Toluene-4-sulphonamide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

July 2006- July 2007

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study performed according to guideline and under GLP.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2007

Report date:

2007

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Tosylchloramide sodium

EC Number:

204-854-7

EC Name:

Tosylchloramide sodium

Cas Number:

127-65-1

IUPAC Name:

sodium chloro[(4-methylphenyl)sulfonyl]azanide

Constituent 2

Reference substance name:

Chloramine-T

IUPAC Name:

Chloramine-T

Details on test material:

Radio labelled test substance:
Identification: [ring-U14C]Chloramine T
Molecular formula: C7H7CINNa02S.3H2O
Molecular weight: 282.4 (at this specific activity)
Description: solid
Batch: CFQ14688 Batch 1
Radiochemical purity: 97.2% (HPLC, The radiochemical purity was determined by the supplier and was also checked at NOTOX
before the start of the experiment)
Chemical purity: Not indicated
Test substance storage: In freezer (≤10°C) in the dark under nitrogen
Stability under storage conditions: Not indicated
Specific activity: 851 MBq/mmol determined by mass spectrometry 2.89 MBq/mg determined by gravimetric analysis equivalent to 814 MBq/mmol
Total activity: 370 MBq (10 mCi)
Supplier: GE Healthcare UK Limited, Amersham Place Little Chalfont, Buckinghamshire HP7 9NA UK

Non-radiolabelled test substance:
Identification: Chloramine T trihydrate
Molecular formula: CH3C6H4S02NCINa.3H20
Molecular weight: 281.69
CAS Number: 7080-50-4
Description: White crystalline powder
Batch: 08616KD
Purity: 99.8% (with sodium thiosulfate)
Test substance storage: At room temperature in the dark under nitrogen
Stability under storage conditions: Stable

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
ADME and TK groups (1-6) : Rat: Wistar, Crl:WI (outbred, SPF quality).Bile-cannulation group (7) : Rat: Wistar HsdCpb : WU.
- Source: ADME and TK groups (1-6) : Charles River Deutschland, Sulzfeld, Germany. Bile-cannulation group (7) : Harlan, Horst, The Netherlands
- Age at study initiation: Young adult animals of 10-12 weeks old were used.
- Weight at study initiation: body weights ≥ 179 gram
- Fasting period before study: No
- Housing:
ADME and TK groups (1-6):
Upon receipt from the supplier animals were group-housed in Macrolon cages (type MIV, height 18 cm) containing sterilized sawdust bedding (Woody-Clean type 314; Tecnilab-BMI BV, Someren, The Netherlands). Certificates of analysis were examined and then retained in the NOTOX archives. In
addition, paper was provided as nest material (Enviro-dri, Tecnilab-BMI BV, Someren, The Netherlands). Animals of groups 3 and 6 remained housed in these cages during the pre-treatment. Following administration of the radioactive dose and 24 hours prior to dosing, rats from ADME groups (1-3) were individually housed in stainless steel metabolism cages (LxWxH = 18.5x19x20 cm). Animals of TK groups (4-6) were housed individually in
Macrolon cages (LxWxH: 30x1 9x1 9 cm), equipped with a bottom grid and paper bedding. Surplus animals were kept in the Macrolon cages.
Bile-cannulation group (7):
Upon receipt from the IMTC animals were individually housed in Macrolon plastic cages (type Mlll height 15 cm) containing sterilized sawdust bedding (Woody-Clean type 314; Tecnilab-BMI BV, Someren, The Netherlands) and tissues. Certificates of analysis of the bedding were examined for contaminants and archived. After the acclimatization period, animals were individually housed in stainless steel metabolism cages (LxWxH = 18.5x19x20 cm). Two surplus animals were kept in the Macrolon cages.
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): ad libitum access to pelleted rodent diet (SM RIM-Z from SSNIFFB Spezialdiaten GmbH, Soest, Germany)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: At least 5 days under laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.0-22.0
- Humidity (%): 45-90
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES:
Grow 1
Start of administration: 18 July 2006
Termination: 21 July 2006

Group 2
Start of administration: 24 July 2006
Termination: 27 July 2006

Group 3
Start of administration "cold": 21 July 2006
Start of administration C14: 31 July 2006
Termination: 03 August 2006

Group 4
Start of administration: 18 July 2006
Blood sampling for toxicokinetics: 18, 19, 20 and 21 July 2006
Termination: 21 July 2006

Group 5
Start of administration: 24 July 2006
Blood sampling for toxicokinetics: 24, 25, 26 and 27 July
Termination: 27 July 2006

Group 6
Start of administration "cold": 21 July 2006
Start of administration C14: 31 July 2006
Blood sampling for toxicokinetics: 31 July, 01, 02 and 03 August 2006
Termination: 03 August 2006

Group 7
Administration: 28 August 2006
Termination: 30 and 31 August 2006

Experimental completion date: 30 and 31 August 2006

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
A weighed amount of unlabeled Chloramine T was placed into an empty glass container. A measured amount of a stock solution of labelled Chloramine T in Milli-Q water and additional Milli-Q water was added to obtain the desired concentration and specific activity. All radiolabelled solutions were prepared immediately prior to dosing and stored at ambient temperature, for a maximum of 4 hours. Before and during the treatment procedure the
treatment solutions were kept on a magnetic stirring device.

The unlabelled Chloramine T formulation used for pre-treatment was prepared immediately prior to dosing and stored at ambient temperature for a maximum of 4 hours.


VEHICLE
Milli-Q water for the labelled formulations.

Milli-U water for the non-labelled Chloramine T formulation (used for the 10 days pre-dosing of group 3 and 6 animals).
- Justification for use and choice of vehicle (if other than water): not applicable
- Concentration in vehicle: Stock solutions of [ring-U-14C]Chloramine T were prepared in Milli-Q water. Four dosing formulations were prepared with the following nominal concentration and specific activity:
Group 1 and 4: 4 mg/ml with a specific activity of 0.5 MBq/mg
Group 2 and 5: 40 mg/ml with a specific activity of 0.05 MBq/mg
Group 3 and 6: 4 mg/ml with a specific activity of 0.5 MBq/mg
Group 7: 4 mg/ml with a specific activity of 0.3 MBq/mg
- Amount of vehicle (if gavage): 5ml/Kg
- Lot/batch no. (if required): not applicable
- Purity: not applicable


HOMOGENEITY AND STABILITY OF TEST MATERIAL:
Before and after dose administration, the homogeneity and radioactivity concentration of each formulation was verified by radioanalysis. For this purpose, weighed aliquots of 25 µl were taken from the top, middle and bottom of the mixture and analyzed by liquid scintillation counting (LSC) using Ultima Gold (Packard) scintillation cocktail.

Duration and frequency of treatment / exposure:

Single dose for groups 1, 2, 4, 5 and 7. In the case of groups 3 and 6, a single oral dose of labelled Chloramine T was administered following pre-treatment with non-labelled Chloramine T for 10 days.

Doses / concentrations

Remarks:

Doses / Concentrations:
ADME and TK groups:
Groups 1 and 4: low-dose of 20 mg/kg bw.
Groups 2 and 5: high-dose of 200 mg/kg bw.
Groups 3 and 6: low-dose of 20 mg/kg bw.
Each oral dose of [ring-U-14C]Chloramine T contained approximately 10 MBq/kg bw of radioactivity.
Bile-cannulation group 7: a single low-dose of 20 mg/kg bw, containing approximately 6 MBq/kg bw of radioactivity.

No. of animals per sex per dose / concentration:

4/sex/dose level (ADME groups: 1-3)
3/sex/dose level (TK groups: 4-6)
4/sex/dose level (bile-cannulation group: 7)

Control animals:

no

Details on study design:

- Dose selection rationale:
Dose levels were chosen based on available acute toxicity data and a 90-d dietary study in rats. The LD50 of a 10% solution of Chloramine T was 935 mg/kg bw. The effect level in the 90-d study was > 150 mg/kg bw/day and the NOAEL was 15 mg/kg bw/day (studies avaialble at that time from 1971). Based on this, the low-dose level in the ADME study was chosen as 20 mg/kg bw and the high-dose level as 200 mg/kg bw. Furthermore, the dose levels were a factor 10 apart, which allowed the investigation of differences in the ADME patterns and bioavailability as a function of dose level.
- Rationale for animal assignment (if not random): random

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled : urine, faeces, blood, plasma, serum, cage washes, bile, bone, Heart, Lung, Spleen, Gonads (testes, seminal vesicles, prostate, uterus, ovaries: all collected separately), Abdominal fat, Muscle, Adrenals, Thymus, Thyroid, Liver, Kidney, Brain, Bone
GI tract (including contents), Skin (shaved), Residual carcass
- Time and frequency of sampling:
For the animals in ADME and bile-cannulation groups (1-3 and 7) bile (group 7 only), urine and faeces were collected over the following time intervals: 0-8, 8-24, 24-48 and 48-72 hours after the dosing with [ring-U-14C]Chloramine T. Urine, bile and faeces were freeze-trapped to avoid atmospheric oxidation, evaporation and bacterial degradation. Urine, bile and faeces samples were stored at ≤ 75°C prior to analysis. At termination, the interior of the metabolism cages was rinsed with methanol/water (50/50). The cage rinse was weighed and stored at 5 -10°C until analyzed. Based on the results of pilot study 462105 (non-GLP), volatiles were not sampled.
For the animals in TK groups (4-6), blood samples from the tail vein of each rat were sampled at the following time-points after dose administration:
15, 30 min, 1 , 2, 4, 8, 24, 48 and 72 hours (max. deviation 1 minute). The amount of sample collected was approximately 300 µl per sampling event. At approximately half an hour prior to blood sampling the animals of groups 4, 5 and 6 were transferred to an incubator set at 40°C where they remained until the time of blood sampling. At the times of blood sampling, the rats were maintained in restrainers. At other times they were housed individually in Macrolon cages and allowed food and water ad libitum. After the final blood sample was obtained, the animals were euthanized by a C02/02 procedure and the carcasses disposed of as radioactive waste. Sampled blood was transferred into tubes containing Liheparin and centrifuged to obtain the plasma which was stored at ≤ -75°C prior to analysis.
At the designated time of euthanasia each animal in ADME groups (1-3) was deeply anaesthetised using isoflurane vapour. The thorax and abdomen were opened with a midline incision. By means of an aorta punction the maximum possible amount of blood was withdrawn, causing the animals to be exsanguinated. Care was taken to avoid contamination of other organs with blood. Sampled blood was transferred into tared tubes containing Li-heparin and weighed. A weighed subsample of approximately 1 ml of the heparinised blood was removed for total 14C analysis. The remaining blood was centrifuged to obtain the plasma which was weighed and stored at ≤ -75°C. The organs listed above were harvested.
Samples from muscle and bone were collected from the left hind leg. The weight of each tissue and blood sample were recorded at the time it was harvested. Tissues and carcass were stored at ≤ -10°C prior to analysis.
At the designated time of euthanasia all animals of bile-cannulation group 7 were euthanized using an oxygen/carbon dioxide procedure. The carcass and GI tract (including contents) were stored at ≤ -10°C prior to analysis.
- Other: None


METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces
- Time and frequency of sampling:
Urine:
ADME Groups (1 -3): 0-8 and 8-24 h
Faeces:
ADME Groups (1-3): 8-24 h
- From how many animals: the samples were pooled in order to obtain one urine and faeces sample per group per sex. That is 4 animals per group per sex
- Method type(s) for identification: LC-RAD-PDA-MS and NMR
- Limits of detection and quantification: see: additional information on materials and methods
- Other: None

Statistics:

Mass balance:
The mean and standard deviation was used to characterize the data, where appropriate (i.e. radioactivity measurement, concentration, etc). Concentrations of radioactivity in blood, plasma and tissues were calculated as mg equivalents of Chloramine T /kg of sample, based on the specific activity of the [ring-U-14C]Chloramine T formulation. The total amounts of radioactivity in tissue and excreta samples were calculated as a percentage of the administered radioactivity by the following formula:
Amount excreted (% of administered dose) = (radioactivity matrix (Bq/total matrix)/dose (Bq/animal))* 100%
and a 14C mass balance were presented. A mean recovery of I00 ± 10% of the administered radioactive dose was achieved. For ADME groups (1-3) and the bile-cannulation group (7): Cumulative amounts (expressed as percentage of the dose) excreted in urine, bile and faeces were calculated by summation of the amounts excreted in the individual urine, bile and faeces samples per collection period, respectively.
The oral absorption was calculated by summing the amounts of radioactivity in urine, bile (group 7), cage-wash and tissues and organs.

Kinetic calculations:
Concentrations of radioactivity in plasma were calculated as mg equivalents of Chloramine T /kg of sample, based on the specific activity of the [ring-U-14C]Chloramine T formulation. For each group, all toxicokinetic parameters were calculated from the curves constructed from the mean values at each time point using the WinNonlin 4.0.1 program. Non-compartmental analysis was applied.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

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. No significant differences were noted in absorption between low and high dosing and single and repeated dosing. The absorption in the bile-cannulation group was lower than in the ADME groups, 75% in both sexes. Urinary excretion of radioactivity in the bile-cannulated animals was about 11 to 23% lower than in the ADME groups and excretion in the faeces was about 7 to 15% higher. The reason for this is unclear: animals in the bile-cannulation group showed more clinical signs and can perhaps be viewed as in worse condition than the other animals, possible influencing absorption. Another explanation can be that the absence of bile influences the absorption of the compound. No sex-differences were noted in oral absorption in any of the groups.

Details on distribution in tissues:

The average total remaining radioactivity in blood, carcass plus tissues in the ADME groups was between 0.6 and 1.4% of the administered dose in all groups. The major part of it was present in carcass, i.e. between 0.4 and 1.1 % of the administered dose in all groups. In the bile cannulation group, the average total remaining radioactivity in carcass and GI tract was less than 1 % of the administered dose.
The residual concentrations of Chloramine T equivalents in group 1 and 3 were in the same
range; concentrations in group 2 (high dose group) were approximately one order of magnitude
higher than in the low dose groups.
The tissue concentration equivalents of Chloramine T were below the concentration observed in blood in all groups. Highest concentrations in tissueslorgans were observed in liver and kidney, which is indicative of the extensive metabolism and excretion of the substance. This indicates that Chloramine T shows no potential for accumulation.

Details on excretion:

Excretion via urine is an important route of elimination for Chloramine T, after oral absorption. 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. The rate of excretion was similar for all ADME groups with the bulk of radioactivity excreted during the first 8h. The excretion rate of radioactivity in the urine in the bile-cannulation group was slightly lower than in the ADME groups in the first time intervals.

Excretion via faeces was a minor route of excretion for Chloramine T equivalents. 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. The excretion of radioactivity in faeces was delayed compared to urine, with significant excretion not until after 8 h post-dose. The highest amount of radioactivity was excreted in the
8-24 h interval.

Excretion via the bile is only a minor route of excretion for for Chloramine T equivalents, after oral absorption. Biliary excretion accounted for 6% of the administered dose in males and 4% in females. Excretion took place mainly in the first interval, from 0-8 hours after dosing.

The results show that 95-101% of the administered dose was excreted during the study period (mean values). Excretion was quick and almost complete within 24h post-dose.

Toxicokinetic parameters

Toxicokinetic parameters:

other: see table below: remarks on results including tables and figures

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

LC-RAD-PDA-MS metabolite analysis
An overview of the data obtained in the metabolite identification part of this study indicated that a wide variety of compounds have been found that may be metabolites of p-TSA, which is formed from the chemically instable Chloramine T. Most of these compounds could not be identified.
In the urine samples, one major radioactivity peak was observed. Despite analysis in negative and positive modes no identification of potential metabolites was possible. Despite the large numbers of potential metabolites that were found with LC-MS analysis in the faeces extracts of the Wistar rats, only two potential metabolites were identified, i.e. p-sulfonicbenzoic acid and an aromatic methoxy compound. In the radioactivity chromatograms 3 major peaks were observed. None of the identified metabolites did correspond to these peaks.

NMR metabolite analysis
The urine of group 2 males was used for analysis. The unknown metabolite, representing approx. 80% of the radioactivity in the chromatogram, was isolated by prep HPLC. Analysis of 1H and 13C NMR indicated that the isolated metabolite was a para-substituted benzene with COOH and SO2NH2 substituents, and identified as 4-Sulfamoyl benzoic acid. In addition, mass spectrometric analysis was carried out which was consistent with the molecule being 4-Sulfamoyl benzoic acid.

Any other information on results incl. tables

Dose verification: The radioactive dose administered to each animal was calculated from the weight of the dose administered and the mean radioactive concentration of the formulations. Animals in ADME and TK groups (1,-6) received average effective radioactive doses ranging between 10.2 and 11.1 MBq/kg bw. Animals in the bile-cannulation group (7) received an average effective radioactive dose of 6.3 MBq/kg bw. Animals in the low-dose groups received an average dose of Chloramine T between 20.1 and 20.6 mg/kg bw. Animals in the high-dose groups received an average dose of Chloramine T between 190.8 and 205.4 mg/kg bw. All the doses were sufficiently close to the target doses in order to fulfill the study's objectives. Toxicokinetic parameters

		group 4 20 mg/kg bw single oral dose		group 5200 mg/kg bw single oral dose		group 620 mg/kg bw repeated oral dose
parameters		m	f	m	f	m	f
Tmax	hr	0.5	0.5	1	1	0.25	0.25
Cmax	mg/kg	11.9	11.3	69.6	101	15.7	18.7
Dose-norm  Cmax	mg/kg/mg*kg	0.595	0.565	0.347	0.505	0.785	0.935
AUClast	hr*mg/kg	70.0	53.3	843	680	101	90.8
Dose-norm AUClast	hr*kg*mg/kg/mg	3.50	2.67	4.22	3.40	5.05	4.54
AUC∞	hr*mg/kg	97.8*	59.9*	1345*	730*	229*	112*
Dose-norm  AUC∞	hr*kg*mg/kg/mg	4.89*	3.00*	6.73*	3.65*	11.5*	5.61*
% extrapolated	%	28.5	11.0	37.4	6.8	56.1	19.1
λz	1/hr	0.012	0.027*	0.008*	0.053*	0.006	0.020
t1/2	hr	60.5	26.1*	82.7*	13.2*	120	35.4
no. points		3	4	3	7	3	4
Corr coef.	r2	0.9615	0.8746	0.8535	0.6724	0.9795	0.9649

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
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.

Executive summary:

Method

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.

RESULTS

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.

CONCLUSIONS

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.