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.