DIMETRIDAZOLE
1. EXPLANATION
Dimetridazole (1,2-dimethyl-5-nitromidazole) is a
5-nitroimidazole with antiparasitic activity useful in the treatment
of enterohepatitis in turkeys and dysentery in swine. The normal level
of inclusion of dimetridazole in feed is between 150 and 500 ppm, and
in drinking water between 300 and 1230 ppm. Dimetridazole has not been
previously evaluated by the Joint FAO/WHO Expert Committee on Food
Additives.
2. BIOLOGICAL DATA
2.1 Biochemical aspects
No data in laboratory animals were available.
2.2 Toxicological studies
2.2.1 Acute toxicity
Species Sex Route LD50 Reference
(mg/kg bw)
Mouse M&F Oral 1790 Cosar, 1957
M&F Oral 1790l-2000 Hood, 1962
601-290
Rat M&F Oral 16001-2500 Hood, 1962
701
1. Administered as "emtryl soluble" which contains dimetridazole
(40%), potassium dihydrogen phosphate (22%) and potassium
sulfate (38%).
2.2.2 Short-term studies
2.2.2.1 Rats
Diets containing 0, 0.2, 0.4, 0.6, 0.8. or 1% of dimetridazole
were fed to groups of 10 Simonsen Albino (SPF) rats of each sex for 13
weeks. Groups of 10 male and 10 female rats of the same strain were
fed restricted unmedicated diet and served as controls. The rats were
observed daily for clinical signs of toxicity. Body weight and food
consumption were measured weekly for all animals. Data submitted in
summary form indicated that male rats from the 0.8% and 1%
dimetridazole groups had albumin in the urine. Three females of the
highest dose group failed to survive the full 13 weeks of the study.
The deaths occurred approximately 4 weeks after the first signs of
ataxia, tilted head, anemic appearance, excitation and convulsion,
which occurred after 5 weeks of treatment.
Histopathology examination revealed that testicular atrophy and
degeneration occurred in all dimetridazole-treated male rats.
Testicular changes involved severe atrophy of seminiferous tubules
with spermatogenic arrest of primary and secondary spermatocytes. A
decrease in the numbers of primary follicles and increased
degeneration of follicular epithelium were also noted in the ovaries
of female rats treated with dimetridazole. Gastritis was observed in
rats from each group except the control and 0.6% groups. Cardiac
alterations characterized by minimal focal infiltrations of leukocytes
and occasional degenerative myocardial fibers were observed in 1 rat
each of the control, 0.4% and 1% groups, and in 3 rats each of the
0.6% and 0.8% groups. This increased frequency of myocardial
alteration in dimetridazole-treated groups was considered by the
authors as suggestive of some myocardial toxicity (Salsbury's
Laboratories, 1962a).
2.2.2.2 Dogs
Diets containing 0.36% or 1.08% of dimetridazole were fed to
groups of one purebred beagle dog of each sex for 4 weeks. No control
group was used in this study. The dogs were observed daily for
clinical signs of toxicity. Body weight and food consumption were
recorded weekly for all animals. Necropsy and histopathological
examinations of major organs were conducted on all animals at the
termination of the experiment.
Results submitted in summary form indicated that food consumption
was markedly reduced in dogs of the 1.08% group when compared to the
0.36% group. Two weeks after the treatment with dimetridazole started,
the female dog from the 1.08% dose level exhibited the first sign of
ataxia which appeared to be more predominant in the hindquarters.
Three days later the male from the same group also showed the same
signs. This paralytic condition grew worse in both dogs until the
trial was terminated. No toxic signs were noted in the animals from
the 0.36% group. The authors reported mild nephrosis, hemorrhagic and
petechial hemorrhages and nephrosis of kidney, hemorrhages of heart
and spleen, central lobular cirrhosis and hemorrhages of liver in dogs
of the high dosage group.
Histopathological examinations of lungs showed a proliferation of
interstitial tissue which reduced the respective air space area to
approximately 1/2 to 2/3 of normal. Kidneys of animals from the 1.08%
group showed moderate cloudy swelling in the cells lining convoluted
tubules and tubules comprising the medullary ray. The reaction was
less in degree in the 0.36% group. Mild atrophy of the seminiferous
tubules with no mature spermatocytes present and moderate degeneration
of spermatids were observed in the testes of the male dog from the
1.08% group. Very mild degenerative changes in spermatids and a
reduced number of spermatocytes were also noted in the testes of the
male dog from the 0.36% group. It was suggested by the authors that
dimetridazole-related changes in the kidneys, testes and possibly the
lungs were present in this study (Salsbury's Laboratories, 1962b).
Groups of 2 male and 2 female purebred beagle dogs, approximately
12 to 30 weeks of age, were given dimetridazole orally at dosage
levels of 16, 33, 66 and 132 mg/kg bw/day for 13 weeks. A similar
number of dogs were used as a control group. The dogs were observed
daily for clinical signs of toxicity. Body weight and food consumption
were recorded weekly for all animals.
Body weight gain and food consumption of all dimetridazole
treated groups were less than those of the control group, particularly
at the dosage levels of 66 and 132 mg/kg bw/day. The dogs in the
control, 16 and 33 mg/kg bw/day dosage groups remained in relatively
good health throughout the study. Anorexia, ataxia, convulsions and
opisthotonos were seen in dogs of the 66 mg/kg bw/day group. At the
dosage level of 132 mg/kg bw/day, all of the dogs exhibited
essentially the same signs as those observed for the dogs at the 66
mg/kg bw/day level except that the signs appeared earlier, were more
intense and of longer duration. Three of the dogs had to be sacrificed
on humane grounds at 40 days post dosing and the other was found dead
in the cage 39 days after treatment with demetridazole (Salsbury's
Laboratories, 1962c).
Groups of 4 male and 4 female beagle dogs were given
dimetridazole orally at dosage levels of 0, 5, 10, 20, or 40 mg/kg
bw/day for 13 weeks. The dogs were observed daily for clinical signs
of toxicity. Body weights were recorded weekly and food consumption
was determined daily.
With the exception of one dog in the 40 mg/kg bw/day group, which
died while under anesthesia for bone marrow biopsy, there were no
mortalities among dimetridazole-treated animals. No unusual clinical
signs were observed in any of the dogs at any time during the
experiment. There were no drug-related effects on body weight, food
consumption, urinalysis, hematology, biochemistry, organ weight or
histopathology. Neither the ophthalmological nor the neurological
examinations revealed any changes attributable to dimetridazole. The
authors concluded that daily doses of up to 40 mg/kg bw of
dimetridazole were well tolerated by the dogs during the period of 13
weeks (Goyder et al., 1974).
2.2.3 Long-term/carcinogenicity studies
2.2.3.1 Rats
Thirty-five female Sprague-Dawley rats were fed 0.2% of
dimetridazole in the diet (equivalent to 200 mg/kg bw/day
demitridazole) for 46 weeks, followed by control diet for an
additional 20 weeks. A group of 35 female rats of the same strain were
fed control diet for 66 weeks and served as the control group. Both
the control and the treated groups were given 0.2 ml Bicillin
intramuscularly at weeks 0, 9, 21, 31, 41 and 56 to control
respiratory infections. Autopsy was performed on animals that died
during the study and on survivors at the end of the study.
Histological examination of tissue sections was conducted on tissues
and gross lesions from all animals.
At 66 weeks there was a clear increase of benign mammary gland
tumors in treated rats (25/35) compared to controls (4/35). The mean
number of mammary tumors per rat was also increased in treated rats
(1.7) compared to controls (1.0). Malignant mammary tumors did not
occur in either group. It could not be determined in this study of
only 66 weeks duration if dimetridazole resulted in an actual increase
in the incidence of tumors or decreased the time fordevelopment of
tumors which occur spontaneously. This strain of rat normally has a
high incidence of mammary gland tumors (Cohen et al., 1973).
Diets containing 0, 100, 400 or 2,000 ppm dimetridazole were fed
to groups of 50 CFY rats of each sex for 122 weeks. The approximate
daily intake of dimetridazole over the period of the study were 0,
3.8, 15.1 and 77.7 mg/kg bw/day in males and 0, 4.6, 18.3 and 94.1
mg/kg bw/day in females. The rats were observed daily for clinical
signs of toxicity and food consumption was recorded weekly. Body
weights were determined weekly during the first 20 weeks of the study,
and biweekly thereafter. Mortalities occurred in all groups,
particularly the high dosage groups. At the termination of the study,
the survival rates were: control, males 30%, females 46%; l00 ppm,
males 38%, females 42%; 400 ppm, males 28%, females 36%; 2000 ppm,
males 20%, females 14%. Throughout the study, the group mean body
weights of the males in the 100 and 400 ppm groups were slightly in
excess of those of the control group, while those of the 2000 ppm
group tended to be equal to or slightly less than those of the
controls. In the females, except for the first 20 weeks of the
experiment, there was a tendency for the group mean body weights of
all the treated groups to be slightly lower than those of the control
group. There were no obvious differences in mean food consumption
between the control and dimetridazole treated groups. Nodules were
palpated sooner and with a higher incidence in the high dose males and
females compared to controls and lower dose groups.
Necropsies were performed on all rats which died during the study
or were sacrificed at the end of the study. Gross lesions and a
complete set of tissues were examined microscopically from 20 rats in
each group. From all other rats gross lesions and a limited set of
tissues were examined microscopically. A significant increase in
benign tumors (adenoma, fibroadenoma, fibroma) of the mammary gland
occurred in male and female rats from the 2000 ppm groups and a
smaller increase was observed in 400 ppm female rats. An increase in
tumor multiplicity (mean number of tumors per tumor bearing animal)
was observed at this site in the mid and high dose level females. It
was noted that nodules from 2 rats in each of the treated female
groups and in the high dose male groups were not examined
microscopically. However, this was not considered to have any effect
on the determination of the NOEL of 100 ppm for benign mammary tumors.
Malignant tumors in the mammary gland were not increased in treated
rats. No significant increase for any tumor type was observed in other
tissues (Lowe et al., 1976).
Diets containing 0 or 10 ppm dimetridazole were fed to groups of
50 CFY rats of each sex for 128 weeks. The approximate daily intakes
of dimetridazole over the period of the study were 0 and 0.45 mg/kg bw
in males and 0 and 0.57 mg/kg bw in females. The experimental protocol
was essentially similar to that described previously (Lowe et al.,
1976). Histopathological examination was confined to the adrenals,
pancreas, pituitary, thyroid (with trachea), liver and all gross
lesions.
At the end of the study the survival rates were: control, males
32%, females 20%; 10 ppm, males 12%, females 22%. Low survival was
attributed by the authors to the length of the study. Treatment with
dimetridazole had no effect on group mean body weights and group mean
food consumption. There were no clinical signs attributable to
treatment.
Although microscopic examination was performed on a limited
number of tissues, this limitation would be expected to have little or
no effect on the evaluation of a potential neoplastic effect on the
mammary gland. Statistical analyses revealed no significant
differences in tumor incidence between dimetridazole treated and
control groups. There was no increase of benign or malignant mammary
tumors in treated rats of either sex. However, at interim sacrifices
during the course of the study, more tumor-bearing rats were found in
dimetridazole treated males than in the controls (Lowe et al.,
1977).
2.2.4 Reproduction studies
2.2.4.1 Rats
Groups of 10 male and 20 female weanling CFY rats comprising the
Fo generation were maintained on diets containing 0, 100, or 2000 ppm
of dimetridazole for approximately 80 days prior to the first mating
and throughout the production of three generations.
Dimitridazole markedly reduced the weight gain and food intake of
Fo males at the 2000 ppm dosage level, but not in females. This
effect was not observed during the pre-mating period of either the
F1b or F2b rats. During each of the six whelping phases, the
fertility, viability, and length of gestation period were comparable
for the control and dimetridazole-treated groups.
With regard to lactation of the dams and pup mortality rates, no
untoward effects on these two parameters were observed in the Fo and
F2b matings. However, the numbers of pups dying in the F1b
offspring from both matings were markedly and often significantly
increased in both treated groups compared to the control group. This
was due almost entirely to the increased number of dams which ceased
lactating. The possibility of drug-induced, non lactation in the F1b
dams could not be excluded, but as similar effects were not observed
in either the Fo or F2b rats, this was most unlikely. The authors
concluded that although some of the results obtained were
contradictory, dimetridazole was not shown to adversely affect
reproduction performance in the rat in any way (Dale, 1975b).
2.2.5 Special studies on embryotoxicity and teratogenicity
2.2.5.1 Rabbits
Dimetridazole was administered by gavage to 4 groups of 23
pregnant New Zealand white rabbits from days 6 through 18 of gestation
at dosage levels of 0, 30, 60, or 120 mg/kg bw/day. On day 29 of
gestation, the animals were killed to allow examination of their
uterine contents.
Dosage-related maternal toxicity as evidenced by reduction in
food intake and body weight gain, and abortion was noted in all
dimetridazole-treated groups. Death and total litter resorption were
seen at the highest dosage level. Although there was evidence of a
slight reduction in fetal and placental weight, the authors concluded
that morphological development of the fetuses was unaffected by
treatment with dimetridazole (Tesh et al., 1988).
2.2.6 Special studies on genotoxicity
Table 1: Results of genotoxicity assays on dimetridazole
Concentration
Test System Test Object of Results References
Dimetridazole
Ames test (1) S.typhimurium 0.03 mM Positive Voogd et
TA1530, TA1532 al., 1974
TA1534, LT2
his-G46
Ames test (2) S.typhimurium Positive Benazet &
TA1535, TA1537 Cartier, 1977
TA98, TA100
Ames test (2) S.typhimurium 0.01 µg/ml Positive Mourot, 1988
TA97a, TA98
TA100, TA102
Ames test S.typhimurium 100 µg/ml Negative Thybaud et
TA100 Frl et al., 1988
(nitroreductase
negative)
TA100 Frl urine from
rats treated
with 400 mg/kg
by oral or
intravenous
route
Luria and K.pneumoniae
Delbrück's E.coli K12HfrH 0.01 mM Positive Voogd et
fluctuation test C.freundi 425 et al., 1974
Sex-linked
recessive D.melanogaster 1.4 mM Negative Kramers, 1982
lethal test
Mitotic gene S.cerevisiae D4 0.05% (w/v) Positive Voogd, 1981
conversion test
Dominant lethal CDA mice 1000 mg/kg Negative Dale, 1975a
bw/day
CHO/HGPRT Chinese hamster 820-2800 Negative Fournier &
µg/ml Cordier, 1986a
Micronucleus test CD1 mice 980 mg/kg Negative Fournier &
bw Cordier, 1986b
Table 1 cont'd: Results of genotoxicity assays on dimetridazole
Concentration
Test System Test Object of Results References
Dimetridazole
Unscheduled Fischer F344 1000 mg/kg Negative Melcion &
DNA synthesis rats hepatocytes bw Cordier, 1988
in vivo
Unscheduled Chinese hamster 200 µg/ml Negative Richold et
DNA synthesis lung fibroblasts al., 1981
in vitro
(1) Without rat liver S-9 fraction.
(2) Both with and without rat liver S-9 fraction.
2.3 Observations in man
No information available.
3. COMMENTS
In the short-term toxicity studies, clinical effects on the
nervous system were seen when dimetridazole was incorporated into the
diets of rats at 500 mg/kg bw/day and of dogs at 270 mg/kg bw/day.
Dose-related testicular atrophy was seen in all treated groups, where
the lowest levels of exposure were equivalent to 100 mg/kg bw/day for
the rat and 90 mg/kg bw/day for the dog. No adverse effects were seen
in a more recent 90-day study in the dog in which dimetridazole was
administered in capsules at doses ranging from 5 to 40 mg/kg bw/day.
Maternal toxicity effects were evident in all treated groups of
pregnant rabbits in a teratogenicity study in which dimetridazole was
administered in capsules at doses of 0-120 mg/kg bw/day. There were
slight dose-related reductions in fetal weight, significant only at
the highest dose, but no evidence of a teratogenic effect.
In a multigeneration study in the rat in which dimetridazole was
incorporated at levels of 100 and 2000 mg/kg in the diet, no
compound-related effects on reproductive performance were seen and
there was no teratogenic effect.
Dimetridazole and its urinary metabolites in the rat gave
positive results in mutagenicity tests on strains of Salmonella
tyhimurium with nitroreductase activity. All of these compounds gave
negative results with nitroreductase deficient strains.
Negative mutagenicity results were obtained in a variety of in
vitro and in vivo mammalian systems including the dominant lethal
assay, micronucleus test, gene mutation assay in Chinese hamster ovary
cells and test for unscheduled DNA synthesis.
The results of the three long-term rat studies were reported
between 1973 and 1977. While meeting the requirements for that
period, they were not conducted in accordance with present-day
standards for carcinogenicity studies. In the first study, female
rats were fed 200 mg/kg bw/day dimetridazole in the diet for 46
weeks and then received the same diet as the controls for 20 weeks.
There was a significantly increased incidence of benign mammary
tumors in the treated group. In the second study, rats of both sexes
were fed diets containing 0, 100, 400 and 2000 ppm dimetridazole for
122 weeks. There was a dose-related increase in the incidence of
benign mammary tumors, with an increase in multiplicity, in females
in the two higher-dose groups. In the third study, rats were fed
diets containing 0 or 10 ppm dimetridazole for 128 weeks. The small
increase in mammary tumors in females was not statistically
significant.
Because of the lack of mutagenic effect of dimetridazole in in
vitro and in vivo mammalian systems, it was considered that the
mechanism for the production of an increased number of benign mammary
tumors in the rat was unlikely to be genotoxic. However, no evidence
was submitted to suggest a possible mechanism.
Although a NOEL of 100 ppm in the diet, equal to 4 mg/kg bw/day,
was reported in the long-term rat study, the Committee could not
establish an ADI solely on the basis of this study in the absence of
the results of a carcinogenicity study in a second species.
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See Also:
Toxicological Abbreviations
DIMETRIDAZOLE (JECFA Evaluation)