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    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.

    5.  REFERENCES

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    FOURNIER, E. & CORDIER, A. (1986a). 8.595 R.P. (Dimétridazole) - Test
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    KRAMERS, P.G.N. (1982). Studies on the induction of sex-linked
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    SALSBURY'S LABORATORIES (1962c). Study of the subacute toxicity of 1,
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    in dogs with specific objectives of establishing a maximum tolerated
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    TESH, J.M., ROSS, F.W., BAILEY, G.P., WILBEY, O.K. & TESH, S.A.
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    THYBAUD, V., MELCION, C. & CORDIER, A. (1988). Investigative studies
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    nitroreductases and,  in vitro metabolism in the liver and the
    intestinal flora on the mutagenic activity of dimetridazole in the
    Ames test. Unpublished report ST/C.R.V./TOX No. 195E from Département
    Toxicologie, Centre de Recherches de Vitry, Rhône-Poulenc Santé,
    Vitry-sur-Seine, France. Submitted to WHO by Rhône-Poulenc Santé,
    Direction Scientifique, Paris, France.

    VOOGD, C.E., VAN DER STEL & JACOBS, J.J.J.A.A. (1974). The mutagenic
    action of nitroimidazoles.  Mut.Res., 26, 483-490.

    VOOGD, C.E. (1981). On the mutagenicity of nitroimidazoles.  Mut.Res.,
    33, 243-277.


    See Also:
       Toxicological Abbreviations
       DIMETRIDAZOLE (JECFA Evaluation)