negative results.
Nitrofurazone promoted metastasis when fed to rabbits that had Brown-
Pierce carcinomas (Dauvarte and Zidermane, 1968). In an j_n vitro study,
nitrofurantoin caused growth inhibition of a mouse bladder tumor cell line
(MBT?) and a human transitional cell carcinoma line (GIBB) induced by a
nHrofuran structurally similar to furlum {Bulbul et al., 1985). Transplan-
tation of the mouse bladder tumor cells to the cauterized bladder of Intact
mice was also Inhibited by nltrofurantoin.
Nomura et al. (1975, 1984) administered nitrofurazone at 75 mg/kg or
nltrofurantoin at 75 mg/kg subcutaneously on days 13, 15 and 17 of gestation
to groups of 20 or 10 mated ICR/Gcl mice, respectively, that were allowed to
deliver. Controls consisted of a group of 22 mice treated with gelatin.
Offspring were foster-nursed by untreated lactating females until weaning
and were maintained until' sacrificed at 32 weeks after birth. A low but
0057d 6-38 09/15/87
-------
significantly Increased Incidence of lung tumors occurred In offspring from
nltrofurantoln (10/78) but not from nltrofurazone (4/67) treated mice
compared with negative controls (5/203 gelatin treated, 29/548 untreated).
In another part of this study, 75 mg/kg subctuaneous doses of nltrofurazone
were given to neonatal mice within 12 hours of birth and on days 7, 14 and
21 after birth. A significantly Increased Incidence of lung tumors occurred
1n nHrofurazone-treated mice (12/61) compared with gelatin-treated controls
(5/203).
A dietary level of 0.1% (1000 ppm) furlum fed to female Swiss mice for
14 weeks Induced a high (26/27) Incidence of leukemia and low (1/27)
Incidence of forestomach tumors (Cohen et a-1., 1973b) (see Section 6.2.2.).
Incidences 1n controls were 1/27 and 0/27, respectively. The lymphocytic
leukemia associated with this compound Is characterized by enlarged thymus,
spleen and lymph nodes. Because other lymphocytic leukemlas 1n mice have
been shown to be dependent on a functional thymus, a thymectomy or splenec-
tomy was performed before exposure to furlum to determine the effect on
furlum-lnduced tumors. Splenectomy had no apparent effect on the Incidence
of leukemia or forestomach tumors; however, thymectomy appeared to prevent
the occurrence of leukemia (0/15) but markedly Increased the Incidence of
forestomach tumors (9/15).
Cohen and Bryan (1978) noted that carcinogenic aromatic amines and
amides appear to be bloactlvated by N-hydroxylat1on to N-hydroxylamlnes and
hydroxamlc adds, respectively, and that coadm1n1strat1on of acetanlllde or
Its metabolic actWatlon product, p-hydroxyacetan1Hde, exerts an Inhibitory
effect on the cardnogenlclty of the aromatic amines and amides. When
p-hydroxyacetan1!1de was administered concurrently with furlum to female
Swiss mice, the leukemogenlc effect was Inhibited at low dosages [d.025 and
0.05% (250 and 500 ppm) of diet] of furlum, but only a prolongation of the
0057d 6-39 09/15/87
-------
latent period was observed with high dosages of furlum (0.1% of diet). The
addition of sulfate or methlonlne to the furlum and p-hydroxyacetan1!1de
diet reversed the Inhibitory effect of p-hydroxyacetanH1de on furlum-
Induced leukemogenesls. Presumably, sulfate and meth1on1ne-der1ved sulfate
conjugated with p-hydroxyacetanH1de to Inactivate 1t. p-Hydroxy-
acetanHlde, with or without sulfate or methlonlne, had no apparent effect
on the Incidence of forestomach tumors Induced by furlum, but these tumors
occurred only In small numbers of animals. The Investigators postulated
that N-hydroxylat1on of the amlno product of nltroreductlon 1s an important
bloactlvatlon step In the mechanism of cardnogenesls of the nltrofurans.
Nltroreductlon, therefore, may be an Important Initial metabolic event in
the bloactlvatlon of the nltrofurans.
6.3. MUTAGENICITY
The genotoxlclty of several nltrofurans has been studied 1n prokaryotes,
eukaryotes and certain mammalian tests (for review, see McCalla, 1979, 1983;
Bryan, 1978). Available genotoxlclty data for nltrofurans are presented In
Tables 6-14 through 6-22.
Nltrofurans are clearly positive 1n gene mutation assays with various
strains of Escher1ch1a coll and Salmonella typhlmurlum (predominantly tester
strain TA100). They are direct-acting mutagens in that they Induce
mutations without the addition of exogenous activating systems, e.g., liver
S9 mix. Addition of liver S9 activation decreases the toxldty and
mutagenldty of these compounds. It 1s also clear that the parent compound
Is not mutagenlc Itself; rather, the bacterial tester strains possess
nltroreductases that plan an Important role In activation of these compounds
to mutagens. It should be cautioned that bacterial tests may present an
exaggerated picture of the mutagenlc potency of nltrofurans relative to
effects seen In animals, because of the greater activity of the
0057d 6-40 09/15/87
-------
TABLE 6-14
Genotoxlclty Testing of Furalaz1nea'b
Assay
Indicator Application Concentration Activating Response
Organism or Dose System
Reverse Escher1ch1a coll spot test 10 yg/plate
mutation WP2, HP2uvrA-
Prophage E.. coll T44
Induction
liquid
suspension
0.1 jig/ml
none
none
aSource: McCalla and Voutslnos, 1974
''Purity not reported
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TABLE 6-20
Genotoxtctty Testing of Nttrofurazone
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nltroreductases 1n bacteria compared with animal cells and with .the
detoxification pathways existing 1n animals {HcCalla, 1983). Nevertheless,
several nHrofurans have been reported to be genotoxlc In whole animal and
mammalian cell culture tests (see Tables 6-14 to 6-22).
Most strains of Escherlchla coll have nltroreductase activity and yielded
positive results In the reverse mutation assay. Ohn1sh1 et al. (1977, 1978)
reported that acetyl furatrlzlne gave positive results 1n E.. coll In
prophage Induction and an unspecified assay. DNA damage assay, prophage
Induction, error-prone repair Induction, SOS function Induction and rec
assays have been almost universally positive. Tests 1n other prokaryotes
such as Klebslella pneumonlae (Knapp et al., 1983), Bacillus subtil Is (Ohta
et al., 1980), Vibrio cholerae (Bannerjee and Chatterjee, 1984) and
HycobacteMum phlel (Ebrlnger et al., 1979) were generally positive.
NHrofurans have been shown to cause a mutation In Euglena qracllls
resulting 1n bleaching of chlorophyll from chloroplasts (Ebrlnger et al.,
1976; Soska et al., 1981). In yeasts such as Asperqlllus nldulans.
Saccharomyces cerevlslae and Neurospora crassa. results have been
consistently positive (Ong, 1978; Blgnaml et al., 1982; Knapp et al.,
1983). Results 1n the sex-linked recessive lethal test 1n DrosophUa
melanoqaster have been mixed (Kramers, 1978, 1982; BUjlevIn et al., 1977;
Lee et al., 1983; Knapp et al., 1983; Zlmmerlng et al., 1985) with no
apparent explanation for the differences.
Results 1n several In vitro and In vivo mammalian systems Including jjn
vitro systems with human cells appeared to be unpredictable. Neither the
type of assay, the type of cell or tissue nor the nltrofuran tested appeared
to have an Impact on the results of the test.
0057d 6-58 09/15/87
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6.4. TERATOGENICITY
Data regarding developmental toxldty associated with oral exposure are
limited to animal experiments with furazolldone, nltrofurantoln and nitro-
furazone, and a retrospective study of humans with nltrofurantoln. In addi-
tion, several other studies by other routes of administration are available.
In an early study, Jackson and Robson (1957) administered furazolldone
at 0, 0.1 or 0.2% (0, 1000 or 2000 ppm) of the diet to pregnant albino C
strain mice to determine the effect on pregnancy. Administration at 2000
ppm on day 1 of pregnancy prevented successful pregnancy (defined as the
absence of abortion or fetal death) 1n 5/5 mice and resulted in the deaths
* *
of 3/5 dams. The dietary level of 1000 ppm prevented successful pregnancy
in 10/10 when started on gestation day 1 and in 4/4 when started on gesta-
tion day 6. When started on day 10, however, no abortions or fetal deaths
occurred at 1000 ppm. In control mice, unsuccessful pregnancies occurred in
5/20.
In another part of this experiment (Jackson and Robson, 1957), single
gavage doses of 0.75-2.0 g/kg bw furazolldone were administered. On day 7,
2.0 g/kg resulted 1n unsuccessful pregnancies 1n 4/4 and deaths of 1/4 dams.
A dose of >0.75 mg/kg given on or before day 7 of gestation interrupted
pregnancy. The effect on pregnancy of 1.0-1.25 mg/kg given on day 10 or 11
was less than when given on days 1-7, although the data are not sufficient
for meaningful evaluation. The investigators stated that Utters produced
by treated mice were well below normal weight, but congenital malformations
were not detected. The method of examination of the offspring, however, was
not stated.
Jackson and Robson (1957) also Investigated the effects of furazolldone
on pregnancy in the rabbit. Intra-aminotlc Injection of >2.0 mg, presumably
0057d 6-59 09/09/87
-------
on day 14 of pregnancy, resulted In fetal resorptlon or abortion. A dose of
1.0 mg appeared to have no effect on pregnancy.
Courtney et al. (1967) performed retrospective studies of a number of
therapeutic agents routinely used In pregnant monkeys, and reported that
furazolldone had no effect on pregnancy In the monkey; however, no data were
presented.
. Prytherch et al. (1983, 1984) and Sutton et al. (1983) performed terato-
genldty toxldty studies 1n Sprague-Dawley rats and New Zealand white
rabbits, and a reproduction rat study using Macrodantlnฎ, a macro-
crystalline form of nltrofurantoln used as a human therapeutic agent, In all
experiments. Treatment was by gavage with a suspension In aqueous methyl-
cellulose. In the rat teratogenldty study, groups of 20 mated rats were
treated with nltrofurantoln at 0, 10.0, 20.0 or 30.0 mg/kg/day on gestation
days 6-15, and were sacrificed on gestation day 20. In the rabbit study,
groups of 19 mated, rabbits were treated with 10.0, 20.0 or 30.0 mg/kg/day on
days 6-18 of gestation and were sacrificed on gestation day 29. In both
species, nltrofurantoln treatment had no effect on clinical signs, survival,
food consumption, body weight gain, Implantation or fetal wastage (reported
only for rabbits), or the Incidence of external, visceral or skeletal
malformations. Fetal body weights were not adversely affected, but fetuses
from the high-dose rats had significantly elevated body weights.
Prytherch et al. (1983, 1984) performed a general reproduction rat
study. Four groups of 15 males were treated with gavage doses of 0, 0, 0 or
10.0 mg/kg/day for 60 days before mating; after mating they were sacrificed
for necropsy and hlstopathologlcal examination of the testes. Groups of 30
females were treated with 0, 10.0, 20.0 or 30.0 mg/kg/day from 14 days
before mating throughout gestation. All females were mated to control males
except that females treated at 10.0 mg/kg/day were mated to males treated at
0057d 6-60 09/09/87
-------
10.0 mg/kg/day. Ten females from each group were sacrificed on gestation
day 13 to determine effects on pregnancy; the remaining females were allowed
to deliver and were maintained through postpartum day 21. Treatment with
nltrofurantoln had no effects on food consumption or body weight gain of
either sex, hlstopathologlcal appearance of the testes (10 mg/kg/day),
percentage pregnant or the number of viable fetuses/Utter. The number of
resorptlons/lltter appeared to be Increased (p<0.05) at 20.0 mg/kg/day but
not at 10.0 or 30.0 mg/kg/day. In dams that delivered there were no effects
on fertility, gestation or lactation Indices. The viability Index was less
than controls (p<0.05) at 20 mg/kg but not at 10.0 or 30.0 mg/kg. There
were no treatment-related adverse effects, on fetal body weight or the
Incidence of gross external or visceral malformations.
Prytherch et al. (1983, 1984) also treated groups of 30 mated females
with 0, 10.0, 20.0 or 30.0 mg/kg/day from gestation day 14 to weaning In a
perinatal study. There were no effects on clinical appearance, food
consumption, body weight gain, length of gestation or Indices of gestation,
viability or lactation. There were no adverse effects on the body weights
of offspring or on the Incidence of external or visceral malformations.
Perry et al. (1967) reported the results of a small retrospective study
1n a group of 101 pregnant women 1n a hospital 1n Texas using nltrofurantoln
at 100-200 mg/kg/day orally for control of asymptomatic bacterlurla. A
group of 101 women not using nltrofurantoln served as a control population.
There were no apparent effects on birth weight, Apgar scores or the
Incidence of congenital malformations of newborn Infants. The Investigators
concluded that nltrofurantoln had no adverse effects on the human fetus, but
this study 1s severely limited 1n sample size, geographic area and criteria
of sample selection.
0057d 6-61 09/09/87
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An oral screening test suggests that nltrofurazone may adversely affect
reproduction 1n mice (U.S. EPA, 1983b). Groups of 50 CD! mice were treated
with nltrofurazone In corn oil by gavage at 0 or 100 mg/kg/day, estimated to
be the MTD, on gestation days 7-14 and allowed to deliver and nurse to post-
partum day 3. Indications that the MTD was reached were the observation of
clinical signs and a statistically nonsignificant trend toward reduced
maternal body weight In treated mice. Treatment had no effects on the
number of pups/Utter or the viability Index, but the reproduction Index
(p<0.05) and gestation Index (p<0.01) were reduced In treated mice. Total
Utter weight 1n treated mice was less than controls on postpartum day 1
(p<0.05), but the difference was no longer significant by day 3.
Nomura et al. (1975, 1976, 1984) Injected ICR/Jcl mice subcutaneously
with nltrofurantoln and nltrofurazone 1n gelatin to test for developmental
toxldty. Groups of 6-17 pregnant mice were treated with gelatin alone on
gestation days 9, 10 and 11; with n1trofurant.o1n at 100 or 250 mg/kg/day on
days 9, 10 and 11; or with nltrofurazone at 100 mg/kg/day on days 9, 10 and
11 or at 300 mg/kg on gestation day 10. The mice were sacrificed on gesta-
tion day 19 for uterine examination. The high dose (300 mg/kg) of nltro-
furazone was associated with an Increased Incidence of fetal deaths. Fetal
body weights were reduced In both sexes with both levels of nltrofurazone
and the high level of nltrofurantoln. A slight but significantly Increased
Incidence of fetal malformations was observed 1n mice treated with the
higher dosage of either nltrofurantoln or nltrofurazone. Skeletal malforma-
tions of the leg, digits and hard palate predominated.
Greenaway et al. (1986) Incubated furazolldone, nlfuroxlme, nltrofuran-
toln and nltrofurazone with cultures of 10-day embryos from Sprague-Dawley
rats for -26 hours to determine effects on fetal viability and the develop-
0057d 6-62 09/15/87
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merit of malformations. Axial asymmetry resulting from right-sided h-ypo-
plasla accompanied by microphthalmla or anophthalmla was the typical
malformation associated with this class of compounds. Other malformations
typically occurred 1n the region of the head. Nlfuroxlme, furazolldone and
nltrofurazone produced a concentration-dependent Increase 1n the Incidence
of malformed fetuses at low (0.01 mM) concentrations. Nltrofurantoln
produced cephalic hypoplasla at 0.02 mM but was 100% lethal at 0.25 mM.
6.5. OTHER REPRODUCTIVE EFFECTS
Studies with several nltrofurans 1n several species suggest that the
testls 1s a sensitive target organ for this class of compounds. Konno et
al. (1977) studied the adverse effects on the testes of Wlstar rats when
furazolldone was fed In the diet at 400, 700 or 1000 ppm for 30 days.
Decreased testlcular size and weight and Interrupted spermatogenesls were
observed. Adverse effects on the testes were not observed at 100 ppm. In
female rats apparently exposed to the same protocol, ,degeneration of the
granulosa cells of the ovary was observed. These changes were especially
marked at 1000 ppm, but 1t 1s unclear 1f there was a dietary level at which
adverse effects on the ovary were not observed.
Hernandez et al. (1985) administered furazolldone at 110, 220, 330 or
660 ppm of the diet to mice for 2 months. After 1 month, mice In the high-
dose group had decreased testlcular weight, degeneration of the seminiferous
tubules, arrested spermatogenesls at the primary spermatocyte stage, and
Infertility. At 330 ppm, the nuclei of pachytene primary spermatocytes were
slightly modified, but there was no change 1n testlcular weight. Testlcular
content of androgens was altered at both 330 and 660 ppm. No effects on
fertility were reported at 110 or 220 ppm. When mice on the 660 ppm diet
were returned to a diet without furazolldone, fertility returned In 1 month.
0057d 6-63 09/15/87
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Nelson and Bunge (1957) administered nltrofurantoln at.10 mg/kg/day
(divided Into four oral doses) to 36 men aged 19-35 years for 2 weeks, and
evaluated the effects on total sperm count for up to 32 weeks after Initia-
tion of treatment and the effects on hlstopathologlcal appearance of the
testls blopsled at 2 or 4 weeks after starting treatment. In seven
subjects, the dosage was reduced by ~50% because treatment was poorly
tolerated. A significant reduction In sperm count was observed in 13
subjects; hlstopathologlcal findings reflected a tendency toward reduced
sperm production In 7 of these 13 subjects. No effects on sperm count or
the hlstopathologlcal appearance of the testes were observed In the remain-
Ing subjects.
Nelson and Stelnberger (1953) reported that In the male rat the testls
1s the most sensitive organ to the toxlclty of nltrofurantoln. A diet
containing 1.5 g/kg diet (1500 ppm) for 30 days was the highest dosage that
produced weight and h1stomorpholog1cal effects on the testls without
producing weight and hlstologlcal changes In other organs. Assuming a food
factor for rats of 0.05 (U.S. EPA, 1980), a dosage of 75 mg/kg/day can be
estimated. The effects on the testes were reversible within 100 days.
Nltrofurantoln administered orally to rats for 20-30 days Interfered
with spermatogenesls and the androgenlc function of the testls, and resulted
In altered nucleic add content and histomorphologlcal appearance (Yunda and
Kushnlruk, 1973, 1974; Kushnlruk, 1974, 1976). These effects occurred with
therapeutic (10 mg/kg/day) or toxic (85 mg/kg/day) doses (Kushnlruk, 1974).
The effects appeared to be reversible (Yunda and Kushnlruk, 1974).
Nelson and Stelnberger (1953) reported that a dietary level of nltro-
furazone of 0.2 g/kg diet (200 ppm) was the highest dosage that caused
marked effects on the weight and histology of the testls but not on other
organs In rats exposed for 30 days. The effects on the testls were revers-
0057d 6-64 09/15/87
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ible within 100 days. Formanek et al. (1971) noted that rats fed a diet
containing nitrofurazone at 1.5 g/kg food (1500 ppm) for 3 weeks had
Inhibited spermatogenesis associated with altered testicular respiration.
Injecting treated rats with testicular phosphatids hastened the recovery
from inhibited spermatogenesis. Hagenas et al. (1978) observed inhibition
of spermatogenesis in rats fed for 3 weeks on a diet containing nitrofura-
zone that provided 64 mg/kg/day.
Nitrofurazone has been tested in a serial mating experiment In mice.
Groups of three or six male white Swiss mice, weighing 27-30 g, were treated
with nitrofurazone in olive oil at 0.75, 1, 1.5, 2, 3 or 6 mg/day by gavage
for 3 weeks (Hershberger et al., 1969). Each treated group had a corre-
sponding vehicle control group of 3-12 mice. Mating was accomplished by
placing each male with two different females within a week on weeks 3, 4, 5
and 6 of the test. Females were necropsled 10 days after the 1-week-long
mating period to ascertain pregnancy, which was defined as having >1 viable
fetus. A marked dose-dependent reduction in fertility was observed at >2
mg/day during all weeks of mating. Using a mean body weight of 28.5 g, a
dosage of 70.2 mg/kg/day corresponds to the dose of 2 mg/day and 52.6
mg/kg/day corresponds to 1.5 mg/day, at which no effects on fertility were
observed.
6.6. SUMHARY
Data regarding the toxidty of the nitrofurans by relevant routes of
exposure are restricted to oral exposure. Most of the nitrofurans tested
have been shown to be oncogenic in animals. Furazolidone (U.S. DHEW,
1976a,b), furium (Erturk et al., 1970c; Cohen et al., 1975) and nitrofura-
zone (Morris et al., 1969; Erturk et al., 1970c; U.S. DHEW, 1976b) have been
shown to Increase the incidence of mammary tumors in female rats. Furazoli-
done has also been associated with the Induction of lung tumors In mice
0057d 6-65 09/09/87
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(U.S. DHEW, 1976a). Furlum 1s also carcinogenic In mice, associated with
leukemlas (Cohen et al., 1970, 1973a,b; Cohen and Bryan, 1978; Headley et
al., 1977). In hamsters, fuMum Is associated with tumors of the urinary
bladder (Croft and Bryan, 1973) and 1n dogs, 1s associated with tumors of
the mammary gland and gall bladder (Erturk et al., 1970b). Nltrofurantoln
was associated with an Increased Incidence of mammary tumors In germ-free
(Wang et al., 1984) but not 1n conventionally-maintained rats (Morris et
al., 1969; Cohen et al., 1973c). Negative results for cardnogenlcHy were
reported for 5-n1tro-2-furancarboxaldehyde dlacetate 1n rats (Morris et al.,
1969) and for nltrovln 1n rats (Erturk et al., 1980, 1983).
All the nltrofurans that have been tested for mutagenldty were positive
1n reverse mutation and other tests In prokaryotes (Rosenkranz and Speck,
1977). Exogenous metabolic activation was not always required, but
bacterial strains with nltroreductase activity did seem to be necessary for
a positive result. Generally positive results were observed In yeasts (Ong,
1978; B1gnam1 et al., 1982; Knapp et al., 1983) and mixed results were noted
In 1). melanogaster (Kramers, 1978, 1982; Z1mmer1ng et al., 1985) and various
\n vitro and jjn vivo mammalian systems (Probst and Hill, 1980; Probst et
al., 1981; Cohen and Sagl, 1979; Tonomura and Sasaki, 1974; Lee et al.,
1980).
The most sensitive target organ to the systemic toxiclty of the
nltrofurans appears to be the testls. Furazolldone (Konno et al., 1977;
Hernandez et al., 1985), nltrofurantoln (Nelson and Bunge, 1957; Nelson and
Stelnberger, 1953; Southern Research Institute, 1980) and nltrofurazone
(Nelson and Stelnberger, 1953; Formanek et al., 1971; Hagenas et al., 1978;
Hershberger et al., 1969; Physiological Research Laboratories, 1980a) all
have adverse effects on the testes of rats, mice and man. Nltrofurantoln
0057d 6-66 09/09/87
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was associated with ovarlon degeneration (Southern Research Institute, 1980)
and nltrofurazone with uterine hypoplasla (Physiological Research Labora-
tories, 1980a) 1n rats.
Furazolldone given orally to female mice can Interrupt pregnancy
(3ackson and Robson, 1957). NHrofurantoln was negative for developmental
toxlclty In oral studies where rats and rabbits were used and had no effect
on male and female reproduction 1n rats at dosages of 10, 20 or 30 mg/kg/day
(Prytherch et al.t 1983, 1984; Sutton et a!., 1983). These dosages,
however, were relatively low. Nltrofurazone given orally at 200 mg/kg/day
during organogenesls was associated with fetotoxldty In the rat (U.S. EPA,
1983b). When administered parenterally .to mice, nltrofurantoln and
nltrofurazone were associated with fetal toxlclty and fetal malformations
(Nomura et al., 1975, 1976, 1984). N1furox1me, furazolldone, nltrofurazone
and nltrofurantoln Induced right-sided hypoplasla and other malformations In
cultured rat embryos (Greenaway et al., 1986).
In humans, therapeutic doses of nltrofurans have been associated with
adverse effects. Nltrofurazone, used as a topical antibacterial, was deter-
mined to be a common sensltlzer among many agents tested In the patch test
(Bajaj and Gupta, 1986). Cavanagh (1973) described a dying back peripheral
neuropathy 1n humans treated for trypanosomlasls with large doses of
nltrofurans.
0057d 6-67 09/09/87
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
Pertinent guidelines and standards, including EPA ambient water and air
quality criteria, drinking water standards, FAO/WHO ADIs, EPA or FDA toler-
ances for raw agricultural commodities or foods, and ACGIH, NIOSH or OSHA
occupational exposure limits could not be located In the available litera-
ture as cited in Appendix A.
7.2. AQUATIC
Guidelines and standards for the protection of aquatic organisms from
the effects of nitrofurans could not be located In the available literature
as cited 1n Appendix A.
0058d . 7-1 06/04/87
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the carclnogenldty of any
of the nltrofurans by Inhalation exposure could not be located 1n the
available literature as cited 1n Appendix A.
8.1.2. Oral. Data regarding the carclnogenldty of orally administered
nltrofurans have been located for furazolldone, fuMum, 5-nitro-2-furan-
carboxaldehyde diacetate, nltrofurantoln, nltrofurazone and nltrovin. The
carclnogenldty data for furazolldone were available only from secondary
sources. U.S. DHEW (1976a,b) reported the Incidences of mammary tumors 1n
female Sprague-Oawley and Carworth Farms rats fed diets containing 1000 ppm
furazolldone. These data, presented in Table 6-2, are sufficient for deri-
vation of carcinogenic potency factors. Exposure was for 45 weeks followed
by a 7- or 8-week observation period. U.S. DHEW (1976a) also reported that
furazolldone was carcinogenic where Sprague-Dawley and Fischer rats and
MBR/ICR mice were administered the chemical in the diet for 18 or 20 months.
Qualitatively, furazolldone Is placed 1n group 82 of EPA classification
(possible human carcinogen). However, since only generalizations regarding
the Incidences of tumors in these studies were reported, they are not useful
for quantitative risk assessment.
Furium has been shown to be carcinogenic in rats, mice, hamsters and
dogs. In two similar studies, furlum administered to Sprague-Dawley rats at
1990 ppm In the diet produced a highly significant incidence of mammary and
salivary tumors (Erturk et al... 1970a) (see Table 6-3) (Cohen et al., 1975)
(see Table 6-4). In both experiments, exposure for 46 weeks was followed by
a 20-week observation period. Additional experiments establish furlum as a
potent leukemogen In mice (Cohen et al., 1970, 1973a,b; Cohen and Bryan,
0059d 8-1 09/10/87
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1978). Dietary levels in these studies ranged from 250-1000 ppm; exposure
was from 13-14 weeks. Hamsters exposed to furlum at 1000 ppm for 48 weeks
followed by a 22-week observation period had a high Incidence of urinary
bladder tumors (Croft and Bryan, 1973). Mammary tumors and gall bladder
tumors developed In 2/2 female dogs treated with furlum at 50 mg/kg/day for
30 months followed by a 5-month observation period (Erturk et al.t 1970b).
In contrast with positive results In rats, mice, hamsters and dogs, negative
results were obtained 1n guinea pigs. No tumors were located In male guinea
pigs fed diets containing 1000 ppm furlum for 50 weeks followed by an
additional 70-week observation period (Croft and Lower, 1981). According to
the EPA classification scheme, furlum 1s placed 1n group 82, possible human
carcinogen.
Morris et al. (1969) Investigated the carclnogenldty of 5-n1tro-2-
furancarboxaldehyde dlacetate 1n two separate experiments with female
Holtzman rats. The chemical was provided 1n the diet at 0 or 2000 ppm for
36 weeks followed by a 17- to 19-week observation period, or for 44.5 weeks
followed by a 15- to 17-week observation period. Tumors, restricted to the
mammary gland, developed only 1n the second experiment but the Incidence was
not significantly greater In treated rats than In controls. According to
the EPA classification, this belongs to group C, probable human carcinogen.
The carclnogenldty studies of nltrofurantoln In animals are Inconclu-
sive. Morris et al. (1969) fed diets containing 0 or 3000 ppm nltrofuran-
toln to female Holtzman rats for 36 weeks followed by a 17- to 19-week
observation period. There were no significant Increases 1n tumor Incidences
In treated rats compared with controls. Negative results were also reported
by Cohen et al. (1973c), who fed a diet containing 1870 ppm nltrofurantoln
for 16 weeks (reduced to 1000 ppm for the next 59 weeks followed by a 5-week
observation period) to female Sprague-Dawley rats. Mammary tumors were the
0059d 8-2 09/10/87
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most common tumors observed but the Incidence was not significantly In-
creased In treated rats. Ito et al. (1983) fed diets containing 0, 750 or
3000 ppm nitrofurantoln to male and female BDF1 mice for 24 months and
observed no Increase 1n the incidence of any tumor type In treated mice. In
males, both the incidence of hepatomas and total tumors was reduced in
treated groups compared with controls. Therefore nitrofurantoln Is placed
in group D (unclassifiable) in EPA classification.
The only experiment that suggested a carcinogenic role for
nitrofurantoln was a 2-year dietary experiment in germ-free Sprague-Oawley
rats (Wang et al., 1984). An increase was noted in the Incidence of mammary
fibroadenomas, but only small numbers of animals were used (see Table 6-9).
The NTP (1987) has sponsored dietary studies of nitrofurantoln with rats and
mice but the results are not yet available.
Nitrofurazone 1s clearly oncogenic 1n female rats. Morris et al. (1969)
fed diets containing nitrofurazone at 1000 ppm to female Sprague-Dawley rats
for 36 weeks followed by a 17- to 19-week observation period, or for 44.5
weeks followed by a 15- to 17-week observation period. A highly significant
9
Increase In mammary tumors was observed (see Table 6-11). Because the
nitrofurazone used by Morris et al. (1969) was contaminated with -3%
5-nitro-2-furaldehyde azine, the experiment was repeated. Erturk et al.
(1970b) fed female Sprague-Dawley rats a diet containing 1000 ppm pure
nitrofurazone for 46 weeks followed by a 20-week observation period. A high
incidence of benign mammary tumors developed in female rats (see Table
6-12). Nitrofurazone could be placed in group C/B2.
U.S. DHEW (1976b) reported the results of dietary studies where female
Sprague-Oawley rats were fed diets containing 0, 500 or 1000 ppm
nitrofurazone, and Carworth Farms rats of both sexes were fed diets
0059d 8-3 09/10/87
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containing 0 or 1000 ppm. In both experiments exposure was for 45 weeks
followed by a 7- or 8-week observation period. A highly significant
Increase 1n the Incidence of mammary tumors developed In female rats of both
strains (see Table 6-13).
Grlswold et al. (1968) treated female Sprague-Dawley rats with nltro-
furazone at total cumulative dosages of 0, 200, 350 or 500 mg/rat divided
Into 10 doses given every third day over a 30-day period. A borderline
response was observed 1n the Incidence of mammary tumors (see Table 6-10).
An NTP (1987) dietary study of nltrofurazone with rats and mice has been
completed but results are not yet available.
The cardnogenlcHy of nltrovln was tested In female Sprague-Dawley rats
fed a diet containing 1000 ppm for 46 weeks followed by a 22-week observa-
tion period (Erturk et al., 1980, 1983). No tumor type occurred with
Increased Incidence In treated compared with control rats. Therefore,
nltrovln can be placed In group D, not classifiable.
8.1.3. Other Routes. Nomura et al. (1975, 1984) administered subcuta-
neous doses of nltrofurantoln or nltrofurazone to pregnant mice on gestation
days 13, 15 and 17. Offspring were foster-nursed by untreated lactatlng
females and maintained until sacrificed at 32 weeks of age. A low but
statistically significant Increase In the Incidence of lung tumors was
observed In the offspring of nltrofurantoln-treated but not nltrofurazone-
treated mice.
8.1.4. Weight of Evidence. Data regarding the carclnogenldty of the
nltrofurans 1n humans were not located; however, a number of animal experi-
ments were located for several of the nltrofurans.
U.S. DHEW (1976a,b) reported that furazolldone was carcinogenic 1n
Sprague-Dawley, Fischer and Carworth Farms rats and Swiss HBR/ICR mice.
0059d 8-4 09/10/87
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These data constitute sufficient evidence of animal carclnogenldty and
furazolldone Is assigned an EPA classification of 82, a probable human
carcinogen (U.S. EPA, 1986b).
Furlum 1s a potent animal carcinogen. It 1s associated with mammary and
salivary tumors In rats (Erturk et a!., 1970a, Cohen et al., 1975), leukemia
In mice (Cohen et al., 1970, 1973a,b; Cohen and Bryan, 1978), urinary
bladder tumors 1n hamsters (Croft and Bryan, 1973) and mammary and gall
bladder tumors In dogs (Erturk et al., 1970b). These data constitute suffi-
cient evidence for the carclnogenldty of fuMum 1n animals and furlum Is
assigned an EPA classification of 82, a probable human carcinogen.
v 4
Animal data for 5-n1tro-2-furancarboxaldehyde dlacetate are limited to
two short-term negative studies with female Sprague-Dawley rats (Morris et
al., 1969). These data are Inadequate for determining the carclnogenldty
of 5-n1tro-2-furancarboxaldehyde dlacetate 1n animals; this compound 1s
classified In EPA Group D, not classifiable as to human carclnogenldty.
The situation regarding the carclnogenldty of nltrofurantoln 1s not
clear. Negative studies Include three dietary rat studies (Morris et al.,
1969; Cohen et al., 1973c) and one mouse study (Ito et al., 1983). An
Increased Incidence of mammary tumors, however, was reported 1n a 2-year
study where female germ-free rats were used (Wang et al., 1984). Only small
numbers of rats were used, however, and the germ-free condition represents
an unnatural animal model. The evidence for animal carclnogenldty
associated with exposure to nltrofurantoln 1s best described as Inadequate
pending the results of the NTP (1987) study. Nltrofurantoln, therefore, 1s
assigned to EPA Group D, not classifiable as to human carclnogenldty.
One borderline response (Gdswold et al., 1968) and several positive
responses (Morris et al., 1969; Erturk et al., 1970c; U.S. DHEW, 1976b)
associate nltrofurazone with the development of mammary tumors In female
0059d 8-5 09/08/87
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Sprague-Dawley and Carworth Farms rats. These data constitute sufficient
evidence for animal cardnogenldty and nltrofurazone 1s assigned an EPA
classification of B2, a probable human carcinogen.
NHrovIn was negative for carclnogenldty 1n female Sprague-Dawley rats
(Erturk et a!., 1980, 1983). Since only one sex, one strain and one species
were examined and since exposure occurred only for 46 weeks, these data are
considered Inadequate for assessing the carclnogenldty of nltrovln In
animals. Therefore, nltrovln 1s assigned to EPA Group D, not classifiable
as to human carclnogenldty.
Carclnogenldty data were not located for the other nltrofurans that are
the subject of this report and they should therefore be placed In EPA Group
D, not classifiable as to human carclnogenldty.
8.1.5. Quantitative Risk Estimates.
8.1.5.1. INHALATION Data regarding the carc1nogen1c1ty of the
nltrofurans by Inhalation exposure were not located. Data were available,
however, for oral exposure to several of the nltrofurans and human carcino-
genic potencies for oral exposure were estimated for furazolldone, fudum
and nltrofurazone (see Section 8.1.5.2.). Although Inhalation data were not
available,.crude estimation of carcinogenic potency by Inhalation exposure
can be made by applying certain assumptions to the estimations of carcino-
genic potency made for oral exposure.
When carcinogenic nltrofurans are administered orally to laboratory
animals, tumors develop at sites removed from the digestive tract (furazoll-
done and nltrofurazone: mammary tumors In female rats; fudum: leukemia In
mice) Indicating that gastrointestinal absorption Is Involved 1n the car-
cinogenic response. Gastrointestinal absorption of furazolldone 1n animals
has been estimated at 80-90% (Tatsuml and Takahashl, 1982; Tennent and Ray,
1971), although there 1s evidence that It Is poorly absorbed 1n humans
0059d 8-6 . 09/08/87
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(IARC, 1983). A minimal estimate of gastrointestinal absorption of furlum
Is -42% {Cohen and Bryan, 1978), and the absorption of nltrofurazone has
been estimated at 88% (Tatsuml et al., 1971).
Absorption data for Inhalation exposure were not located, but ConkHn
(1978) reported that Intratrachael administration of nltrofurantoln to dogs
resulted In plasma and urinary levels virtually Identical to those achieved
with Intravenous treatment. These data suggest that respiratory tract
absorption may proceed more rapidly than gastrointestinal absorption, at
least for nltrofurantoln In dogs.
Data were not sufficient for estimating carcinogenic potencies for
Inhalation exposure to any of the nltrofurans that are the subject of this
report.
8.1.5.2. ORAL ~ Furazolldone has been associated with an Increased
Incidence of mammary tumors 1n rats and lung tumors In mice (U.S. DHEW,
1976a,b). These data were available only from secondary sources. Data
sufficient for estimation of carcinogenic potency were available only for
Sprague-Dawley and Carworth Farms rats exposed to furazoTldone at 1000 ppm
In the diet for 45 weeks followed by a 7- or 8-week observation period (see
Table 6-2). The data used for estimation of oral carcinogenic potencies for
furazolldone are presented 1n Appendix B-l and B-2. A q * of g.lxlO'1
(mg/kg/day)"1 was estimated from data In female Sprague-Dawley rats and
3.8 (mg/kg/day)'1 was estimated from data In female Carworth Farms rats;
both estimates are based on the Induction of total mammary tumors (U.S.
DHEW, 1976a,b). The larger q * 3.8 (mg/kg/day T1, Is recommended to
represent the cardnogenlclty of furazolldone to humans by oral exposure.
The corresponding human dosage associated with an excess cancer risk level
of 10~5 1s 2.6xlO~6 mg/kg/day or l.SxlO"4 mg/day for a 70 kg human.
0059d 8-7 09/08/87
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Assuming drinking water consumption of 2 I/day, a drinking water concen-
tration of 9.1xlO~5 mg/i Is associated with an excess cancer risk of
10~5. Drinking water concentrations of 9.1x1(T6 mg/l and 9.1xlO~7
mg/i correspond to Increased excess cancer risks of 10~* and 10~7t
respectively.
It Is probable that the longer-term rat and mice studies described by
U.S. DHEW (1976a,b) may allow more accurate estimation of the carcinogenic
potency of furazolldone; however, these studies are confidential (U.S. DHEW,
1976b).
Furlum was associated with mammary and salivary tumors In rats (Erturk
et al., 1970a; Cohen et al., 1975), leukemia In mice (Cohen et al., 1970,
1973a,b; Cohen and Bryan, 1978), urinary bladder tumors In hamsters (Croft
and Bryan, 1973) and mammary and gall bladder tumors In dogs (Erturk et al.,
1970b). An Increased Incidence of mammary tumors was observed 1n two
similar rat studies that are summarized 1n Tables 6-3 (Erturk et al., 1970a)
and 6-4 (Cohen et al., 1975). Since body weight data were provided by
Erturk et al. (1970a) but not by Cohen et al. (1975), only data from the
former study (see Table 6-3) were used to estimate carcinogenic . potency
based on the Incidence of mammary tumors In rats. Data used In this
estimation are presented 1n Appendix B-3.
Data Indicated that fuMum Is a leukemogen 1n mice. Cohen et al. (1970)
presented data regarding the Incidence of leukemia In female Swiss mice fed
diets containing 0 or 1000 ppm for 13 weeks with an observation period of 14
weeks; In female Swiss mice fed diets containing 0, 100, 250, 500 or 1000
ppm for 14 weeks followed by a 14-week observation period; and 1n female
Swiss, RF, BALB/c and C3H mice fed diets containing 1000 ppm for 14 weeks
followed by a 14-week observation period (see Table 6-5). The multiple dose
0059d 8-8 09/08/87
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study with female Swiss mice seems the most appropriate of these studies for
estimating carcinogenic potency. In this experiment, a nearly maximal
leukemogenlc response of 7/10 occurred at 100 ppm, the lowest dose tested,
which Indicates the sensitivity of mice to furlum. Data from this
experiment used In estimation of a carcinogenic potency factor are presented
In Appendix B-4. In two subsequent experiments from this laboratory, the
Incidence of leukemia was reported 1n female Swiss mice fed diets containing
0, 500 or 1000 ppm furlum for 14 weeks followed by a 16-week observation
period (Cohen et a!., 1973a) (see Table 6-6) and 1n female Swiss mice fed
diets containing 0, 250, 500 or 1000 ppm furlum for 14 weeks followed by a
16-week observation period (Cohen and Bryan, 1978} (see Table 6-7). These
data are used to estimate carcinogenic potencies as detailed 1n Appendices
B-5 and B-6.
Croft and Bryan (1973) fed diets containing 0 or 1000 ppm furlum to male
hamsters for 48 weeks followed by a control diet for an additional 22
weeks. A variety of tumors derived from transitional cells and squamous
epithelial cells developed 1n the urinary bladder. The details of this
study and the tumor Incidence are presented 1n Table 6-8. These data are
sufficient for estimation of carcinogenic potency, the derivation of which
1s presented In Appendix B-7.
A human q * of 6.7xlO~2 {mg/kg/day)"1 for oral exposure to furlum
was calculated from the rat study by Erturk et al. (1970a) associated with
the development of mammary tumors In rats (Appendix B-3). Human q *s for
oral exposure based on the Induction of leukemia In mice were 50.4 (mg/kg/
day)'1 calculated from the data of Cohen et al. (1970) (Appendix B-4), 22
(mg/kg/day)"1 calculated from the data of Cohen et al. (1973a) (Appendix
B-5) and 16.9 (mg/kg/day)"1 calculated from the data of Cohen and Bryan
0059d 8-9 09/08/87
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(1978) (Appendix B-6). A human q * of 1.6 (mg/kg/day)'1 for oral
exposure was calculated from the data of Croft and Bryan (1973) based on the
Induction of bladder tumors In male hamsters (Appendix B-7). These data
support the marked potency of furlum to Induce leukemia In mice, since the
largest q,*s were associated with this cancer type. Of the three q,*s
associated with leukemogenesls In mice, 50.4 (mg/kg/day)"1, based on the
multiple dose study by Cohen et al. (1970) (Appendix B-4), Is chosen to
represent the carcinogenic potency of oral exposure of humans to furlum. A
dosage of 2.0xlO~7 mg/kg/day or 1.4xlO~5 mg/day for a 70 kg human Is
associated with an excess cancer risk of 10~5. Assuming humans drink
2 i of water/day, this dosage corresponds .to a drinking water concentra-
tion of 7.0xlO~6 mg/s. associated with an excess cancer risk of 10~5.
Water concentrations of 7.0xlO~7 and 7.0xlO~8 mg/i are estimated for
excess cancer risk levels of 10~6 and 10~7, respectively.
Cardnogenldty data regarding 5-n1tro-2-furancarboxaldehyde diacetate
are restricted to two negative female rat studies (Morris et al., 1969). A
carcinogenic potency factor for 5-n1tro-2-furancarboxaldehyde diacetate
cannot be estimated.
The carcinogenic potency of nltrofurantoin Is not clear. Three dietary
experiments in rats (Morris et al., 1969; Cohen et al., 1973c) and one in
mice (Ito et al., 1983) yielded negative results, but an Increased incidence
In mammary fibroadenomas was observed by Wang et al. (1984) In an experiment
with small numbers of germ-free rats (see Table 6-9). The NTP (1987) has
sponsored dietary cancer studies (rats and mice) with nltrofurantoin but the
results are not yet available. Because the weight of evidence for carcino-
genicity of nltrofurantoin is largely negative; because only small numbers
of rats were used in the Wang et al. (1984) experiment; because the
0059d 8-10 09/08/87
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germ-free rat represents an unnatural animal model; and because the results
of a more adequate study (NTP, 1987) are forthcoming, a carcinogenic potency
factor for nltrofurantoln Is not derived at this time.
NHrofurazone has been shown to Induce mammary tumors In treated female
rats. A borderline response was observed by GMswold et al. (1968) 1n a
30-day gavage study using small numbers of rats. This study Is Inadequate
for derivation of a cancer potency factor. Morris et al. (1969) observed a
highly significant Increase 1n the Incidence of mammary tumors 1n female
rats fed nltrofurazone at 1000 ppm of the diet for 36 or 44.5 weeks. The
nltrofurazone used 1n this experiment was contaminated with -3% 5-n1tro-2-
furaldehyde azlne; this study is not chosen, for estimation of carcinogenic
potency. A highly significant Incidence of mammary tumors was also observed
1n female Sprague-Dawley rats In a slightly modified repeat of this study
with pure nltrofurazone (Erturk et al., 1970c). These data (see Table 6-12)
are suitable for estimation of carcinogenic potency and are detailed In
Appendix B-8.
A highly significant Increase 1n the Incidence of mammary tumors was
also observed In female Sprague-Dawley and Carworth Farms rats In dietary
experiments with nltrofurazone (U.S. DHEW, 1976b) (see Table 6-13).
Although these data were only available from a secondary source and the
tumor Incidence In female Sprague-Dawley rats In the high group 1s debated,
both of these studies are used for estimation of carcinogenic potency. The
data used are detailed 1n Appendices B-9 and B-10.
The largest human q * for oral exposure to nltrofurazone, 1.5
(mg/kg/day)"1, Is associated with the Induction of total mammary tumors In
female Sprague-Dawley rats as shown 1n Appendix B-8 (Erturk et al., 1970c).
0059d 8-11 09/08/87
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This q-j* Is chosen to represent the cancer potency of nltrofurazone to
orally exposed humans. A dosage associated with an excess cancer risk of
10~5 Is 6.5xlO~6 mg/kg/day or 4.6xlO~4 mg/day for a 70 kg human.
Assuming humans drink 2 l of water dally, this dosage corresponds to a
drinking water concentration of 2.3xlO~4 mg/j. that Is associated with an
excess cancer risk of 10~5. Drinking water concentrations of 2.3xlO~5
and 2.3xlO~6 mg/i correspond to excess cancer risks of 10~6 and
10"7, respectively.
Data were not sufficient for estimating carcinogenic potencies for oral
exposure to any of the other nltrofurans that are the subject of this report.
ป ซ
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure. Pertinent data regarding the toxIcHy of the
nltrofurans by Inhalation exposure could not be located In the available
literature as cited 1n Appendix A. Inhalation RfDs, therefore, were not
derived for any of the nltrofurans that are the subject of this document.
8.2.2. Oral Exposures.
8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) Minimal
systemic toxldty data were located for the nltrofurans, many of which are
animal carcinogens. Rogers et al. (1956) fed diets containing 0, 330, 1000
or 3000 ppm furazolldone to rats of both sexes for 35 days. A marked
decrease 1n growth rate and adverse effects on spermatogenesls occurred at
>1000 ppm. Adverse effects were not observed at 330 ppm. Rogers et al.
(1956) also treated dogs with oral doses of 7.5, 25 or 50 mg furazolldone/
kg/day for 6 months. Neurologic signs, anorexia and weight loss, accom-
panied by hlstopathologic lesions In the brain and testls occurred at >25
mg/kg/day. Lesions In the testes and brain, not accompanied by clinical
neurologic signs, occurred at 7.5 mg/kg/day. Neurologic signs were also
0059d 8-12 09/08/87
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observed In Nubian goats treated with furazolldone at 40-320 mg/kg/day for
<10 days (A11 et al., 1984). Because furazolldone Is an animal carcinogen
for which data are adequate for estimation of carcinogenic potency, a
subchronlc oral RfD for furazolldone Is not derived.
Minimal, systemic toxlclty data are available from short- and Inter-
mediate-term cancer studies with furlum 1n laboratory animals. No apparent
effects on growth were reported 1n female Sprague-Dawley rats fed diets
containing furlum at 1990 ppm for 46 weeks (Cohen et a!., 1975; Erturk et
al., 1970a). In dogs treated with furlum at 50 mg/kg/day for 30 months, no
effects on growth, hematology or BUN were observed (Erturk et al., 1970b).
Furlum at 1000 ppm In the diet of guinea pigs, for 50 weeks had no effects on
growth (Croft and Lower, 1981). Mice apparently are highly sensitive to
furlum. Progressive weight loss beginning at 10 weeks of exposure occurred
1n mice fed a diet containing 1000 ppm. Exposure of mice to 100 ppm furlum
1n the diet for <13 weeks depressed both cell-mediated and antibody-mediated
Immunity (Headley et al., 1977, 1981). Because furlum 1s a potent carcino-
gen 1n several species of laboratory animals for which data are sufficient
for estimation of carcinogenic potency, an oral subchronlc RfD Is not
calculated.
Little 1s known about the systemic toxldty of 5-nitro-2-furancarbox-
aldehyde dlacetate. Morris et al. (1969) fed diets containing 2000 ppm
5-n1tro-2-furancarboxaldehyde dlacetate to groups of female Holtzman rats
for 36 or 44.5 weeks, and observed that the rats tolerated the compound with
no obvious signs of toxlclty. Although the compound was not carcinogenic,
parameters of systemic toxldty were insufficiently evaluated to permit
derivation of a subchronlc RfD for oral exposure.
0059d 8-13 09/08/87
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The effects of nltrofurantoln on the growth of rats Is not clear.
Morris et al. (1969) fed diets containing nltrofurantoin at 3000 ppm to
female Holtzman rats for 36 or 44.5 weeks, and noted no overt signs of
toxldty. Cohen et al. (1973c), however, reduced the dietary concentration
of nltrofurantoln fed to female Sprague-Dawley rats from 1870 to 1000 ppm
after 16 weeks of feeding because of Impaired growth.
Southern Research Institute (1980) fed diets containing 0, 600, 1300,
2500, 5000 or 10,000 ppm nltrofurantoln to rats and diets containing 0, 300,
600, 1300, 2500 or 5000 ppm nitrofurantoin to mice for 13 weeks. Each group
consisted of 10 males and 10 females. In rats, the dietary level of 2500
ppm was a LOAEL associated with reduced' growth rate and testicular and
ovarian degeneration. The dietary level of 1300 ppm was a NOAEL associated
with very slight reduction in rates of body weight gain. Using average
weekly food consumption and body weight data provided by the investigators,
the dietary level of 1300 ppm corresponds to Intakes of nltrofurantoln of
82.8 mg/kg/day for males and 90.2 mg/kg/day for females. In mice, testicu-
lar degeneration and reduced spermatogenesls were noted at >600 ppm, which
1s considered a LOAEL 1n males. No adverse effects were reported at 300
ppm, a NOAEL 1n male mice in this study. Ovarian degeneration occurred In
females at >2500 ppm, but not at 1300 ppm. Male mice appear to be more
sensitive than females to the effects of nltrofurantoln. Using weekly food
consumption and body weight data provided by the investigators, the 300 ppm
level In males corresponds to a dosage of 69.7 mg/kg/day and the 600 ppm
level In males to 135.4 mg/kg/day.
An RfD for subchronlc oral exposure to nltrofurantoln can be derived
from the study with rats and mice (Southern Research Institute, 1980) .
NOAELs 1n rats are estimated at 82.8 mg/kg/day for males and 90.2 mg/kg/day
0059d 8-14 09/08/87
-------
for females, both calculated for the dietary level of 1300 ppm. Since male
.mice are more sensitive than female mice It 1s appropriate to consider data
for male mice In derivation of the RfD. The NOAEL for male mice was
estimated at 69.7 mg/kg/day (300 ppm) and the LOAEL at 135.4 mg/kg/day (600
ppm). The NOAEL of 90.2 mg/kg/day In female rats Is the highest NOAEL below
the LOAEL of 135.4 mg/kg/day 1n male mice and 1s chosen as the basis for the
RfD. Application of an uncertainty factor of 100, 10 for animal to human
extrapolation and 10 to protect unusually sensitive Individuals, results in
an RfO for subchronic oral exposure to nitrofurantoin of 0.9 mg/kg/day or 63
mg/day for a 70 kg human. Confidence in this RfD is high because the sub-
chronic oral toxidty of nitrofurantoin was -well studied in a comprehensive
experiment in two species and the carcinogenicity, developmental and repro-
ductive toxiclty have been investigated. The subchronic oral RfD is also
well below the therapeutic dosage (50-100 mg, 4 times dally for adults and
5-7 mg/kg/ day for children) (PDR, 1985).
Nltrofurazone appears to be more toxic than nitrofurantoin. Morris et
al. (1969) fed diets containing 1000 ppm nltrofurazone to female Holtzman
rats for 36 or 44.5 weeks and noted Irritability within 2 days of the
beginning of exposure. Irritability and other CNS signs persisted through-
out the exposure period. Dietary administration of nltrofurazone to rats
for 13 weeks was associated with reduced rate of body weight gain in males
at >620 ppm and females at >1250 ppm, elevated relative liver weight at >150
ppm (lowest level tested) and gross and hlstopathologic evidence of atrophy
of skeletal muscle in both sexes at >2500 ppm, osteomalacia in both sexes at
>1250 ppm, testicular degeneration at >310 ppm and uterine hypo- plasla at
>1250 ppm. Nltrofurazone 1s an EPA Group B2 carcinogen and a subchronic RfD
for oral exposure Is not derived.
0059d . 8-15 09/08/87
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PUsek et al. (1975) fed diets containing nltrovln at 10, 20 or 40 ppm
to male rats for 60 days. There were no adverse effects at any dietary
concentration on general condition, body weight or growth, food consumption,
hematology, clinical chemistry or gross appearance at necropsy. It Is not
clear 1f a hlstopathologlc examination was performed. The data provided are
Insufficient for derivation of a subchronlc RfD for oral exposure.
Data were not sufficient for deriving subchronlc RfDs for oral exposure
for any of the other nltrofurans that are the subject of this report.
8.2.2.2. CHRONIC EXPOSURES Minimal chronic toxldty data are
available from the long-term cancer studies performed with furazolldone.
U.S. DHEW (1976a) reported Increased mortality In rats maintained for 2
years on a diet that provided 5 mg furazolidone/kg/day. Increased mortality
was not observed at 1 mg/kg/day, the lowest dose tested. U.S. DHEW (1976a)
also reported Increased mortality rates 1n mice fed a diet containing 150
ppm furazolldone for 18 months, followed by a 10-month observation period.
Furazolldone 1s an EPA Group B2 carcinogen for which an estimation of
carcinogenic potency has been made, and a chronic RfD for oral exposure 1s
not considered.
Chronic exposure to nltrofurantoln appears to depress growth rate and
body weight In rats and mice. Wang et al. (1984) fed a small group of
germ-free rats a diet containing nltrofurantoln at 1880 ppm for 2 years and
observed a slightly reduced growth rate compared with controls. Nltro-
furantoln administered to mice at 3000 ppm In the diet resulted 1n body
weights consistently below those of controls throughout the 24-month study
by Ito et al. (1983). No effects on growth occurred at 750 ppm. The
subchronlc dietary study 1n rats and mice used as the basis for an RfD for
subchronlc oral exposure to nltrofurantoln provides data sufficient for
0059d 8-16 09/08/87
-------
derivation of an RfO for chronic oral exposure. Applying an additional
uncertainty factor of 10 to expand from subchronlc to chronic exposure,
resulting In an overall uncertainty factor of 1000, to the subchronlc NOAEL
of 90.2 mg/kg/day yields an RfD for chronic oral exposure of 0.09 mg/kg/day
or 6 mg/day for a 70 kg human. Confidence In this RfD Is high for the
reasons discussed 1n Section 8.2.2.1. regarding the subchronlc oral RfD. In
addition, the PDR (1985) recommends an adult dosage of 50-100 mg/day for
long-term suppresslve therapy. The RfD for chronic oral exposure Is below
the lower limit of recommended therapeutic dosage.
Data were not sufficient for deriving chronic RfDs for oral exposure to
any of the other nltrofurans that are the subject of this report.
0059d 8-17 09/08/87
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
Table 9-1 contains the relevant systemic toxlclty data from the studies
reviewed In Chapter 6 under consideration for derivation of an .RQ for
furazolldone. The data 1n Table 9-1 Indicate that the most sensitive
endpolnts of furazolldone toxlclty are mortality and hlstopathologlc lesions
of the testls and CNS. CSs (the product of RVe x RV.) for hlstopatho-
loglcal lesions of the testis and CNS 1n dogs and mortality In rats are
calculated and presented In Table 9-2. The CS of 28, corresponding to an RQ
of 100, 1s chosen to represent the systemic toxlclty of furazolldone
(Table 9-3).
Systemic toxlclty data for fuMum were discussed 1n Chapter 6 and are
presented in Table 9-4. Studies reporting cardnogen1c-1ty as the only
effect are not Included In Table 9-4. The two effects attributed to expo-
sure to fuMum are progressive weight loss, at 130 mg/kg/day and depressed
Immune function at 13 mg/kg/day In mice. CSs for these effects are pre-
sented 1n Table 9-5. The magnitude of the CSs reflects the sensitive nature
of the Immune system of mice to the effects of fuMum. The CS of 12.6,
associated with depressed Immune function, Is chosen to represent the
systemic toxlclty of fuMum and Is presented In Table 9-6.
Cancer, subchronlc toxlclty, teratogenldty and reproductive studies
provided systemic toxlclty data for nltrofurantoln. Morris et al. (1969)
fed diets containing nltrofurantoln at 3000 ppm to female Holtzman rats for
36 or 44.5 weeks and noted no overt signs of toxlclty. In a later study In
female Sprague-Dawley rats, however, diet concentration was reduced from
1870 ppm nltrofurantoin to 1000 ppm because of slightly Impaired growth
(Cohen et al., 1973c). The Southern Research Institute (1980) study
0060d 9-1 07/10/87
-------
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TABLE 9-3
Furazolldone
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 63 mg/day
Effect: mortality
Reference: U.S. DREW, 1976a
RVd: 2.8 '
RVe: 10
Composite Score: 28
RQ: 100
*Equ1valent human dose
0060d 9-4 06/05/87
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0060d
9-6
06/05/87
-------
TABLE 9-6
Furlum
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 6.9 mg/day
Effect: depressed Immune function
Reference: Headley et al., 1977, 1981
RVd: 4.2
RVe: 3
Composite Score: 13
RQ: 1000
*Equ1valent human dose
0060d 9-7 06/05/87
-------
Indicated that the gonad is the target organ of nltrofurantoln 1n male and
female rats and mice. Degeneration of the gonad, a more serious effect than
reduced body weight, was the critical effect In this study in both species.
These and other studies for derivation of CSs are presented In Table 9-7.
Teratogenlclty studies that used rats and rabbits, and reproductive effects
studies using rats at dosages of 10, 20 or 30 mg/kg/day (Prytherch et a!.,
1983, 1984; Sutton et a!., 1983) are not Included because effects were not
observed.
The study by Nelson and Bunge (1957) in which testicular effects
occurred in 13/36 human males treated with nitrofurantoin at 10 mg/kg/day
Indicates the sensitivity of the human testis to this drug. In an earlier
study (Nelson and Stelnberger, 1953) rats fed a diet containing 1500 ppm
nitrofurantoin for 30 days exhibited testicular effects. This level,
equivalent to a dosage of 75 mg/kg/day, was the highest associated with
testicular effects without effects on other organs; the lowest level asso-
ciated with testicular effects in this study was not reported. Testlcular
effects 1n rats are associated with therapeutic dosages of 10 mg/kg/day
(Yunda and Kushniruk, 1973, 1974; Kushniruk 1974, 1976). These studies are
not Included 1n Table 9-7 because they were available only as abstracts and
were Insufficient for critical evaluation. Other reproductive studies with
nitrofurantoin by parenteral routes are also not Included in Table 9-7.
Mortality, impaired growth rate and gonadal effects are associated with
oral exposure to nitrofurantoin (see Table 9-7). The 16-week study with
rats fed nitrofurantoin at 1870 ppm in the diet (Cohen et a!., 1973c) is
chosen for derivation of a CS based on reduced growth rate. Although a
chronic rat study is available that might be considered more suitable (Wang
et al., 1984), a slightly lower human equivalent dosage Is calculated for
the subchronic study, which would yield a more conservative result.
0060d 9-8 07/06/87
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Only short-term studies are available for derivation of a CS based on
gonadal effects. The 30-day rat study by Nelson and Stelnberger (1953) will
not be used because It 1s not known how closely the estimated dosage of 75
mg/kg/day approximates the MED for this effect. The 91-day study by
Southern Research Institute (1980) reported testlcular and ovarian effects
1n rats and mice. Testlcular degeneration 1n mice 1s associated with the
lowest equivalent human dose and Is chosen as the basis for a CS based on
gonadal degeneration. The human study by Nelson and Bunge (1957) 1s chosen
as the basis for a CS associated with reduced spermatogenesls. Although the
study was extremely short, the effects In only 13/36 suggests that the
dosage, 10 mg/kg/day, may be near the threshold for these effects. Rat
studies (Yunda and Kushnlruk, 1973, 1974; Kushniruk, 1974, 1976), although
Insufficiently reported for derivation of a CS, provide limited support for
testlcular effects at 10 mg/kg/day. CSs for mortality, Impaired growth rate
and gonadal effects are derived and presented 1n Table 9-8. The highest CS,
22, associated with reduced spermatogenesls In humans Is selected to repre-
sent the systemic toxldty of nltrofurantoln (Table 9-9).
Relevant data for calculation of a CS for nHrofurazone are presented In
Table 9-10. Morris et al. (1969) observed severe signs of CNS Impairment 1n
rats fed a diet containing 1000 ppm nHrofurazone for 36 weeks. In a
reproduction screening test, fetotoxldty was observed 1n mice treated with
nltrofurazone at 100 mg/kg during organogenesls (U.S. EPA, 1983b). Nelson
and Stelnberger (1953) reported 200 ppm as the highest dietary level at
which testlcular effects were observed 1n rats in the absence of effects on
other organs. Physiologic Research Laboratories (1980a) observed elevated
relative liver weights In rats at >150 ppm, the lowest level tested 1n a
13-week dietary study. Mortality, hyperexcltabUHy and convulsions
0060d 9-11 07/06/87
-------
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0060d
9-12
06/05/87
-------
TABLE 9-9
NHrofurantoln
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 70.0
Effect: reduced spermatogenesls
Reference: Nelson and Bunge, 1957
RVd: . 2.7
RVe: 8
Composite Score: 22
RQ: 100
*Equ1valent human dose
0060d 9-13 06/05/87
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occurred 1n mice exposed to >620 ppm for 13 weeks (Physiologic Research
Laboratories, 1980a). Reduced rate of body weight gain was noted In female
mice at >310 ppm. Impaired male fertility 1n mice occurred in a 3-week
gavage study at 2 mg/day (70.2 mg/kg/day) but not at 1.5 mg/day (52.6
mg/kg/day) (Herschberger et a!., 1969). Toxlclty studies not Included in
Table 9-10 include developmental toxicity studies using parentenal adminis-
tration on embryo culture.
CSs for mortality in mice, elevated relative liver weight In rats,
testlcular degeneration in rats and Impaired fertility in male mice are
presented in Table 9-11. The CS for testicular effects in rats was based on
the study by Physiologic Research Laboratories (1980a) rather than the data
by Nelson and Steinberger (1953) because the former study was longer and
more completely reported. CSs range from 16.4-25.6. The CS of 25.6
associated with Impaired male fertility Is chosen to represent the systemic
toxicity of nitrofurazone (Table 9-12).
Data regarding other nltrofurans that are the subject of this report
were insufficient for derivation of RQs based on systemic toxicity.
9.2. BASED ON CARCINOGENICITY
Data were not located regarding the carcinogenicity of the nltrofurans
to humans by oral or inhalation exposure; however, several oral exposure
studies 1n animals were available.
The carcinogenicity data for furazolldone were available only from
secondary sources. U.S. DHEW (1976a,b) reported the incidences of mammary
tumors in female Sprague-Dawley and Carworth Farms rats fed diets containing
1000 ppm furazolldone for 45 weeks and observed for a total of 53 or 52
weeks (see Table 6-2). U.S. DHEW (1976a) also reported that furazolldone
Induced tumors 1n Sprague-Dawley and Fischer rats fed diets containing 1000
0060d 9-16 07/06/87
-------
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0060d
9-17
06/05/87
-------
TABLE 9-12
NHrofurazone
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 36.4 mg/day
Effect: Impaired fertility
Reference: Hershberger et al., 1969
RVd: 3.2
RVe: 8
Composite Score: 26
RQ: 100
*Equ1valent human dose
0060d 9-18 06/05/87
-------
ppm for 18 or 20 months, In Sprague-Dawley rats at 15 mg/kg/day from the
diet for 2 years and In Swiss MBR/ICR mice at 150 or 300 ppm in the diet for
18 months. Because tumor incidence data were not reported, these data are
not useful for quantitative risk assessment. These data constitute suffi-
cient evidence for the carclnogeniclty of furazolldone, which was assigned
an EPA classification of 82.
Carcinogenic potencies for furazolldone were estimated based on the
induction of mammary tumors in female Sprague-Dawley and female Carworth
Farms rats In the 52- to 53-week studies reported by U.S. DHEW (1976a,b)
{Appendices B-l, B-2). The larger human q,*, 3.8 {mg/kg/day)"1, for
oral exposure, was based on the data in Carworth Farms rats. These data are
also appropriate for derivation of a Potency Factor (F) for furazolldone
(Table 9-13). An F factor for furazolldone of 22 (mg/kg/day)"1 places the
chemical in Potency Group 2, which, combined with an EPA classification of
82, results in a Hazard Ranking of MEDIUM, corresponding to an RQ of 10.
Furium is carcinogenic in rats, mice, hamsters and dogs. In two similar
studies in female Sprague-Dawley rats, furlum at 1990 ppm in the diet
Induced a highly significant Incidence of mammary and salivary tumors
(Erturk et al., 1970a) (see Table 6-3) and mammary tumors (Cohen et al.,
1975) (see Table 6-4). Several experiments establish furlum as a potent
leukemogen in mice fed the compound In the diet (Cohen et al., 1970,
1973a,b; Cohen and Bryan, 1978) and as an Inducer of urinary bladder tumors
in guinea pigs exposed through the diet (Croft and Bryan, 1973). Mammary
tumors and tumors of the gall bladder developed In dogs treated orally with
furium (Erturk et al., 1970b). These data constitute sufficient evidence
for the carclnogeniclty of furlum, which was ass'igned an EPA classification
of B2.
0060d 9-19 07/06/87
-------
TABLE 9-13
Derivation of Potency Factor (F) for Furazolldone
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Lifespan of animal:
Target organ:
Tumor type:
Experimental dose/exposure (ppm):
Transformed dose (mg/kg/day):
Tumor incidence:
Unadjusted 1/ED10:
Adjusted 1/ED-|0 (F factor):
U.S. DHEW, 1976a,b
oral
rat
Carworth Farms
Female
' diet
0.350 kg*
45 weeks
52 weeks
104 weeks
mammary gland
total mammary tumors
0 1000
0 43.3
0/15 15/17
0.47 (mg/kg/day)"1
21.9 (mg/kg/day)'1
*Reference body weight for rats (U.S. EPA, 1980)
0060d
9-20
07/06/87
-------
Estimations of q,*s for furlum were based on the Incidence of total
mammary tumors in female Sprague-Dawley rats (Erturk et al., 1970a,
(Appendix B-3), the induction of leukemia in female Swiss mice (Cohen et
al., 1970, Appendix B-4; Cohen et al., 1973a, Appendix B-5; Cohen and Bryan,
1978, Appendix B-6), and the Induction of tumors of the urinary bladder "In
male Syrian golden hamsters (Croft and Bryan, 1973, Appendix B-7). The
largest human q,*, chosen to represent the carcinogenic potency of furlum,
was based on Induction of leukemia In mice In the study by Cohen et al.
(1970) (Appendix B-4). These data are suitable for derivation of an F
factor (Table 9-14). The F factor for furium of 347 (mg/kg/day)""1 places
the chemical in Potency Group 2, which, when combined with an EPA
classification of B2, results in a Hazard Ranking of MEDIUM and corresponds
to an RQ of 10.
Morris et al. (1969) Investigated the cardnogenicity of 5-nitro-2-
furancarboxaldehyde dlacetate in experiments where the material was fed at
2000 ppm 1n the diet to female rats for 36 or 44.5 weeks. Mammary tumors
developed 1n rats after 44.5 weeks, but the Incidence 1n treated rats was no
higher than in controls. These data were judged to be Inadequate evidence
for carcinogenlcity and 5-nitro-2-furancarboxaldehyde dlacetate was placed
1n EPA Group D. Data are insufficient for derivation of a Potency Factor
(F) and no hazard ranking based on cardnogenicity is possible.
NHrofurantoln was negative for cardnogenicity in two dietary studies
In which 3000 ppm was fed to female Holtzman rats for periods of 36 or 44.5
weeks (Morris et al., 1969), and 1n a 75-week feeding period 1n female
Sprague-Oawley rats (Cohen et al., 1973c). Nitrofurantoin was also negative
in a 24-month dietary experiment in male and female mice (Ito et al., 1983).
An Increased incidence of mammary tumors, however, was reported In an
experiment with small numbers of germ-Tree rats fed dietary nitrofurantoln
0060d 9-21 07/06/87
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TABLE 9-14
Derivation of Potency Factor (F) for FuMum
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Hfespan of animal:
Target organ:
Tumor type:
Experimental dose/exposure (ppm):
Transformed dose (mg/kg/day):
Tumor Incidence:
Unadjusted 1/ED10:
Adjusted 1/ED10 (F factor):
Cohen et al., 1970
oral
mice
Swiss
Female
diet
0.03 kg
14 weeks
28 weeks
104 weeks
lymphatic organs
leukemia
0 100 250
0 6.5 16.3
0/15 7/10 8/12
0.51 (mg/kg/day)'1
347 (mg/kg/day)'1
500
32.5
9/13
1000
65.0
8/9
0060d
9-22
07/06/87
-------
for 2 years (Wang et a!., 1984). In view of the other negative rat studies,
the small numbers used by Wang et al. (1984), the unnatural condition of the
germ-free rat and the fact that the results of an NTP dietary study In rats
and mice are pending, the data base was considered to be Inadequate evidence
of cardnogenlclty for animals and nltrofurantoin was classified 1n EPA
Group D. Data are Insufficient for derivation of a Potency Factor (F) and
no hazard ranking based on cardnogenlclty 1s possible.
Nltrofurazone 1s clearly oncogenlc In female rats. A borderline
response 1n mammary tumors was reported by GMswold et al. (1968) who
administered 10 gavage doses to female rats over a 30-day period. A marked
Increase In the Incidence of mammary tumors was noted In female rats fed
nltrofurazone 1n the diet for 36 or 44.5 weeks (Morris et al., 1969) or for
46 weeks (Erturk et al., 1970c). U.S. DHEW (1976b) also reported a highly
significant Increase 1n the Incidence of mammary tumors 1n rats fed nltro-
furazone In the diet for 45 weeks. These data were considered sufficient
evidence for the cardnogenlcHy of nltrofurazone, which was assigned an EPA
classification of B2.
Carcinogenic potencies for nltrofurazone were estimated from the data
from three studies In which the Incidence of mammary tumors 1n female rats
was markedly Increased (Erturk et al., 1970c; U.S. DHEW, 1976b). The
largest human q,*, 1.5 (mg/kg/day)"1, for oral exposure was based on the
Incidence of mammary tumors In female Sprague-Dawley rats reported by Erturk
et al. (1970c) (see Table 6-12, Appendix B-8). These data are also suitable
for derivation of a Potency Factor (F) {Table 9-15). An F factor of 10
(mg/kg/day)"1 places nltrofurazone In Potency Group 2, which, with an EPA
classification of B2, results In a cancer hazard ranking of MEDIUM and a
cancer-based RQ of 10.
0060d 9-23 07/10/87
-------
TABLE 9-15
Derivation of Potency Factor (F) for NHrofurazone
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Llfespan of animal:
Target organ:
Tumor type:
Experimental dose/exposure (ppm):
Transformed dose (nig/kg/day):
Tumor Incidence:
Unadjusted 1/EDig:
Adjusted 1/ED10 (F factor):
Erturk et al., 1970c
oral
rat
Sprague-Dawley
Female
diet
0.350 kg
46 weeks
66 weeks
104 weeks
mammary gland
all tumors
0 1000
0 29.7
2/29 22/29
0.43 (mg/kg/day)"1
9.87 (mg/kg/day)'1
0060d
9-24
07/06/87
-------
In the only cancer experiment with nitrovin, Erturk et al. (1980, 1983)
fed a diet containing 1000 ppm to female Sprague-Dawley rats for 46 weeks
with negative results. The data were judged inadequate to evaluate the
carcinogenicity of nitrovin in antmals and nitrovin was assigned to EPA
Group D. No hazard ranking based on carcinogenicity is possible.
Cancer-based RQs were not derived for the other nitrofurans that are a
subject of this report.
0060d 9-25 06/05/87
-------
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U.S. DHEW (U.S. Department of Health, Education and Welfare). 1976b. Fur-
azolldone (NF-180): Notice of opportunity for hearing on proposal to with-
draw approval of certain new animal drug applications. Federal Register.
41: 19907-19921.
U.S. EPA. 1977. Computer print-out of non-confidential production data
from TSCA Inventory. OPTS, CID, U.S. EPA, Washington, DC.
U.S. EPA. 1980. Guidelines and Methodology for the Preparation of Health
Effect Assessment Chapters of the Ambient Water Quality Criteria Documents.
Federal Register. 45(231): 49347-49357.
U.S. EPA. 1983. Final Report on Screening of Priority Chemicals for
Reproductive Hazards with Cover Letter. FYI-OTS-0483-0240.
U.S. EPA. 1984. Methodology and Guidelines for Reportable Quantity
Determinations Based on Chronic Tox1c1ty Data. Prepared by the Office of
Health and Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1985. Reference Values for Risk Assessment. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington,
DC.
0061d 10-31 07/10/87
-------
U.S. EPA 1986a. Methodology for Evaluating Potential Carclnogenlclty 1n
Support of Reportable Quantity Adjustments Pursuant to CERCLA Section 102.
Prepared by the Office of Health and Environmental Assessment, Carcinogen
Assessment Group, for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1986b. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1987. Graphical Exposure Modeling System (GEMS). Octanol-Water
Partition Coefficient (CLOGP) and/or Fate of Atmospheric Pollutants (FAP)
computer data systems. U.S. EPA, Research Triangle Park, NC.
Veronese, M., M. Salvaterra, D. Barzaghl and I. Setnlkar. 1974. Urinary
excretion In the rat of nlfurplpone (NP) and of nltrofurantoln (NTF) admin-
istered by different routes. Arznelm.-Forsch. 24(1): 39-43.
Wang, C.Y. and L.H. Lee. 1976. Mutagenlc activity of carcinogenic and
noncardnogenlc nltrofurans and of urine of rats fed these compounds.
Chem-B1ol. Interact. 15(1): 69-75.
Wang, C.Y., C.W. Chlu and G.T. Bryan. 1975. Metabolism and disposition of
N-4-(5-n1tro-2-furyl)-(2-l4-C)th1azolyl acetamlde In the rat. Drug Metab.
Olspos. 3(2): 89-95.
Wang, C.Y., W.A. Croft and G.T. Bryan. 1984. Tumor production In germ-free
rats fed 5-n1trofurans. Cancer Lett. 21(3): 303-308.
0061d 10-32 07/10/87
-------
Watarl, N., K. Alzawa and N. Kaneniwa. 1985. Dose- and- time-dependent
kinetics of the renal excretion of nltrofurantoln 1n the rabbit. J.
Pharmacol. Scl. 74(Feb 1985): 165-170.
Waters, M.E. and M.K. Handy. 1969. Effect of nltrofurans and chlortetra-
cycllne on microorganisms associated with shrimp. Appl. Mlcroblol. 17(1):
21-25.
Wentzell, B. and D.R. McCalla. 1980. Formation and excision of nitrofuran-
DNA adducts In Escherlchla coll. Chem-Blol. Interact. 31(2): 133-150.
Wlerzba, K., B. Wankowlcz, A. Rogoyski, et al. 1982. Experimental and
clinical pharmacoklnetlcs of nltrofurantoln In the early period of life.
Paedlatr. Paedol. 17(2): 293-299.
Wlerzba, K., B. Wankowlcs, J Prokopszyk and A. Plekkarczyk. 1984. Studies
of drug pharmacoklnetlcs In the developing organism. Pedlatr. Pol. 59(11):
955-963.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co., Rahway,
NJ. p. 14, 613, 861, 938, 946, 957, 954.
Wise, M.L., C.L. Stlebel and J.M. Grizzle. 1987. Acute toxlclty of rtHro-
furazone to channel catfish. Ictaluru punctatus. and goldfish, Carasslus
auratus. Bull. Environ. Contam. Toxlcol. 38(1): 42-46.
0061d 10-33 07/10/87
-------
Yahagi, T., M. Nagao, K. Hara, T. Matsushlma, T. Sublmura and G.T. Bryan.
1974. Relationships between the carcinogenic and mutagenic or DNA-modlfyIng
effects of nHrofuran derivatives, Including 2-(2-furyl)-3-(5-n1tro-2-
furyl)acrylam1de, a food additive. Cancer Res. 34: 2266-2273.
Yahagi, T., T. Matsushlma, M. Nagao, Y. Selno, T. Suglmura and G.T. Bryan.
1976. MutagenlcHles of nHrofuran derivatives on a bacterial tester strain
with an R factor plasmld. Mutat Res. 40: 9-14.
Yeung, T.C., G. Sudlow, R.L. Koch and P. Goldman. 1983. Reduction of
nltroheterocycllc compounds by mammalian, tissues In vivo. Blochem.
Pharmacol. 32(14): 2249-2253.
Yunda, I.F. and Y.I. Kushnlruk. 1973. Influence of antibacterial prepara-
tions on the endocrine function of-the testicle. KUn. Kh1r. 10: 37-40.
(CA 80:116249u)
Yunda, I.F. and Y.I. Kushnlruk. 1974. Effect of nltrofuran preparations on
spermatogenesls. Byull. Eksp. Blol. Med. 77(5): 68-70. (CA 81:99521c)
Zamplerl, A. and J. Greenberg. 1964. NUrofurazone as a mutagen 1n Esche-
rlchla coll. Blochem. Blophys. Res. Commun. 14: 172-176.
Zlmmerlng, S., l.M. Mason, R. Valencia and R.C. Woodruff. 1985. Chemical
mutagenesls testing In Drosophlla. II. Results of 20 coded compounds tested
for the National Toxicology Program. Environ. Mutagen. 7(1): 87-100.
0061d 10-34 07/10/87
-------
APPENDIX A
LITERATURE SEARCHED
This HEED Is based on data Identified by computerized literature
searches of the following:
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXBACK 76
TOXBACK 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
These searches were conducted 1n February, 1987. In addition, hand searches
were made of Chemical Abstracts (Collective Indices 5-9), and the following
secondary sources should be reviewed:
ซ
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1986-1987. TLVs: Threshold Limit Values for Chemical Substances In
the Work Environment adopted by ACGIH with Intended Changes for
1986-1987. Cincinnati, OH. Ill p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John WHey and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2B. John WHey and
Sons, NY. p. 2879-3816.
Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
A-l
-------
Grayson, M. and D. Eckroth, Ed. 1978-1984. Kirk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, HA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. WHO, IARC, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
SRI International, Menlo Park, CA. EPA 600/6-84-010. NTIS
PB84-243906.
NTP (National Toxicology Program). 1986. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1986. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report In the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call In Programs.
Office of Pesticide Programs, Washington, DC.
U.S. EPA. 1985. CSB Existing Chemical Assessment Tracking System.
Name and CAS Number Ordered Indexes. Office of Toxic Substances,
Washington, DC.
USITC (U.S. International Trade Commission). 1985. Synthetic
Organic Chemicals. U.S. Production and Sales, 1984, USITC Publ.
1422, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
A-2
-------
In addition, approximately 30 compendia of aquatic toxldty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxldty
of Chemicals to Fish and Aquatic Invertebrates. Summaries of
Toxlclty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
A-3
-------
APPENDIX 81
Cancer Data Sheet for Derivation of q-|* for Furazolldone
1n Sprague-Dawley Rats
Compound: furazolldone
Reference: U.S. DHEW, 1976a,b
Specles/strain/sex: rat/Sprague-Dawley/female
Body weight = 0.350 kga
Length of exposure (le) = 45 weeks
Length of experiment (Le) = 53 weeks
Llfespan of animal (L) = 104 weeks
Tumor site and type: total mammary tumors
Route/vehicle: oral/diet
Experimental Doses Transformed Dose " Incidence
Exposure (ppm) (mg/kg/day) No. Responding/No. Tested
0 0 0/33
1000 . 42.5b 14/32
Unadjusted q-|* = 2.05xlO"2 (mg/kg/day)"
Human q-|* = 9.1-xlO"1 (mg/kg/day)"ld
Reference body weight for rats (U.S. EPA, 1980)
Estimated by assuming a food factor for rats of 0.05 (U.S. EPA, 1980) and
multiplying the dietary concentration In ppm by 45/53 to expand to contin-
uous exposure throughout the experimental period.
cCompuU'd using Global 82, the multistage model of Howe and Crump (1982).
^Calculated by multiplying the unadjusted q-j* by the cube root of the
ratio of reference human to animal body weight (70 kg/0.350 kg)1/3 and a
factor (104 weeks/53 weeks)3 to correct for the experimental duration
which was less than the natural Hfespan of the rat.
B-l
-------
APPENDIX B2
Cancer Data Sheet for Derivation of q-j* for Furazolldone
In Carworth Farm Rats
Compound: furazolldone
Reference: U.S. DHEW, 1976a,b
Specles/straln/sex: rat/Carworth Farms/F
Body weight = 0.350 kga
Length of exposure (le) = 45 weeks
Length of experiment (Le) = 52 weeks
Llfespan of animal (L) = 104 weeks
Tumor site and type: total mammary tumors
Route/vehicle: oral/diet
Experimental Doses Transformed Dose Incidence
Exposure (ppm) (mg/kg/day) No. Responding/No. Tested
0 0 0/15
1000 43.3b 15/17
Unadjusted q-|* = 8.2xlO~* (mg/kg/day)~lC
Human q-|* = 3.8 (mg/kg/day)"ld
Reference body weight for rats (U.S. EPA, 1980)
bEst1mated by assuming a food factor for rats of 0.05 (U.S. EPA, 1980) and
multiplying the dietary concentration In ppm by 45/52 to expand to contin-
uous exposure throughout the experimental period.
cComputed using Global 82, the multistage model of Howe and Crump (1982).
Calculated by multiplying the unadjusted q-|* by the cube root of the
ratio of reference human to animal body weight (70 kg/0.350 kg)1/3 and by
a factor (104 weeks/52 weeks)3 to correct for the experimental duration
which was less than the natural Hfespan of the rat.
B-2
-------
Cancer Data Sheet for Derivation of q-|* for Furlum
1n Sprague-Dawley Rats
Compound: furl urn
Reference: Erturk et al., 1970a
Spec1es/strain/sex: rat/Sprague-Dawley/F
Body weight = 0.225 kga
Length of exposure (le) = 46 weeks
Length of experiment (Le) = 66 weeks
Llfespan of animal (L) = 104 weeks
Tumor site and type: total mammary tumors
Route/vehicle: oral/diet
Experimental Doses Transformed Dose Incidence
Exposure (ppm) (mg/kg/day) No. Responding/No. Tested
0 0 0/28
1990 82.3b 6/56
Unadjusted q-|* = 2.5xlO"3 (mg/kg/day)"lC
Human q-|* = 6.7xlO~2 (mg/kg/day)~ld
Estimated from growth curve
blnvest1gators reported cumulative dose of 8.55 g/rat.
cComputed using Global 82, the multistage model of Howe and Crump (1982).
^Calculated by multiplying the unadjusted q-j* by the cube root of the
ratio of reference human to animal body weight (70 kg/0.225 kg)^/3 an(j by
a factor (104 weeks/66 weeks)3 to correct for the experimental duration
which was less than the natural Ufespan of the rat.
B-3
-------
APPENDIX B4
Cancer Data Sheet for Derivation of q-|* for Furlum
in Swiss Mice (1)
Compound: furl urn
Reference: Cohen et al., 1970
Specles/straln/sex: mlce/Swiss/F
Body weight = 0.030 kga
Length of exposure (le) = 14 weeks
Length of experiment (Le) = 28 weeks
Llfespan of animal (L) = 104 weeks
Tumor site and type: leukemia
Route/vehicle: oral/diet
Experimental Doses Transformed Dose Incidence
Exposure (ppm) (mg/kg/day) No. Responding/No. Tested
0
100
250
500
1000
Unadjusted q-j* =
Human q-|* = 50.4
0
6.5
16.3
32.5
65.0
7.4xlO~2 (mg/kg/day)~lC
(mg/kg/day)~ld
0/15
7/10
8/12
9/13
8/9
Reference body weight for mice (U.S. EPA, 1980)
bEstimated by assuming a food factor for mice of 0.13 (U.S. EPA, 1980) and
applying a factor of 14/28 to expand to continuous exposure throughout the
experimental period.
cComputed using Global 82, the multistage model of Howe and Crump (1982).
^Calculated by multiplying the unadjusted q-j* by the cube root of the
ratio of reference human to animal body weight (70 kg/0.030 kg)l/3 and by
a factor (104 weeks/28 weeks)3 to correct for the experimental duration
which was less than the natural Hfespan of the mouse.
B-4
-------
APPENDIX B5
Cancer Data Sheet for Derivation of q-j* for FuMum
1n Swiss Mice (2)
Compound: furl urn
Reference: Cohen et al., 1973a
Specles/straln/sex: m1ce/Sw1ss/F
Body weight = 0.030 kga
Length of exposure (le) = 14 weeks
Length of experiment (Le) = 30 weeks
Llfespan of animal (L) = 104 weeks
Tumor site and type: leukemia
Route/vehicle: oral/diet
Experimental Doses Transformed Dose
Exposure (ppm) (mg/kg/day)
0
500
1000
Unadjusted q-|* =
Human q-|* = 22.0
0
46. 0B
93. 7C
4.0xlO~2 (mg/kg/dayrid
(mg/kg/day)"^
Incidence
No. Responding/No. Tested
1/28
18/25
26/27
Reference body weight for mice (U.S. EPA, 1980)
blnvest1gators estimated a cumulative dosage of 0.29 g/mouse.
Clnvest1gators estimated a cumulative dosage Of 0.59 g/rnouse.
dComputed using Global 82, the multistage model of Howe and Crump (1982).
"^Calculated by multiplying the unadjusted q-j* by the cube root of the
ratio of reference human to animal body weight (70 kg/0.030 kg)1/3 and by
a factor (104 weeks/30 weeks)3 to correct for the experimental duration
which was less than the natural Ufespan of the mouse.
B-5
-------
APPENDIX B6
Cancer Data Sheet for Derivation of q-j* for Furium
in Swiss Mice (3)
Compound: furium
Reference: Cohen and Bryan, 1978
Species/strain/sex: mice/Sw1ss/F
Body weight = 0.030 kga
Length of exposure (le) = 14 weeks
Length of experiment (Le) = 30 weeks
Lifespan of animal (L) = 104 weeks
Tumor site and type: leukemia
Route/vehicle: oral/diet
Experimental Doses
Exposure (ppm)
Transformed Dose
(mg/kg/day)
Unadjusted q^ = 3.1xlO~2 (mg/kg/day)'
Human qi* = 16.9 (mg/kg/day)~lf
Incidence
No. Responding/No. Tested
0
250
500
1000
0
23. 8b
54. Oc
109. 5d
0/27
8/22
17/22
23/25
Reference body weight for mice (U.S. EPA, 1980)
DInvestigators estimated a cumulative dosage of 0.15 g/mouse.
clnvestigators estimated a cumulative dosage Of 0.34 g/mouse.
Investigators estimated a cumulative dosage of 0.69 g/mouse.
Computed using Global 82, the multistage model of Howe and Crump (1982).
^Calculated by multiplying the unadjusted q-j* by the cube root of the
ratio of reference human to animal body weight (70 kg/0.030 kg)1/3 and by
a factor (104 weeks/30 weeks)3 to correct for the experimental duration
which was less than the natural Hfespan of the mouse.
B-6
-------
APPENDIX 87
Cancer Data Sheet for Derivation of q-j* for Furlum
1n Syrian Golden Hamsters
Compound: furl urn
Reference: Croft and Bryan, 1973
Specles/straln/sex: hamster/Syrian golden/M
Body weight = 0.175 kg (controls)3
0.140 kg (treated)3
Length of exposure (le) = 48 weeks
Length of experiment (Le) = 70 weeks
Llfespan of animal (L) = 125 weeksb
Tumor site and type: urinary bladder, all tumors
Route/vehicle: oral/diet
Experimental Doses Transformed Dose Incidence
Exposure (ppm) (mg/kg/day) No. Responding/No. Tested
0
1000
0
46. 5C
0/24
16/24
Unadjusted q-|* = 3.6xlO~2 (mg/kg/day)~ld
Human q-|* = 1.6 (mg/kg/day) ie
aEst1mated from graphic data provided by Investigators.
bReference llfespan for hamsters (U.S. EPA, 1985).
Clnvest1gators estimated cumulative dosage at 12.6 mmol (3191 mg)/hamster.
dComputed using Global 82, the multistage model of Howe and Crump (1982).
^Calculated by multiplying the unadjusted q-|* by the cube root of the
ratio of reference human to animal body weight (70 kg/0.140 kg)1/3 and by
a factor (125 weeks/70 weeks)3 to correct for the experimental duration
which was less than the natural llfespan of the hamster.
B-7
-------
APPENDIX B8
Cancer Data Sheet for Derivation of q-j* of NHrofurazone
in Sprague-Dawley Rats (1)
Compound: nltrofurazone
Reference: Erturk et al., 1970c
Species/strain/sex: rat/Sprague-Daw!ey/F
Body weight = 0.350 kga
Length of exposure (1e) = 46 weeks
Length of experiment (Le) = 66 weeks
Llfespan of animal (L) = 104 weeks
Tumor site and type: total mammary tumors
Route/vehicle: oral/diet
Experimental Doses
Exposure (ppm)
Transformed Dose
(mg/kg/day)
Incidence
No. Responding/No. Tested
0
1000
0
29.7b
Unadjusted q-|* = 6.7xlO~2 (mg/kg/day)~
Human q-|* = 1.5 (mg/kg/day)~ld
1C
2/29
22/29
Reference body weight for rats (U.S. EPA, 1980).
blnvest1gators estimated cumulative dosage of 4800 mg/rat.
cComputed using Global 82, the multistage model of Howe and Crump (1982).
^Calculated by multiplying the unadjusted q-|* by the cube root of the
ratio of reference human to animal body weight (70 kg/0.350 kg)1/3 and by
a factor (104 weeks/66 weeks)3 to correct for the experimental duration
which was less than the natural Hfespan of the rat.
B-8
-------
APPENDIX B9
Cancer Data Sheet for Derivation of q-j* of NHrofurazone
In Sprague-Dawley Rats (2)
Compound: nltrofurazone
Reference: U.S. DHEW, 1976b
Spec1es/strain/sex: rat/Sprague-Daw!ey/F
Body weight = 0.350 kga
Length of exposure (le) = 45 weeks
Length of experiment (Le) = 53 weeks
Llfespan of animal (L) = 104 weeks
Tumor site and type: total mammary tumors
Route/vehicle: oral/diet
Experimental Doses
Exposure (ppm)
Transformed Dose
(mg/kg/day)
Incidence
No. Responding/No. Tested
0
500
1000
0
23.8b
46.7C
Unadjusted q-j* = 2xlO~2 (mg/kg/day)"ld
Human q-j* = S.SxlO'1 (mg/kg/day)~*e
0/33
12/33
13/30
Reference body weight for rats (U.S. EPA, 1980).
Investigators estimated dosage rate at 28 mg/kg/day during exposure
period.
Clnvest1gators estimated dosage rate at 55 mg/kg/day drulng exposure
period.
Computed using Global 82, the multistage model of Howe and Crump (1982).
Calculated by multiplying the unadjusted q-|* by the cube root of the
ratio of reference human to animal body weight (70 kg/0.350 kg)1/3 and by
a factor (104 weeks/53 weeks)3 to correct for the experimental duration
which was less than the natural Hfespan of the rat.
B-9
-------
APPENDIX BIO
Cancer Data Sheet for Derivation of q-|* for NHrofurazone
1n Carworth Farms Rats
Compound: nltrofurazone
Reference: U.S. DHEW, 1976b
Specles/straln/sex: rat/Carworth Farms/f
Body weight = 0.350 kga
Length of exposure (le) = 45 weeks
Length of experiment (Le) = 52 weeks
Llfespan of animal (L) = 104 weeks
Tumor site and type: total mammary tumors
Route/vehicle: oral/diet
Experimental Doses
Exposure (ppm)
Transformed Dose
(mg/kg/day)
Incidence
No. Responding/No. Tested
0
1000
0
.43.3b
Unadjusted qi* = 3.2xlO~2 (mg/kg/day)~lC
Human q-|* = 1.5 (mg/kg/day)~ld
0/15
11/19
Reference body weight for rate (U.S. EPA, 1980).
^Investigators estimated dosage rate at 50 mg/kg/day during exposure
period.
cComputed using Global 82, the multistage model of Howe and Crump (1982).
^Calculated by multiplying the unadjusted q-|* by the cube root of the
ratio of reference human to animal body weight (70 kg/0.350 kg)l/3 and by
a factor (104 weeks/52 weeks)3 to correct for the experimental duration
which was less than the natural Hfespan of the rat.
B-10
-------
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