OLAQUINDOX
First draft prepared by
Dr M. Miller
Center for Veterinary Medicine
Food and Drug Administration, Rockville, Maryland, USA.
1. EXPLANATION
Olaquindox is an antimicrobial drug with a long history of use as
a growth promoter in pigs. The commercial product is intended for use
in starter and/or grower rations but not in finisher rations. It is
usually administered in the feed at concentrations of 25-100 mg/kg
feed and may be used in pigs up to four months of age.
Olaquindox was previously evaluated at the thirty-sixth Meeting
of the Committee (Annex 1, reference 91), at which time the Committee
was unable to establish an ADI because of uncertainty regarding the
mechanism involved in the slight increase in the incidence of adrenal
cortical adenomas in male mice and the genotoxic potential of
olaquindox. The Committee requested information on the toxic potential
of the residues. In the meantime, the Committee concluded that
residues resulting from the use of olaquindox in food-producing
animals under conditions of good practice in the use of veterinary
drugs were temporarily acceptable.
This monograph addendum summarizes information that has become
available since the previous evaluation.
2. BIOLOGICAL DATA
2.1 Biochemical aspects
Information evaluated by the thirty-sixth Committee showed that
olaquindox was almost completely absorbed from the gastrointestinal
tract and that urine is the major route of excretion.
Residue depletion studies in pigs were reviewed by the present
Committee, which are summarized in the residue evaluations (Annex 1,
reference 112).
2.2 Toxicological studies
2.2.1 Special studies on photoisomerization products
Olaquindox causes photoallergic reactions in humans and animals
(DeVries, 1990a). Upon exposure to light, olaquindox forms a reactive
oxaziridine derivative. This imino-N-oxide reacts with protein to form
a photoallergen (DeVries, 1990b). In rats, oral treatment with
olaquindox at 60 mg/kg bw/day combined with exposure to ultraviolet
light (ultraviolet A for 12 hours) for four consecutive days induced
a photoallergic reaction characterized by weight loss, severe erthema,
edema, and necrosis of the ears. A NOEL for phototoxicity was not
established (DeVries, 1990a)..
3. COMMENTS
In its thirty-sixth report the Committee summarized a wide range
of studies on biochemical aspects, short-term toxicity, long-term
toxicity/carcinogenicity, reproductive toxicity,
embryotoxicity/feto-toxicity and special studies on genotoxicity and
pharmacological effects.
The current residue studies confirm that olaquindox is
extensively metabolized. Repeated oral administration of olaquindox to
mice, rats and pigs, produced a large number of metabolites at short
withdrawal times. The metabolites detected varied depending on the
tissues and species investigated. All metabolites found in the target
species were also present in the tissues of rodents. Therefore, it was
possible to conclude that the general toxicity of all metabolites had
been tested.
The Committee concluded that the toxicological concern associated
with olaquindox residues when the drug is used under conditions of
good practice in the use of veterinary drugs overshadowed any level of
concern for microbiological effects.
4. EVALUATION
The Committee concluded that due to the genotoxic potential of
the parent compound and the absence of specific toxicity studies on
the metabolites it was still unable to allocate an ADI. However, the
Committee noted that the parent drug was absent in muscle at the
proposed withdrawal time and the toxicity of the metabolites could be
partially evaluated on the basis of toxicity studies in experimental
animals because the metabolites are similar to those in the target
species. The Committee extended the temporary acceptance of residues
resulting from the use of olaquindox in pigs under conditions of good
practice in the use of veterinary drugs. Results of studies to
determine residues in liver and kidney of pigs using 3-methyl-
quinosaline-2-carboxylic acid (MQCA) as the residue marker are
required by 1996.
5. REFERENCES
DeVRIES, H., BEYERSBERGEN VAN HENEGOUWEN, M.J., KALLOE, F. &
BERKHUYSEN, M.H.J. (1990a). Phototoxicity of olaquindox in the rat.
Research in Veterinary Science, 48: 240-244.
DeVRIES, H., BOJARSKI, J., DONKER, A.A., BAKRI, A. & BEYERSBERGEN VAN
HENEGOUWEN, M.J. (1990b). Photochemical reactions of quindoxin,
olaquindox, carbodox and cyandox with protein, indicating
photoallergic properties. Toxicology, 63: 85-95.