IPCS INCHEM Home

    SULFATHIAZOLE

    1.  EXPLANATION

         Sodium sulfathiazole is effective against a wide range of gram
    positive and gram negative pathogenic microorganisms. Common uses of
    sulfathiazole in cattle include: the treatment of bovine respiratory
    disease complex (shipping fever complex); bacterial pneumonia; calf
    diphtheria and necrotic pododermatitis (foot rot) and acute metritis.
    Common uses of sulfathiazole in pigs include: treatment of bacterial
    pneumonia; porcine colibacillosis (bacterial scours); and, in
    combination with chlortectracyline and penicillin, for increased rate
    of weight gain and improved feed efficiency, reduction of the
    incidence of cervical abscesses, and treatment of bacterial swine
    enteritis (salmonellosis or necrotic enteritis and vibrionic
    dysentery). This compound has not previously been evaluated by the
    Joint FAO/WHO Expert Committee on Food Additives.

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

         Metabolism of sulfonamide drugs in animals includes conjugation
    at the N4-position (acetyl, sulfate, glucuronic acid, and glucose),
    conjugation at the N1-position (sulfate and glucuronic acid),
    removal of the p-amino group (formation of the desamino metabolite),
    ring hydroxylation, and conjugation of the ring hydroxylation
    products. Dietary nitrite enhances the production of the desamino
    metabolite of sulfathiazole. The intermediate leading to the desamino
    metabolite of sulfamethazine is weakly mutagenic in the Ames test
    (Nelson  et al., 1987; Paulson  et al., 1987).

    2.2  Toxicological studies

    2.2.1  Acute toxicity

         No data are available.

    2.2.2  Short-term studies

    2.2.2.1  Rats

         Sodium sulfathiazole was administered once daily, seven days a
    week, for thirteen weeks by oral intubation to three groups of 15 male
    and 25 female Charles River, Sprague-Dawley, CD rats (approximately
    7-8 weeks of age) at dosage levels of 2, 6, and 18 mg/kg bw/day. Two
    additional groups of 15 male and 15 female rats served as controls and
    each received the vehicle only (distilled water) on a similar regimen.
    Treatment with sulfathiazole failed to elicit systemic toxicity at any
    dose. Appearance, behavior, growth rate, food consumption, and
    survival data for the test animals were comparable with that of the
    controls. No compound-related findings were observed with respect to
    clinical laboratory studies, ophthalmoscopic examinations, organ
    weights, organ/body weight ratios, or gross or microscopic pathology
    (Reno & Banas, 1975).

    2.2.2.2  Dogs

         Sodium sulfathiazole was administered orally in gelatin capsules
    once daily, seven days a week, for 13 weeks to three groups of four
    male and four female purebred beagle dogs at dosage levels of 2, 6 and
    18 mg/kg bw/day. Two additional groups of four male and four female
    dogs each served as two separate control groups and received empty
    gelatin capsules on a similar regimen. The authors concluded that
    there was no sign of drug-induced systemic toxicity at any dose
    throughout the 13 week treatment period. Although not mentioned by the
    authors, there were slight increases, which were not statistically
    significant, in the thyroid weight and thyroid to body weight ratio in
    female dogs receiving the 18 mg/kg bw/day dose (Reno & Voelker, 1975).

    2.2.3  Long-term/carcinogenicity studies

         No data are available.

    2.2.4  Reproduction studies

         No data are available.

    2.3  Observations in man

         A general discussion of adverse reactions to sulfonamide therapy
    in man is found in the thirty-fourth report of the Joint FAO/WHO
    Expert Committee on Food Additives.

    3.  COMMENTS

         From the 90-day study in rats, it was concluded that the NOEL was
    18 mg/kg bw/day, which was the highest dose tested. It was also
    concluded that the NOEL in the 90-day study in dogs was 6 mg/kg
    bw/day. A biologically significant increase in relative and absolute
    thyroid weights occurred in females in the highest dose group.

         The Committee did not establish an ADI because of the lack of
    data on the hormonal effects of sulfathiazole.

         Based on the results of studies on sulfadimidine conducted by the
    United States Government and published data on other sulfonamides,
    that the mechanism of sulfonamide toxicity involved the
    thyroid-hypothalamus-pituitary axis, it was decided that
    carcinogenicity and long-term studies on sulfathiazole were not
    necessary. Instead, the Committee would wish to see the results of
    studies designed to assess the effects of sulfathiazole on sensitive
    parameters of thyroid and pituitary function in rodents. The Committee
    would also wish to see the results of studies designed to elucidate
    the metabolism of sulfathiazole and to determine the residues of
    sulfathiazole in food-producing animals by administration of
    14C-labelled sulfathiazole. In addition, data from mammalian
    genotoxicity studies would be necessary for a full evaluation of
    sulfathiazole.

    5.  REFERENCES

    NELSON, P.A., PAULSON, G.D., & FEIL, V.J. (1987). The effect of
    nitrite on 14C-sulphathiazole metabolism in the rat.  Xenobiotica,
    17, 829-838.

    PAULSON, G.D., FEIL, V.J. & MacGREGOR, J.T. (1987). Formation of a
    diazonium cation intermediate in the metabolism of sulfamethazine to
    desaminosulfamethazine in the rat.  Xenobiotica, 17, 697-707.

    RENO, F.B., & BANAS, D. (1975). 13-week oral toxicity study in rats,
    sodium sulfathiazole, unpublished report from Hazelton Laboratories,
    Inc., Vienna, Virginia, for the Merck Institute for Therapeutic
    Research, West Point, Pennsylvania, submitted to WHO by the US
    Coordinator of the Codex Alimentarius, US Department of Agriculture,
    Washington, D.C.

    RENO, F.B., & VOELKER, R.W. (1975). 13-week oral toxicity study in
    dogs, sodium sulfathiazole, unpublished report from Hazelton
    Laboratories, Inc., Vienna, Virginia, for the Merck Institute for
    Therapeutic Research, West Point, Pennsylvania, submitted to WHO by
    the US Coordinator of the Codex Alimentarius, US Department of
    Agriculture, Washington, D.C.


    See Also:
       Toxicological Abbreviations
       SULFATHIAZOLE (JECFA Evaluation)