RONIDAZOLE
1. EXPLANATION
Ronidazole (1-methyl-5-nitroimadozole-2-methanol carbamate) is a
5-nitroimadazole with antiparasitic activity useful in the treatment
of enterohepatitis in turkeys and dysentery in swine. The normal
level of inclusion of ronidazole in a feed is between 60 and 120 ppm.
Ronidazole has not been previously evaluated by the Joint FAO/WHO
Expert Committee on Food Additives.
2. BIOLOGICAL DATA
2.1 Biochemical aspects
2.1.1 Absorption, distribution and excretion
Absorption: A number of studies using 14C-ronidazole in
several animal species revealed that the drug is readily absorbed from
the gastrointestinal tract (Rosenblum et al., 1972; Wolf et al.,
1983). Plasma concentrations of 0.09 and 0.5 µg/ml were attained in
rats 24 hours following oral administration of 2 and 10 mg/kg bw of
14C-ronidazole respectively (Wolf et al., 1983).
Distribution: Data obtained from studies with 14C-ronidazole
indicate that the drug is widely distributed in the body of animals
(Rosenblum et al. , 1972; Wolf et al., 1983). Ronidazole-related
radioactivity was shown to be present in brain, fat, heart, kidney,
liver, lung, muscle, pancreas, skin and spleen.
Excretion: Ronidazole is excreted mainly in the urine and feces
of animals. Up to 3% of the administered dose is exhaled as carbon
dioxide. Animals receiving a single oral dose of ronidazole have been
shown to excrete 30-36% of the dose in urine and 16-40% in feces
during a 24-hour period (Rosenblum et al., 1972); Wolf et al.,
1984). Subsequent excretion is slow and incomplete. In rats combined
urinary and fecal excretion have been shown to decrease from 36% and
40% in the first day and to 2% and 6% in the second day, respectively
(Wolf et al., 1984).
2.1.2 Biotransformation
The biotransformation of ronidazole to protein-bound metabolites
was examined in rat liver by West et al., (1982). The authors
demonstrated that rat liver microsomal fraction catalyzes both NADH
and NADPH-dependent covalent binding of ronidazole metabolites to
protein under either aerobic or anaerobic conditions. NADPH was more
efficient than NADH and the binding was greater under anaerobic
conditions, suggesting that the metabolism of ronidazole to
protein-bound metabolites occurs via a reductive pathway.
Purified rat liver microsomal NADPH-cytochrome P-450 reductase
was able to catalyze the activation of ronidazole to metabolites which
bind covalently to protein. Like the reaction catalyzed by rat liver
microsomes, protein alkylation by the purified reductase required
reducing equivalents, was sensitive to oxygen, was inhibited by
sulfhydryl-containing compounds and was stimulated several fold by
either flavin mononucleutide or methylviologen. It was also
demonstrated that both the phenobarbital and
3-methylcholanthrene-inducible forms of cytochrome P-450 purified from
rat liver microsomes are not involved in bound metabolite formation,
suggesting that other cytochrome P-450 isozymes present in rat liver
microsomes may be responsible for ronidazole activation (West et al.,
1982).
Evidence that persistent tissue residues of ronidazole could
result from metabolic degradation of the imidazole nucleus to one or
two carbon fragments which could form endogenous substances capable of
entering cellular macromolecules via normal protein synthesis
reactions has been obtained in rats dosed with ronidazole labelled
with 14C at different positions (Wolf et al., 1984).
2.2 Toxicological studies
2.2.1 Acute Toxicity
Species Sex Route LD50 Reference
(mg/kg bw)
Mouse F Oral 2330, 2440 Peck, 1974
F i.p. 1250 Lankas et al.,
1988
F s.c. 1730 Lankas et al.,
1988
Rat M Oral 2850 Peck, 1974
F Oral 3140 Lankas et al.,
1988
M i.p. 1140 Lankas et al.,
1988
F i.p. 969 Lankas et al.,
1988
M s.c. 3080 Lankas et al.,
1988
F s.c. 3350 Lankas et al.,
1988
Rabbit M&F Oral 1250 Peck, 1974
2.2.2 Short-term studies
2.2.2.1 Rats
Groups of 15 FDRL strain albino rats/sex/dose were administered
0,50, 100 or 200 mg/kg bw/day ronidazole orally by gavage five days a
week for 13 weeks. Excessive salivation was noted in all treated
animals and the time of onset of salivation was dose related, the
earliest appearance being the third week at the 200 mg/kg bw/day
dosage level. Excessive micturition was noted also in several animals
of the middle and high dosage groups. A decrease of body weight gain
was observed in rats of the middle and high dosage levels. There were
no ophthalmological or hematological changes that could be
attributable to treatment.
Necropsy revealed that the testes of all rats from the high
dosage group and 11 rats from the middle dosage group were reduced to
about one-half normal size. Microscopic examinations of the testes
showed moderate to marked tubular atrophy among the high dosage rats
and very slight to marked tubular atrophy among the middle dosage
rats. No spermatoza or normal spermatids were present in the high
dosage rats. There was no difference in testicular size between the
rats from the low dosage and the control groups. The average weight of
the liver of the male rats in the high dosage group was increased as
was that of the spleen. Very slight hepatic cellular enlargement was
noted in the rats of the high dosage group. The ceca of treated rats
of all dosage groups were increased in size, but there were no
significant microscopical changes (Lankas et al., 1988).
2.2.2.2 Dogs
Groups of 2 male and 2 female purebred beagle dogs were given
ronidazole orally at dosage levels of 25, 50, 100, and 200 mg/kg
bw/day, five days a week for 17 weeks. A similar number of dogs were
used as a control group. The dogs in the control and 25 mg/kg bw/day
groups remained in good health throughout the study. After one week,
all 4 dogs from the 200 mg/kg bw/day group were sacrificed because of
poor physical condition. These dogs had tonic convulsions and
exhibited opisthotonus, fine tremors, ataxia, hindquarter stiffness,
dry mouth and gums, slight tachycardia, and slow and shallow
respiration. After two weeks, the dogs from the 100 mg/kg bw/day group
showed similar signs and were sacrificed because of poor physical
condition. Three of the 4 dogs from the 50 mg/kg bw/day group were
also sacrificed at 5 and 8 weeks for the same reason.
Two of the 4 dogs from the 100 mg/kg bw/day group had a widening
of the Q-T interval of the ECG tracing after one week of treatment and
the only dog from the 200 mg/kg bw/day group for which an ECG was
taken showed a similar pattern. The dogs from the 100 and 200 mg/kg
bw/day groups showed hemoconcentration. Slight increases of serum
glucose and serum glutamic oxalacetic transaminase were noted in some
dogs from the 50, 100, and 200 mg/kg bw/day groups. Two dogs from the
200 mg/kg bw/day group had moderate increases of blood urea and
alkaline phosphatase. All dogs that received 200 mg/kg bw/day of
ronidazole had albuminurea and erythrocytes in the urine.
Testicular hypoplasia was a common finding in dogs from 50, 100,
and 200 mg/kg bw/day groups. In addition, epicardial, myocardial, and
valvular hemorrhages, increased liver and kidney weights, lymphoid
atrophy, lipid infiltration of the liver and kidney, and elevated
adrenal weights were noted among the dogs from the 200 mg/kg bw/day
dose level (Lankas et al., 1988).
Groups of 5 young adult dogs/sex/dose were administered 0, 10,
20, or 40 mg/kg bw/day ronidazole orally in gelatin capsules for two
years. After 34 days of treatment, the high dosage level was reduced
to 30 mg/kg bw/day because of intolerance. At the completion of one
year of the study, 2 dogs/sex/group were sacrificed for gross and
microscopic examinations. The remaining dogs were sacrificed after two
years of treatment.
The dogs from the 10 mg/kg bw/day group showed occasional fine
tremors and slight dehydration. The dogs from the 20 mg/kg bw/day
group developed a nervous behaviour and became hyperreactive. Three of
the dogs at this dosage level failed to survive the duration of the
study. The dogs from the 30 mg/kg bw/day group exhibited the same
signs with more intensity and longer duration. In addition, the dogs
showed anorexia, weight loss, ataxia, and clonic and tonic
convulsions. At the end of one year, 7 of 10 dogs in the high dosage
group had either died or been sacrificed in a moribund condition.
Hematological changes including leucocytopenia, elevations in
erythrocyte sedimentation rates, and reductions in hemoglobin and
hematocrit values were observed in dogs from the 20 and 30 mg/kg
bw/day groups.
Gross pathological lesions involving the ventral internal capsule
at the level of the optic chiasma and the globus pallidus were seen in
the brain of 2 male dogs from the 30 mg/kg bw/day group. Slight
hydrocephalus, subdural hemorrhage and pale yellowish coloration of
the brain were noted among the dogs from the 20 mg/kg bw/day group.
Histopathological changes involving focal hemorrhage of the
cerebellum, leukomalacia, vascularization with endothelial
proliferation, neurophagia, and phagocytosis were seen in brain tissue
of dogs from the 20 and 30 mg/kg bw/day groups.
Hemorrhages in various areas of the heart occurred among dogs
from the 20 and 30 mg/kg bw/day groups. Absolute testes weights of
ronidazole-treated dogs at all dosage levels were decreased when
compared with those of controls. Microsocopic examinations of
testicular tissues revealed aspermatogenesis and oligospermia. These
testicular lesions were considered by the authors to be treatment
related (Wazeter et al., 1969c; Lankas et al., 1988).
2.2.3 Long-term/carcinogenicity studies
2.2.3.1 Mice
Three groups of 60 male and 60 female Alderly Park strain mice
were maintained on diets containing 5, 10, or 20 mg/kg bw/day
ronidazole for 81 weeks. Two groups of 60 male and 60 female mice of
the same strain were fed unmedicated diet and served as controls. Body
weight and food consumption were measured weekly for all animals. At
the end of the study, animals were necropsied and subjected to a
complete gross examination. Microscopic examination was conducted on
the tissues and gross lesions from all animals.
Data submitted in summary form suggested that during the course
of study there were no significant effects on body weight gain or food
consumption in any of the treated groups. No treatment-related effects
on the survival and physical condition of animals were seen in any
group throughout the study.
At necropsy there were no gross lesions attributed to treatment
in any group. However, a dose-dependent increase in combined benign
and malignant pulmonary tumors was observed in both sexes in the mid
and high dosage groups as summarized in Table 1 (Lankas et al.,
1988).
Table 1: Incidence of pulmonary neoplasms in control and treated male
and female mice in 81-week feeding study with ronidazole
Males
Group (N=60) Adenoma Carcinoma Total
Control 1 4 3 7
Control 2 3 1 4
5 mg/kg bw/day 8 2 10
10 mg/kg bw/day 9 3 12
20 mg/kg bw/day 191 81 271
Females
Adenoma Cardinoma Total
Group (N=60)
Control 1 1 0 1
Control 2 5 1 6
5 mg/kg bw/day 3 1 4
10 mg/kg bw/day 8 2 10
20 mg/kg bw/day 141 61 201
1. P<0.05
2.2.3.2 Rats
In a 95 week study, ronidazole was administered in the feed at 0,
10, 20, or 40 mg/kg bw/day to groups of 42 Manor Farm Albino rats of
each sex. An increase in benign mammary tumors was seen in males in
the 40 mg/kg bw/day group and in females in all ronidazole treated
groups after 52 weeks. In addition, 5/41 malignant tumors occurred in
the high dose females compared to 0/39 in the controls (Table 2). The
biological significance of the malignant tumors was not clear. There
was no dose-related effect, as 2 malignant tumors also occurred in the
low dose group but none were observed in the mid-dose group. No
information on the historical incidence of mammary tumors in this
strain of rats was submitted for evaluation.
Table 2: Incidence of mammary neoplasms in control and treated male
and female rats in 95-week feeding study with ronidazole
Males
Group (N=42) Adenoma/Fibroma Adenocarcinoma Total
Control 0/341 0/341 0/341
10 mg/kg bw/day 0/40 0/40 0/40
20 mg/kg bw/day 0/40 0/40 0/40
40 mg/kg bw/day 5/32 1/32 6/32
Females
Group (N=42) Adenoma/Fibroma Adenocarcinoma Total2
Control 7/391 0/391 7/391
10 mg/kg bw/day 13/41 2/41 14/41
20 mg/kg bw/day 21/41 0/41 21/41
40 mg/kg bw/day 19/41 5/41 20/4l
1. Denominator is number of rats surviving after 52 weeks. No
tumors were seen in rats dying prior to 52 weeks.
2. Some rats had both benign and malignant tumors, hence this
column is not a sum of the first two.
During the first 52 weeks of the study no ronidazole-related
pharmacodynamic or toxic signs were observed at any dosage level.
During the later part of the study, rats from the 40 mg/kg bw/day
groups did not gain weight as well as those from the control groups.
There were no meaningful alterations in group mean food consumption,
hematology, clinical biochemistry and urinalysis at any dosage level
in either sex of rats. Testicular atrophy was observed in rats from
the high dosage group and was considered by the authors to be a
ronidazole-related effect (Wazeter et al., 1969a).
Ronidazole was administered in the diet for at least 104 weeks to
three groups of Charles River CD rats with each group consisting of 60
males and 60 females. The dietary concentration of ronidazole was
adjusted to achieve dosage levels of approximately 5, 10, and 20 mg/kg
bw/day. Satellite groups of 15 animals/sex/group were also treated
with the drug at these same dosage levels and were used for blood
sampling and urinalysis in weeks 6, 13, 25, 52 and 78. Two groups of
60 animals/sex/group were fed unmedicated diet and served as controls.
Ronidazole treatment continued for a minimum of 104 weeks with
necropsies completed by week 108. Microscopic examination was
conducted on tissues from all main groups.
Data submitted in summary form suggested that there were no
treatment-related physical signs during the study. A significant
decrease in survival was noted in the 20 mg/kg bw/day groups during
the last few months of the study. Survival in all other treated groups
was comparable to controls. Body weight gain in the 10 and 20 mg/kg
bw/day groups of both sexes decreased slightly compared to controls
during the second year of the study.
The only non-neoplastic lesion due to ronidazole treatment was an
increased incidence of testicular atrophy at the 20 mg/kg bw/day
dosage level. The only significant neoplastic effect was an increased
incidence of benign fibro-epithelial mammary tumors in the 20 mg/kg
bw/day males and in females at the 10 and 20 mg/kg bw/day levels. The
incidence of these tumors is summarized in Table 3 (Lankas et al.,
1988).
Table 3: Incidence of mammary neoplasms in control and treated
male and female rats in 108-week feeding study with
ronidazole
No. of Rats with One or More Benign Mammary Tumors
Group (N=60) Males Females
Control 1 3 45
Control 1 2 42
5 mg/kg bw/day 3 49
10 mg/kg bw/day 6 531
20 mg/kg bw/day 81 541
1. P<0.05
2.2.4 Reproduction studies
2.2.4.1 Rats
Groups of 10 male and 20 female Charles River CD strain albino
rats, 35 days old at the beginning of the study, were maintained on
diets containing 0, 0.02, 0.04 or 0.089% ronidazole, seven days a week
70 days prior to the first mating and throughout the production of
three generations. These dietary concentrations resulted in
approximate dosage levels of 25, 30 and 60 mg/kg bw/day. Two litters
were produced with each generation of parents. The second litter was
used to produce the succeeding generation and the first litter was
examined and then discarded at weaning.
There were no alterations in behaviour, appearance, body weights
or mean food consumption values of dams. No treatment-related
abnormalities were noted in the pups at any dietary level of
ronidazole. During each of the six whelping phases, the fertility,
gestation period, viability and lactation indices were comparable for
the control and treated group. There were no adverse effects on the
average body weight of pups at birth. At 60 mg/kg bw/day, ronidazole
significantly reduced the numbers of pups per litter as compared to
the control or lower dosage levels. Although there were slightly fewer
pups per litter at the 30 mg/kg bw/day level, the difference from the
control group was not significant. Because of the smaller number of
pups, the average pup weight at weaning was greater for the pups from
the 40 and 60 mg/kg bw/day groups. There were no treatment-related
gross or microscopic changes in any of treated pups of the second
litter of the third generation (Wazeter et al., 1969b).
2.2.5 Special studies on embryotoxicity (and/or teratogenicity)
2.2.5.1 Mice
Ronidazole was administered by gavage to 3 groups of 20 pregnant
mice (strain not specified) from days 6 through 15 of gestation at
dosage levels of 50, 100, and 200 mg/kg bw/day. Two additional groups
of 20 pregnant mice each served as controls. At 200 mg/kg bw/day,
there was a significant decrease in average maternal weight gain as
compared to the control group. The average number of implants,
resorptions, and live fetuses per litter, and average fetal weight per
litter from the low and mid dosage level groups were comparable to the
control groups. The average number of implants and the average number
of live fetuses per litter were slightly decreased at 200 mg/kg
bw/day.
External examination of all fetuses from the control and treated
groups revealed no evidence of a teratogenic effect attributable to
ronidazole. Visceral and skeletal examination of the fetuses from the
control and the high dose level groups revealed no evidence of
drug-related teratogenicity. The four visceral malformations observed
at 200 mg/kg bw/day were from the same fetus and were considered to be
spontaneous in origin (Zwickey et al., 1975).
2.2.5.2 Rats
Ronidazole was administered by gavage to 3 groups of 20 pregnant
Charles River-CD rats from days 6 through 15 of gestation at dosage
levels of 50, 100, and 200 mg/kg bw/days in Study 1 and at dosage
levels of 100, 150, and 200 mg/kg bw/day in Study 2, respectively. Two
additional groups of 20 pregnant rats served as controls in both Study
1 and 2. No drug-related embryotoxicity occurred at 50, l00, or 150
mg/kg bw/day of ronidazole. A slight but significant increase in
resorptions at 200 mg/kg bw/day was observed in Study 1 but not in
Study 2.
At 100 mg/kg bw/day and above, a decrease in average fetal weight
per litter was seen in both studies. At 100 mg/kg bw/day average
maternal weight gain was nonsignificantly and significantly retarded
in Study 1 and Study 2, respectively. At dosage levels of 150 or 200
mg/kg bw/day, average maternal weight gain was significantly retarded.
External examination of all fetuses from the control and
drug-treated group in Study 1 revealed no malformations at 50 mg/kg
bw/day. At 100 mg/kg bw/day, microphthalmia occurred in one stunted
fetus which also had severe hydrocephalus. At 200 mg/kg bw/day, 4
fetuses exhibited malformations involving the head (2 microphthalmia,
1 displaced eyes, and 1 micrognathia and cleft palate). Visceral and
skeletal examination of all fetuses from the control and 200 mg/kg
bw/day groups and of the one externally malformed fetus from the 100
mg/kg bw/day group revealed no additional evidence of drug-related
teratogenicity. However, an increased incidence of skeletal variations
including unossified sternebrae, incompletely ossified interparietals,
supraoccipitals and zygomatics were seen in the 200 mg/kg bw/day
group. External examination of all fetuses from the control and
treated groups in Study 2 revealed no evidence of treatment-related
teratogenicity. One fetus from one of the control groups had
microphthalmia of the left eye, and l fetus from the 200mg/kg bw/day
group had edema of the neck, but not micrognathia. Visceral
examination of approximately one-third of the fetuses from the two
control groups and from the 200 mg/kg bw/day group revealed no
evidence of drug-related teratogenicity. The 11 malformations observed
in the 200 mg/kg bw/day group were considered to be spontaneous in
origin, because they all occurred in the same fetus which was also
severely stunted and externally malformed. An increased incidence of
skeletal variations and unossified sternebrae were also seen in the
200 mg/kg bw/day group (Zwickey et al., 1976).
2.2.5.3 Rabbits
Two separate studies have been reported by Zwickey et al.,
(1975). In the first study, ronidazole was administered by gavage to
3 groups of 15 pregnant New Zealand rabbits from days 7 through 15 of
gestation at dosage levels of 3, 10, and 30 mg/kg bw/day. Two
additional groups of 15 pregnant rabbits served as controls. The
protocol of the second study was similar to the first study, except
that the 3 mg/kg bw/day ronidazole group was omitted.
No teratogenic, embryotoxic, or fetotoxic effects attributable to
treatment with ronidazole were observed at dosage levels of 3 and 10
mg/kg bw/day. A significant decrease in maternal weight gain and
average fetal weight occurred with ronidazole at 30 mg/kg bw/day.
Fetuses from the 30 mg/kg bw/day group exhibited malformations
involving the heart and great vessels. Heart and great vessel
malformations have been observed to occur spontaneously in rabbits. In
seven studies, the incidence of control fetuses with such
malformations varied from 0.4 to 2.4% compared with an incidence of
2.7 to 2.8% in fetuses from the 30 mg/kg bw/day dose levels in the two
studies of ronidazole. The authors concluded that the cardiovascular
malformations seen among the fetuses from dams given ronidazole were
not related to treatment.
2.2.6 Special studies on genotoxicity
Table 4: Results of genotoxicity assays on ronidazole
Concentration
of
Test System Test Object ronidazole Results Reference
Ames test (1) S.typhimurim 0.03 mM Positive Voogd et
TA1530, TA1532 al., 1974
TA1534,
Lt2his-G46
Ames test (2) S.typhimurim 10-50µg/plate Positive Hite et
TA1530, TA1531 al., 1976
TA1532, TA1534
TA2535, TA1536
TA1537, TA1538
Ames test (2) S.typhimurim 0.1µg/ml Positive Mourot, 1988
TA97a, TA98
TA100, TA102
Luria and K.pneumoniae 0.01 mM Positive Voogd et
Delbruck's E.Coli K12HfrH al., 1974
fluctuation test C.freundii 425
Sex-linked D.melanogaster 10 mM Positive Kramers, 1982
recessive
lethal test
Bone marrow DF2S mice 100-200 Positive Hite et
cytogenic assay mg/kg bw/day al., 1976
Dominant lethal CF2S mice 200 Negative Hite et
assay mg/kg bw/day al., 1976
Micronucleus CF2 mice 200 Negative Hite et
test mg/kg bw/day al., 1976
Micronucleus Swiss/RIV mice 280 Negative Oud et
test mg/kg bw/day al., 1979
(1) Without rat liver S-9 fraction
(2) Both with and without rat liver S-9 fraction.
2.3 Observations in man
No information is available.
3. COMMENTS
Ronidazole is absorbed from the gastrointestinal tract in both
laboratory and target species. In studies using radio-labelled
ronidazole, the radioactivity has been found to be widely distributed
in tissues and eliminated in the urine, feces and expired air of the
animals. The parent compound accounts for part of the urinary
excretion but is essentially absent from feces. Ronidazole is rapidly
degraded in pig urine and feces. The ultimate fate of ronidazole
metabolites has not been fully determined.
The mutagenic potential of ronidazole was investigated in a range
of studies. Positive findings were recorded in bacterial assays with
and without metabolic activation, and in the sex-linked recessive
lethal test in Drosophila melanogaster. The bone-marrow cytogenetic
assay in CF1S mice yielded weakly positive or negative results,
while micronucleus tests and a dominant lethal assay were negative.
In addition, a range of postulated and/or identified metabolites
of ronidazole and extract of muscle from ronidazole-treated pigs gave
negative results in Ames tests. The Committee found that these studies
contributed to the safety assessment of ronidazole.
The carcinogenicity studies most appropriate for evaluation were
an 81-week feeding study in Alderly Park mice and a 104-week feeding
study in Charles River CD rats. The data on individual animals were
not available to the Committee. The mice received ronidazole in the
diet at 0, 5, 10 or 20 mg/kg bw/day. The increased occurrence of lung
adenoma/carcinoma was statistically significant at 20 mg/kg bw/day in
males and females. The rats received ronidazole in the diet at 0, 5,
10 or 20 mg/kg bw/day and the increased occur-rence of benign mammary
tumors was statistically significant in females at 10 and 20 mg/kg
bw/day and in males at 20 mg/kg bw/day. The NOEL in these studies was
5 mg/kg bw/day.
The mechanism by which ronidazole exerts its dose-dependent
carcinogenic effects had not been elucidated.
In the rat carcinogenicity study, it was also noted that
testicular atrophy was present in males receiving 20 mg/kg bw/day
which died between 52 weeks of treatment and the planned end of the
trial. In a two-year study in which ronidazole was administered at 20
or 30 mg/kg bw/day, the same phenomenon was observed, in terms both of
a decrease in absolute testicular weight and of the presence of
histopathological change. Clinical signs of toxic effects in the
central nervous system were observed at all dose levels in this study.
Compound-related histopathological changes were found only in brain
tissues from five of seven dogs dosed at 30 mg/kg bw/day and killed in
the first year of the study. A subsequent two-year study in dogs
established a NOEL of 5 mg/kg bw/day for both these effects.
In a three-generation reproduction study in Charles River CD
rats, ronidazole was included in the diet at 200, 400 and 800 mg/kg.
There were no adverse effects on reproduction nor were
compound-related teratogenic effects seen, but the average number of
pups per litter was significantly reduced at 800 mg/kg. In two other
studies of Charles River CD rats, no drug-related teratogenic effects
were evident at doses up to 200 mg/kg bw/day. Maternal weight gain was
depressed at 200 mg/kg bw/day, while fetal weight was reduced at doses
of 100 mg/kg bw/day and above. In other studies, CF1S mice received
ronidazole at 50, 100 or 200 mg/kg bw/day by gavage and New Zealand
rabbits received doses of 3, 10, 30 mg/kg bw/day. Despite evidence of
maternal toxicity at the highest doses, there was no statistically
significant evidence of teratogenicity.
A NOEL of 5 mg/kg bw/day or higher was observed in these
long-term and reproductive studies. On the basis of a NOEL of 5 mg/kg
bw/day, therefore, and a safety factor of 200, the Committee
established a temporary ADI of 0-0.025 mg/kg bw/day. The safety factor
was selected by the Commiteee in the light of the results of
genotoxicity studies on ronidazole in mammalian systems and of the two
recent carcinogenicity studies in which no-observed-effect levels for
carcinogenicity and for other toxicological effects of concern were
identified. It was also influenced by the lack of mutagenicity of
several metabolites of ronidazole.
4. EVALUATION
Level causing no effect
Rat: 5 mg/kg bw/day
Dog: 5 mg/kg bw/day.
Estimate of temporary acceptable daily intake
0-0.025 mg/kg bw
Further work or information
Required (by 1993):
(a) A complete submission, including data on individual animals
of the carcinogenicity studies.
(b) The results of studies aimed at investigating the mechanism
of tumorigenesis.
5. REFERENCES
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4-nitrobenzenes, and related compounds. J.Natl. Cancer Inst., 51,
403-417.
HITE, M., SKEGGS, H., NOVEROSKE, J. & PECK, H. (1976). Mutagenic
evaluation of ronidazole. Mutation.Res., 40, 289-304.
KRAMERS, P.G.N. (1982). Studies on the induction of sex-linked
recessive lethal mutations in Drosophila melanogaster by
nitroheterocyclic compounds. Mutation Res., 101, 209-236.
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Merck Institute for Therapeutic Research, Merck Sharp & Dohme Research
Laboratories, Merck & Co., Inc., West Point, PA, USA. Submitted to WHO
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USA.
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See Also:
Toxicological Abbreviations
RONIDAZOLE (JECFA Evaluation)