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.

    See Also:
       Toxicological Abbreviations
       Olaquindox (WHO Food Additives Series 27)
       OLAQUINDOX (JECFA Evaluation)