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.