Sodium cumenesulphonate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: published data

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Data source

Reference

Reference Type:

publication

Title:

Metabolism of Sodium Tosylate-35S by Rats and Dogs

Author:

Dreyfuss, J., Shekosky, J.M., Ross, J.J. Jr.

Year:

1971

Bibliographic source:

Toxicology and Applied Pharmacology, vol. 20, p. 548-551

Materials and methods

Objective of study:

distribution

excretion

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Purebred beagles were fasted overnight before they were treated. Animals were housed in metabolism cages designed to allow the separate collection of urine and feces. Samples of feces were homogenized with 2-3 vol methanol. About 50-100 mg of homogenate was transferred to a tared scintillation vial containing 1 ml of NCS solubilizer.
The sample was shaken for at least 1hr, bleached with 30% hydrogen peroxide, and counted with 15 ml of Bray scintillation fluid. Samples of urine were counted directly in 15 ml of Bray scintillation fluid.
Blood was analyzed by digesting a 0.2-ml sample in 0.5 ml of 1.0N NaOH and heating overnight at 80 degrees C.
The sample was then bleached with 30% hydrogen peroxide, neutralized with 0.2 ml of 2 -ethylhexanoic acid, and counted with 15 ml of Bray scintillation fluid. For extraction, fecal homogenates were centrifuged; the supernatant fluid was recovered and saved.
A volume of chloroform-methanol (1:1) equal to that of the supernatant fluid recovered above was added to the fecal residue, and the mixture was shaken for 30 min and centrifuged; the supernatant fluid was recovered and saved. This last step was repeated a second time.
The supernatants were combined, and spotted directly for chromatography, or were first concentrated to a suitable volume at 40 -50 degrees C under reduced pressure.
The extraction procedure removed from the feces of rats and dogs that had been treated with sodium p-toluene sulfonate-35S an average of 81.9 and 72.6 % of the radioactivity present, respectively.
In other experiments, when sodium p-toluenesulfonate-35S was added to fecal homogenates from untreated rats and dogs, the procedure extracted 87.0 and 80.0% of the radioactivity, respectively. Radioactivity was measured with a Packard Tri-Carb liquid scintillation spectrometer, Model 3380.
Counting efficiency was determined with automatic external standardization and the use of previously prepared quench curves.
Samples of urine or of fecal extracts were spotted on plates of silica gel Q1-F2 and developed in the following solvent systems: benzene-ammonia-dioxane (35:5:60); n-butanol-100% ethanol-ammonia-Water (40:4:1:9); and 95% ethanol-1 N ammonia (95:5).

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Sodium toluene-4-sulphonate

EC Number:

211-522-5

EC Name:

Sodium toluene-4-sulphonate

Cas Number:

657-84-1

Molecular formula:

C7H8O3S.Na

IUPAC Name:

sodium 4-methylbenzene-1-sulfonate

Test material form:

solid

Details on test material:

Test substance:Purity: 94.9% (isomer ratio, p- 76.7%: o- 23.3%), Impurities: inorganic matter 4.7%

Specific details on test material used for the study:

Sodium p-toluenesulfonate-35S (specific activity: 7.0uCi/mg, radiochemical purity: 99%)

Radiolabelling:

yes

Test animals

Species:

dog

Strain:

Beagle

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Duration and frequency of treatment / exposure:

Single administration

Doses / concentrations

Dose / conc.:

17.4 mg/kg bw/day (nominal)

No. of animals per sex per dose / concentration:

1/sex/dose

Control animals:

not specified

Results and discussion

Main ADME results

Type:

excretion

Results:

Excretion of the unchanged parent substance measured: urine 84.5% of which 80.4% was excreted in the first 24 hours; feces 17.5% of which 12.2% was excreted in the first 24 hours.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The substance is rapidly absorbed given that almost 85% of the substance was excreted in the urine within 24 hours of dosing.

Details on distribution in tissues:

Not specified

Details on excretion:

The substance was excreted primarily in the urine, with 84.5% being excreted over 4 days.

Toxicokinetic parameters

Key result

Toxicokinetic parameters:

half-life 1st: 75 minutes

Metabolite characterisation studies

Metabolites identified:

not specified

Details on metabolites:

Chromatographic analysis of excreta indicated that only the unaltered tosylate-35S moeity had been excreted. In none of the three solvent systems employed was the presence of any metabolite detected.

Any other information on results incl. tables

The excretion of radioactivity by dogs with sodium p-toluenesulfonate-35S 17.4 mg/kg is shown in Table 1.

Table1. Average excretion of sodium p-toluenesulfonate-35S, its metabolites, or both in the urine and feces of dogs (oral).

==========================================================

              Average % of dose +/- SE Time   

      ------------------------------------------------

(days)       Urine         Feces          Total

----------------------------------------------------------

1        80.4+/-14.1    12.2+/-7.3     92.6+/-8.4 

2        1.93+/-0.81    1.83+/-1.02    3.77+/-1.83 

3        0.35+/-0.16    1.29+/-0.68    1.64+/-0.84 

4        0.25+/-0.12    1.41+/-0.97    1.66+/-1.04 

5        0.30+/-0.16    0.78+/-0.44    1.08+/-0.58

Pan rinse  1.30+/-0.73        -          1.30+/-0.73

          --------       ----------      ---------

          84.5           17.5            102.1

===========================================================

No difference in the amounts of radioactivity excreted was noted between dogs that had been treated with oral administration or intraperitoneal injection. In dogs, maximum levels of sodium p-toluenesulfonate-35S equivalents, 34.01 and 51.37 μg/mL, were present in the blood and plasma, respectively, within 30 min after dosing.

The half-life of the decline of drug equivalents in the plasma was 75 min during the interval of 1-6 hr.

Chromatographic analysis of excreta indicated that only the unaltered p-toluenesulfonate-35S moiety had been excreted.

This study demonstrated that dogs do not metabolize sodium p-toluenesulfonate

 

Applicant's summary and conclusion

Conclusions:

Interpretation of results : no bioaccumulation potential based on study results
The substance is rapidly absorbed following oral gavage adminstration and the substance is excreted unchanged primarily in the urine.

Executive summary:

In a metabolism study the substance was administered to beagle dogs (1 animals/sex/dose) by oral gavage at a dose level of 17.4 mg/kg bw (single administration). Urine and feces were collected daily for 4 days. The substance was excreted unchanged primarily in the urine.