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EC number: 215-578-1 | CAS number: 1333-07-9
Absorption, distribution, metabolism and excretion of [ring-U-14C]Chloramine T in the Wistar rat. The study was conducted according to the following guidelines: OECD Guideline no. 417: Toxicokinetics. Seven groups of rats were included in the study: Three (n=4 males and 4 females) for the massbalance, three (n=3 males and 3 females) for the toxicokinetics and one (n= 4 males and 4 females) for bile collection. Rats were dosed with a single oral dose of 20 mg/kg b.w. or 200 mg/kg b.w., or dosed repeatedly with 20 mg/kg b.w.for 10 days with unlabelled test substance
prior to a labeled dose. In the mass-balance groups, urine, faeces and bile (bile-cannulation group only) were collected in 0-8, 8-24, 24-48 and 48-72 hr intervals. Animals were euthanized 72 hours after dose administration, and several tissues and organs were collected. Total radioactivity in urine, faeces, bile, tissues and organs was determined. Selected urine and faeces samples were pooled per group and the metabolite profile in these pooled samples was investigated. In the toxicokinetic groups, blood was sampled from each rat at the following time points: 0.25, 0.5, 1 , 2, 4, 8, 24, 48 and 72 hour after dosing. Total radioactivity and Chloramine T equivalent concentrations were determined.
No mortality was observed in the study. One animal in the bile-cannulation group was killed in extremis, due to problems with the bile cannula. This animal displayed piloerection and hunched posture.
Clinical signs were observed mainly in the high dose ADME group and the bile cannulation group and consisted of piloerection.
From the plasma data it was evident that oral absorption proceeded fast, with Tmax values of 0.25 to 1 hour. Plasma concentration versus time curves of Chloramine T equivalents after oral dosing were similar, with similar Tmax values, and dose-normalised Cmax and AUC, in the same
order of magnitude. This suggests linear kinetics over the investigated dose range. Variable apparent terminal half-lives were observed, ranging from 13.2 to 120 hours. In general, it appeared that females had a shorter half-life of radioactivity than the males, but this was not reflected in the mass-balance data. The most important route of excretion of Chloramine T equivalents was urine. Urinary excretion accounted for 90% for males and 88% for females after low dosing, 81 % for males and 79% for females after high dosing and 87% for males and 78% for females after repeated dosing. In the bile-cannulation group urinary excretion accounted for 67% for the males and 66% for the females after oral dosing.
Faecal excretion was only a minor route of excretion. Faecal excretion accounted for 10% for the males and females after low dosing, 13% for the males and females after high dosing and 13% for the males and 16% for the females after repeated dosing, in the ADME groups. In the bile-cannulation group faecal excretion accounted for 25% for the males and 23% for the females. Biliary excretion accounted for 6% of the administered dose in males and 4% in females, in the bile-cannulation group. The absorption of Chloramine T equivalents was high, 92% and 91 % for the males and females in group 1 respectively, 83% in the males and females of group 2, and 89% and 85% of the males and females in group 3 respectively. The absorption in the bile-cannulation group was lower than in the ADME groups, 75% in both sexes. At termination of the study, the average total remaining radioactivity in blood, carcass plus tissues was between 0.6 and 1.4% of the administered dose in all groups..
The tissue concentration equivalents of Chloramine T were below the concentration observed in blood in all groups. 'This indicates that Chloramine T shows no potential for accumulation. The average total recovery of radioactivity in groups 1 to 3 and 7 was between 96 and 102% of
the administered dose. In the urine samples, one major radioactivity peak was observed, which accounted for 80-92% of the radioactivity in the radio-chromatogram and 65-81 % of the applied dose. This metabolite was isolated by prep HPLC from the urine pool of group 2 males and then identified as being 4. Sulfamoyl benzoic acid by NMR and Mass Spectrometry. Based on the radioactivity data (same major peak present in all groups and sexes at a similar retention time) it was concluded that the major radioactivity peak represented 4-Sulfamoyl benzoic acid in all groups.
In the radioactivity chromatograms of the faeces extracts 3 major peaks were observed, but these peaks could not be identified with MS. Two potential minor metabolites were identified i.e. p-sulfonic-benzoic acid and an aromatic methoxy compound.
It can be concluded that Chloramine T administered orally was highly absorbed and excreted mainly via the urine. The data indicated that there were no sex differences in urinary, faecal or biliary excretion of radioactivity and no sex differences in total absorption. In addition, no differences were observed in urinary, faecal, biliary excretion or total absorption between the low and high dose or between single and repeated administrations. Linear plasma kinetics were observed. One major metabolite was observed in urine of all groups and identified as 4-Sulfamoyl benzoic acid.
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