ANNEX 5

    FURTHER TOXICOLOGICAL STUDIES AND OTHER INFORMATION REQUIRED OR DESIRED

    Anthelmintic drug

    Albendazole

         A marker residue substance in milk needs to be identified and
    further information is required on the quantitative relationship
    between the concentration of 2-aminobenzimidazole sulfone and total
    residues in muscle, kidney, and fat of cattle and sheep.

    Antiprotozoal agents

    Dimetridazole

         Before reviewing the compound again, the Committee would wish to
    see results from the following studies:

         (1)  long-term study in mice;
         (2)  studies investigating the mechanism of tumorigenesis;
         (3)  adequate total residue depletion studies in poultry and
              swine using ring-labelled 14C-dimetridazole; and
         (4)  metabolism studies in swine and poultry that characterize
              the total/bound residues.

    Ipronidazole

         Before reviewing the compound again, the Committee would need
    results from the following studies:

         (1)  adequate  in vitro and  in vivo genotoxicity studies in
              mammalian systems;
         (2)  a carcinogenicity study in rats to assess the effect of
              ipronidazole on the mammary gland and other tissues;
         (3)  studies to investigate mechanisms that might explain the
              effect of the drug on in increasing the incidence of mammary
              tumors in rats and lung tumors in mice;
         (4)  an  in vivo metabolism study in rats using ring-labelled
              ipronidazole (special emphasis should be placed on the
              detection of metabolites in which the 5-nitro group has been
              reduced);
         (5)  adequate total residue depletion studies in swine and
              turkeys using ring-labelled 14C-ipronidazole; and
         (6)  metabolism studies in swine and turkeys to characterize the
              total residues.


    Metronidazole

         Before reviewing the compound again, the Committee would need the
    following information:

         (1)  comprehensive toxicological information to permit a safety
              evaluation;
         (2)  the results of studies of total residue depletion in
              food-producing animals using ring-labelled
              14C-metronidazole;
         (3)  the results of metabolism studies in food-producing animals
              to elucidate the nature of the total residue; and
         (4)  development of an analytical procedure for identifying and
              measuring the residues of metronidazole in the edible
              tissues of food-producing animals.

    Ronidazole

         Results of the following studies are required by 1993:

         (1)  complete submission, including data from individual animals,
              from the carcinogenicity studies in mice and rats that were
              used in the evaluation; and

         (2)  the results of studies to investigate the mechanism of
              tumorigenesis.

         In order to establish MRLs, data providing a relationship between
    a marker compound and the total residue will be needed. In addition,
    the toxicological significance of the bound residue will have to be
    assessed further.

    Antimicrobial sulfonamides

    Sulfadimidine

         Results of studies known to be in progress on the effects of
    sulfadimidine on the thyroid gland in various animal species are
    required by 1991.

    Sulfathiazole

         Before reviewing the compound again, the Committee would need
    results from the following studies:

         (1)  studies designed to assess the effects of sulfathiazole on
              sensitive parameters of thyroid and pituitary function in
              rodents;
         (2)  mammalian genotoxicity studies;


         (3)  studies designed to elucidate the metabolism of
              sulfathiazole; and
         (4)  studies designed to determine the residues of sulfathiazole
              in food-producing animals using 14C-labelled sulfathiazole.

    Trypanosides

    Diminazene

         Before reviewing the compound again, the Committee would need the
    following:

         (1)  results of a teratogenicity study;
         (2)  results of  in vitro and  in vivo mutagenicity studies so
              that the genotoxic and carcinogenic potential of the
              compound can be evaluated;
         (3)  results of studies on residue levels in food-producing
              animals; and
         (4)  information on available methods for measuring milk and
              tissue residues of diminazene.

    Isometamidum

         Before reviewing the compound again, the Committee would need the
    following:

         (1)  results of studies designed to indicate the nature of the
              metabolites of isometamidium in the target species, and an
              indication of the extent of their absorption in laboratory
              species after oral administration;
         (2)  results of adequate mutagenicity studies so that the
              genotoxic and carcinogenic potential of the compound can be
              evaluated;
         (3)  results of a teratogenicity study using the oral route;
         (4)  results of a 90-day study in rats;
         (5)  results of studies on residue levels in food-producing
              animals; and
         (6)  information on available methods for measuring milk and
              tissue residues of isometamidium.

    See Also:
       Toxicological Abbreviations