Asphalt, sulfonated, sodium salt

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

publication

Title:

Toxicology Studies of Linear Alkylbenzene Sulphonate (LAS) In Rhesus Monkeys. II. The Disposition of [14C]LAS After Oral or Subcutaneous Administration

Author:

Cresswell, D.G., Baldock, G.A., Chasseaud, L.F., and Hawkins, D.R.

Year:

1978

Bibliographic source:

Toxicology, 11:5-17

Materials and methods

Objective of study:

absorption

excretion

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

yes

Remarks:

(1) Only focused on plasma, urine and feces.

Principles of method if other than guideline:

N/A

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Benzenesulfonic acid, C10-13-alkyl derivs., sodium salts

EC Number:

270-115-0

EC Name:

Benzenesulfonic acid, C10-13-alkyl derivs., sodium salts

Cas Number:

68411-30-3

IUPAC Name:

sodium 4-undecylbenzenesulfonate

Details on test material:

- Sodium alkyl [14C] benzenesulphonate ([14C]LAS, mean mol. wt. 349), stated specific activity of 2 mCi/mmol as a 2.178% (w/v) aqueous solution
- Non-radioactive sodium LAS as a 20.5% (w/v) aqueous solution
- Supplied by the Japan Soap and Detergent Association, Tokyo
- Radiochemical purity > 99%, checked by TLC

Radiolabelling:

yes

Remarks:

[14C]

Test animals

Species:

monkey

Strain:

other: Macacca mulatta

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Body weight: approx. 5 kg
- Individual metabolism cages: During the excretion studies, animals were housed in stainless steel metabolism cages which allowed separate collection of urine and feces.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: The solution of [14C]LAS was diluted to a specific activity of 26.6 uCi/mL (4.6 mg/mL) and individual doses were weighed out and diluted with appropriate amounts of the non-radioactive LAS solution.

- Single oral doses of [14C]LAS (30 mg/kg, about 25 uCi) were administered by oral intubation as a solution in water (10-15 mL) for excretion studies. Plasma concentrations were also measured for these animals.
- For the studies focused strictly on plasma concentrations, the same animals used for excretion were administered single oral doses of [14C]LAS at dose levels of 150 mg/kg (about 26 uCi) and 300 mg/kg (about 26 uCi) at intervals of 2-3 weeks.

Duration and frequency of treatment / exposure:

One single exposure

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

30 mg/kg bw/day

Remarks:

excretion studies

Doses / concentrations 2

Dose / conc.:

150 mg/kg bw/day

Remarks:

plasma concentration studies

Doses / concentrations 3

Dose / conc.:

300 mg/kg bw/day

Remarks:

plasma concentration studies

No. of animals per sex per dose / concentration:

Two/sex/dose

Control animals:

no

Positive control reference chemical:

No

Details on study design:

N/A

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, plasma, cage wash
- Time and frequency of sampling: Urine was collected 0-8 h and 8-24 h after dose administration, and thereafter at 24-h intervals for another 4 days. The cage interiors were washed with water at 24 h intervals and the washings retained. Feces was collected at 24-h intervals for 5 days. Blood samples (3 mL) were withdrawn from the femoral vein into heparinized tubes at 30, 48, 72 and 96 h after dosing for excretion studies. Cells were separated by centrifugation and the concentrations of radioactivity measured in the plasma. For the plasma studies, blood samples (3 mL) were withdrawn before dosing and at 0.5, 1, 2, 4, 6, 7.5 and 24 h, and then at 24-h intervals after dosing until concentrations of radioactivity in plasma were below the limit of detection.

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine
- Time and frequency of sampling: Urine was collected 0-8 h and 8-24 h after dose administration, and thereafter at 24-h intervals for another 4 days.
- Method type(s) for identification: Aliquots of urine were partially purified by high performance liquid chromatography using a Waters high pressure liquid chromatography and a 10 um ODS Spherisorb silica column 250 mm x 4 mm i.d. The column was equilibrated with water at a flow rate of 1 mL/min for about 30 min. Urine (1-2 mL) was injected onto the column and eluted for 4.5 min. with water and then with methanol. Aliquots of fraction of the column eluate were measured for radioactivity. More than 95 % of the radioactivity was contained in the fraction collected during 4.5-15 min. These fractions were evaporated to dryness and the residue dissolved in methanol. Aliquots of these solutions were applied directly to the silica gel TLC plates which were developed in the solvent systems: (a) isobutyl alcohol-acetone-water- 26 % ammonia (8:7:4:1, v/v) and (b) benzene-methanol-acetone-acetic acid (14:1:1:1, v/v). In these systems, [14C] LAS chromatographed as a single radioactive component representing more than 99 % of the total radioactivity, with Rf values of 0.42 and 0.08, respectively. Radioactive components on TLC plates were detected by autoradiography using Kodak Kodirex X-ray film. Areas of silica gel containing radioactive components were removed, mixed with water (4 mL) and counted in the toluene-Triton X-100 scintillator (10 mL).

Statistics:

N/A

Results and discussion

Preliminary studies:

N/A

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Plasma concentrations of animals receiving 300, 150 or 30 mg/kg were 36.3 (4 hrs), 41.2 (4 hrs), or <2 (30 hrs) ug/mL, respectively

Main ADME results 2

Type:

excretion

Results:

At a nominal dose level of 30 mg/kg most of the dose was excreted within 24 h. Means of 68.3% (males) and 74.0% (females) of the dose were excreted in the urine and means of 25.9% (males) and 20.3% (females) in the faeces.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

- Plasma concentrations of radioactivity in samples taken from animals receiving 30 mg/kg at 30, 48, 72 and 96 hrs were less than 2 ug/mL. Mean concentrations declined from 1.5 ug/mL at 30 h, to 0.2 ug/mL at 96 h.
- After single oral doses at a nominal dose level of 150 mg/kg, plasma concentrations of radioactivity reached a maximum mean concentrations of 0.0056% dose/mL (41.2 ug/mL) at 4 hrs. Concentrations declined during the period 6-24 hrs with a mean half life of about 6.5 hrs and were below the limit of detection (<0.0001%, <1.0 ug/mL) at 48 hrs.
- After single oral dose of 300 mg/kg, mean plasma concentrations of radioactivity of 0.0024 % dose/mL (36.3 ug/mL) also reached a maximum at 4 h. These mean levels decreased to below limit of detection at 48-hrs. Plasma concentrations declined during 6-24 hrs with a mean half life of about 5.5 hrs.

Details on distribution in tissues:

N/A

Details on excretion:

Excretion of oral doses:
- After single oral doses of [14C]LAS to rhesus monkeys at a nominal dose level of 30 mg/kg, most of the dose was excreted within 24 h.
- During 5 days, means of 68.3% (males) and 74.0% (females) of the dose were excreted in the urine (66.5% and 72.1%, respectively during the first 24 h) and means of 25.9% (males) and 20.3% (females) in the faeces (14.9% and 12.7%, respectively during the first 24 h). About 5% of the dose was measured in the cage washings and cage debris, and the mean overall recovery of radioactivity was 100.3%.

Toxicokinetic parameters

Toxicokinetic parameters 1

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: Mean half life of about 6.5 hrs at nominal dose level of 150 mg/kg

Toxicokinetic parameters 2

Test no.:

#1

Toxicokinetic parameters:

Cmax: 41.2 (4 hrs) at nominal dose level of 150 mg/kg

Toxicokinetic parameters 3

Test no.:

#2

Toxicokinetic parameters:

half-life 2nd: Mean half time of about 5.5 hrs at nominal dose level of 300 mg/kg

Toxicokinetic parameters 4

Test no.:

#2

Toxicokinetic parameters:

Cmax: 36.3 (4 hrs) at a nominal dose level of 300 mg/kg

Metabolite characterisation studies

Metabolites identified:

no

Details on metabolites:

Radioactive components in urine:
- TLC of urine extracts after oral doses (30 mg/kg) of [14C]LAS showed that no more than trace amounts of the unchanged substance were present, and that most of the radioactivity was associated with components more polar than [14C]LAS.
- TLC, using a more polar solvent system, separated the radioactivity into 5 major components; these same components were present in urine extracts after dosing.
- In some instances, some of the components were insufficiently resolved to enable their separate quantitation.
- In all the extracts examined, 2 of the major components each represented about 30% of the total radioactivity in the sample. Incubation of urine samples with beta- glucuronidase/sulphatase showed that all of the components were unaffected by this treatment and were probably not present as the corresponding conjugates.

Any other information on results incl. tables

N/A

Applicant's summary and conclusion

Conclusions:

Interpretation of results: no bioaccumulation potential based on study results
After single 30 mg/kg oral doses the radioactivity was rapidly excreted, mostly during the first 24 h. Means of 71.2% and 23.1% of the dose were excreted in the urine and faeces, respectively, during 5 days. After single oral doses peak plasma concentrations, at 4 h in all cases, were very similar representing. No unchanged LAS was detected in urine samples after oral doses. About 5 major radioactive components were detected in urine extracts; all were apparently more polar than LAS, but were not sulphate or glucuronide conjugates.

Executive summary:

N/A