Sodium cumenesulphonate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

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

Objective of study:

distribution

excretion

toxicokinetics

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

Specific details on test material used for the study:

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

Radiolabelling:

yes

Species:

dog

Strain:

Beagle

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

water

Duration and frequency of treatment / exposure:

Single administration

Dose / conc.:

17.4 mg/kg bw/day (nominal)

No. of animals per sex per dose / concentration:

1/sex/dose

Control animals:

not specified

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.

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.

Key result

Toxicokinetic parameters:

half-life 1st: 75 minutes

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.

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

 

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.

Reference 2

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

Objective of study:

distribution

excretion

toxicokinetics

Qualifier:

no guideline followed

Principles of method if other than guideline:

Rats of the Sprague-Dawley strain (Charles River CD) 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 1 hour, 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. Rat carcasses were ground in a meat grinder, and about 100 mg of the well-mixed sample was treated with 2 ml of NCS solubilizer. Similarly, a 0.4 -ml sample of plasma was dissolved in 2 ml of NCS solubilizer.
Both the tissue and plasma samples were counted with 15 ml of toluene scintillation fluid, which contained, per liter of toluene, 5 g of 2,5-diphenyloxazole and 300 mg of 1,4-bis-2(4-methyl-5-phenyloxazolyl) benzene.
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 minutes 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

Specific details on test material used for the study:

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

Radiolabelling:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

water

Duration and frequency of treatment / exposure:

Single administration

Dose / conc.:

34.8 mg/kg bw/day (nominal)

Remarks:

Single dose.

No. of animals per sex per dose / concentration:

Males: 2/doseFemales: 2/dose

Control animals:

not specified

Type:

excretion

Results:

Excretion of the unchanged parent substance: urine 82% of which 80% was excreted within the first 24 hours; Feces 13% of which the first 11.7% was excreted within the first 24 hours.

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 primary excretory pathway is urinary with 82 to 85% of the dose being elimited via this route.

Key result

Toxicokinetic parameters:

half-life 1st: 75 minutes

Metabolites identified:

no

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.

The excretion of radioactivity by rats with sodium p-toluenesulfonate-35S 34.8 mg/kg is shown in Table1.

 

Table1. Average excretion of sodium p-tolueneslfonate-35S, its metabolites, or both in the urine and feces of rats.

 

___________________________________________________________________

 

                    Average % of dose +/- SE

Time             --------------------------------------

(days)        Urine        Feces           Total

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

1           80.8+/-4.2   11.7+/-5.4     92.5+/-1.7

2          1.04+/-0.38  1.26+/-0.76    2.30+/-1.13

3         0.085+/-0.029 0.023+/-0.015   0.108+/-0.04

4         0.050+/-0.021 0.013+/-0.006   0.063+/-0.02

Cage rinse 0.014+/-0.011      -         0.014+/-0.011

   _____________________________________________________________

               82.0         13.0            95.0

______________________________________________________________________

 

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

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

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 Sprage Dawley rats (2 animals/sex/dose) by oral gavage at a dose level of 34.8 mg/kg bw (single administration). Urine and feces were collected daily for 4 days. The substance was excreted unchanged primarily in the urine.

Reference 3

Endpoint:

dermal absorption

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

QSAR prediction: US EPA accepted QSAR method for organic chemicals properties assessment.

Qualifier:

no guideline required

Principles of method if other than guideline:

Using the DERMWIN v2.01 QSAR model

GLP compliance:

no

Remarks:

not applicable to QSAR models

Radiolabelling:

no

Species:

other: QSAR model,

Strain:

other: QSAR model,

Sex:

not specified

Type of coverage:

other: QSAR model

Vehicle:

other: QSAR model

Duration of exposure:

not applicable to QSAR models

Doses:

not applicable to QSAR models

No. of animals per group:

not applicable to QSAR models

Control animals:

no

Details on study design:

not applicable to QSAR models

Details on in vitro test system (if applicable):

not applicable to QSAR models

Signs and symptoms of toxicity:

not specified

Dermal irritation:

not specified

Absorption in different matrices:

A QSAR model predicts that the permeability of Sodium cumenesulphonate to human skin is quite low. The permeability coefficient was determined to be 0.0165 mg/cm2, which is around 1% of the skin penetration rate.Predicted dermally absorbed coefficient was determined to be Kp (est)= 8.99e-006 cm/hr.

A QSAR model predicts that the permeability of Sodium cumenesulphonate to human skin is quite low. The permeability coefficient was determined to be  0.0165 mg/cm2, which is around 1% of the skin penetration rate.Predicted dermally absorbed coefficient was determined to be Kp (est)= 8.99e-006  cm/hr.

Conclusions:

A QSAR model predicts that the permeability of Sodium cumenesulphonate to human skin is quite low. The permeability coefficient was determined to be 0.0165 mg/cm2, which is around 1% of the skin penetration rate.Predicted dermally absorbed coefficient was determined to be Kp (est)= 8.99e-006 cm/hr.

Executive summary:

A QSAR model predicts that the permeability of Sodium cumenesulphonate to human skin is quite low. The permeability coefficient was determined to be  0.0165 mg/cm2, which is around 1% of the skin penetration rate.Predicted dermally absorbed coefficient was determined to be Kp (est)= 8.99e-006  cm/hr.

Reference 4

Endpoint:

dermal absorption in vivo

Type of information:

other: published data

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

Radiolabelled test substance (3 mM solution) was applied to the shaved skin of female rats. The exposure lasted 15 min, after which is was rinsed off. After a 24 hr observation period during feces, urine, and expired air was collected, the animals were sacrificed and the excised skin was examined by autoradiography

GLP compliance:

not specified

Radiolabelling:

yes

Species:

rat

Strain:

other: Colworth-Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 100-120 g
- Housing: sealed metabolism cages
- Individual metabolism cages: yes

ENVIRONMENTAL CONDITIONS
- Air changes (per hr): 1.5 L/min

Type of coverage:

open

Vehicle:

other: Two test solutions were made: water, and 25% polyethylene glycol 400 in water.

Duration of exposure:

15 min

Doses:

- Nominal doses: 3 mM solution
- Dose volume: 0.2 ml

No. of animals per group:

no data

Control animals:

no

Details on study design:

DOSE PREPARATION
- Method for preparation of dose suspensions: The test substance was added to the vehicle and homogenized and equilibrated at 40 degrees C for 24 hrs. The pH was then adjusted to 9.5 by adding 0.01 n NaOH or HCl.

TEST SITE
- Preparation of test site: 24 hrs before application, hair was removed with clippers. Only animals with intact skin were used.
- Area of exposure: 7.5 cm^2

SITE PROTECTION / USE OF RESTRAINERS FOR PREVENTING INGESTION: yes: Animals were anesthetized during exposure. During the 24 hr observation period the animals were fitted with restraining collars or non-occlusive patches. Non-occlusive patches were made of three layers of surgical gauze 1 cm larger in each dimension than the exposure area. Over this, a stainless steel 100 mesh gauze was placed and secured with surgical strapping with holes punctured in it.

SAMPLE COLLECTION
- Collection of urine and faeces: for 24 hrs after exposure
- Collection of expired air: for 24 hrs after exposure

SAMPLE PREPARATION
- Preparation details: feces were freezed dried, carcasses were homogenized in a blender and then freeze dried

ANALYSIS
- Method type(s) for identification: Liquid scintillation counting, excised skin was examined by autoradiography

Signs and symptoms of toxicity:

not specified

Dermal irritation:

not specified

Absorption in different matrices:

- Non-occlusive cover: < 2 micrograms
- Skin wash: 135 +/- 27 micrograms
- Skin test site: Heavy deposition was seen on the skin surface, and in the upper hair follicles, 11+/-4 micrograms
- Urine: none
- Faeces: none

Dose:

250 micrograms

Parameter:

percentage

Absorption:

< 0.3 %

Remarks on result:

other: 24 hrs after exposure

The amount of test substance that penetrated the skin was below the detection limit of 0.1 micrograms/cm2 or less than 0.3% of the initial dose.

Conclusions:

The in vivo penetration through rat skin after a 15 min exposure was < 0.3%.

Executive summary:

Radiolabelled test substance (3 mM solution) was applied to the shaved skin of female rats. The exposure lasted 15 min, after which is was rinsed off. After a 24 hr observation period during feces, urine, and expired air was collected, the animals were sacrificed and the excised skin was examined by autoradiography. Results show that the test substance, which is of low solubility, did not penetrate through the skin to any significant degree. The amount of test substance penetrating the skin was below the detection limit. The penetration through rat skin was < 0.3%.

Description of key information

The studies on absorption, distribution, metabolism and elimination for Sodium p-toluenesulfonate-35S were identified as read across for sodium cumenesulphonate.

 

Sodium p-toluenesulfonate-35S was rapidly absorbed and excreted by rats and dogs given an oral or intraperitoneal administration. Both species excreted the radioactivity primarily in the urine (82–85 % of the dose) and, to a lesser extent, in the feces (13–18 % of the dose). In dogs, sodium p-toluenesulfonate-35S had a biological half-life in the plasma of 75 min. Only the unaltered p-toluenesulfonate-35S moiety was detected chromatographically in the excreta of both species.

A QSAR model predicts that the permeability of Sodium cumenesulphonate to human skin is quite low. The permeability coefficient was determined to be  0.0165 mg/cm2, which is around 1% of the skin penetration rate.Predicted dermally absorbed coefficient was determined to be Kp (est)= 8.99e-006  cm/hr.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - dermal (%):

1