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Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is similar to OECD Test Guidelines with acceptable deviations. However as this study is used in the context of a read across, Klimisch 2 is assigned.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
(1) Only focused on plasma and tissue distribution; (2) Non-standard route of exposure.
GLP compliance:
no
Radiolabelling:
yes
Remarks:
[14C]
Species:
monkey
Strain:
other: Macacca mulatta
Sex:
male/female
Details on test animals and environmental conditions:
- Body weight: approx. 5 kg
Route of administration:
subcutaneous
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.
- Each animal received seven consecutive daily subcutaneous doses of [14C] LAS (1 mg/kg/day, about 24 uCi/day) in water (3 mL).
Duration and frequency of treatment / exposure:
Single daily doses for 7 consecutive days
Remarks:
Doses / Concentrations:
1 mg/kg
No. of animals per sex per dose:
Two/sex/dose/timepoint
Control animals:
no
Positive control:
no
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: plasma, liver, kidneys, brain, spinal cord, pituitary, thyroid, eyes, lungs, gonads, heart, adrenals, pancreas, spleen, stomach, small and large intestine, omentum, mesentery, and samples of adipose tissue and muscle
- Time and frequency of sampling: Blood samples were withdrawn at predose and at 0.5, 1, 2, 4, 6 and 7.5 h after the first dose and immediately before administration of the following 6 doses. After the 7th and last dose, blood samples were taken at different times until sacrifice for the measurement of plasma concentrations. Single animals were sacrificed at 2, 4, 24 and 48 hr and tissues were taken.
Statistics:
N/A
Preliminary studies:
N/A
Type:
absorption
Results:
After the first seven consecutive daily 1 mg/kg subcutaneous doses, dose concentrations of radioactivity reached a maximum mean concentration of 1.13 ug/mL at 2 hrs.
Type:
distribution
Results:
Concentrations were generally highest at 2 h when they were greatest in the intestinal tract, kidneys, lungs, spleen, thyroid ,and pituitary.
Details on absorption:
After the first seven consecutive daily 1 mg/kg subcutaneous doses, dose concentrations of radioactivity reached a maximum mean concentration of 1.13 ug/mL at 2 hrs. These levels declined to 0.28 ug/mL with a mean half-life of about 10 hrs. The mean predose levels on the succeeding 6 days increased gradually to 0.71 ug/mL before the final dose. After the seventh and final dose, mean plasma concentrations reached a peak of 1.1 ug/mL at 4 hrs and declined until 24 hrs with a mean half-life of about 13 h. Concentrations in the male and female sacrificed at 24 and 48 hrs, respectively, after the last dose were 0.49 and 0.47 ug/mL.
Details on distribution in tissues:
- Concentrations were generally highest at 2 h when they were greatest in the intestinal tract (2.41 ug/g), kidneys (1.83 ug/g), lungs (2.45 ug/g), spleen (2.43 ug/g), thyroid (1.24 ug/g) and pituitary (1.00 ug/g).
- Concentrations in most tissues were generally lower at 4 h except in the liver (1.74 ug/g) and kidneys (1.92 ug/g), organs associated with biotransformation and excretion.
- The relatively high concentrations of radioactivity in the gastrointestinal tract probably indicates the presence of material eliminated in the bile.
- At 24 h, concentrations had declined in most tissues, but were highest in the liver (0.39 ug/g), kidneys (0.29 ug/g), lungs (0.27 ug/g) and adrenals (0.41 ug/g), although lower than those in plasma (0.49 ug/g).
- In the animal sacrificed at 48 h, the plasma concentration (0.47 ug/g) was similar to that in the animal sacrificed at 24 h and correspondingly the tissue concentrations were also similar, being highest in the liver (0.41 ug/g), kidneys (0.22 ug/g), lungs (0.23 ug/g) and adrenals (0.53 ug/g).
- Apart from the gastrointestinal tract, tissue concentrations of radioactivity were similar to or lower than the corresponding plasma concentrations at all times indicating that there was no specific accumulation or localization of LAS and/or its metabolites in these tissues.
Details on excretion:
N/A
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: Mean half-life of about 10 hrs after the first seven consecutive daily 1 mg/kg subcutaneous doses
Test no.:
#1
Toxicokinetic parameters:
Cmax: After the first seven consecutive daily 1 mg/kg subcutaneous doses, dose concentrations of radioactivity reached a maximum mean concentration of 1.13 ug/mL at 2 hrs
Metabolites identified:
no
Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
During seven consecutive daily subcutaneous doses, there was no accumulation of radioactivity from [14C]LAS in plasma. Mean peak concentrations and biological half-lives were similar after the first and seventh doses. After 7 doses, there was no localization of radioactivity in any tissue.
Executive summary:

During seven consecutive daily subcutaneous doses, there was no accumulation of radioactivity from [14C]LAS in plasma. Mean peak concentrations and biological half-lives were similar after the first and seventh doses. After 7 doses, there was no localization of radioactivity in any tissue.

Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is similar to OECD Test Guidelines with acceptable deviations. However as this study is used in the context of a read across, Klimisch 2 is assigned.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
(1) Only focused on plasma and excreta (expired air); (2) Non-standard route of exposure
GLP compliance:
no
Radiolabelling:
yes
Remarks:
[14C]
Species:
monkey
Strain:
other: Macacca mulatta
Sex:
male/female
Details on test animals 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.
Route of administration:
subcutaneous
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The solution of [14C] LAS was dilutd 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.
- For the excretion studies, single subcutaneous doses of [14C]LAS (1 mg/kg, about 16-40 uCi) were administered as a solution in water by injection into the subcutaneous tissue between the shoulder blades.
For the study of plasma levels, the same animals that were dosed with 1 mg/kg were administered subcutaneous doses of [14C] LAS at dose levels of 0.5 mg/kg (8-22 uCi) and 0.1 mg/kg (2-5 uCi) at intervals of 2-3 weeks.
Duration and frequency of treatment / exposure:
Single dose
Remarks:
Doses / Concentrations:
1 mg/kg for excretion studies, and 0.1 or 0.5 mg/kg for plasma concentration-only studies
No. of animals per sex per dose:
Two/sex/dose
Control animals:
no
Positive control:
no
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
Preliminary studies:
N/A
Type:
absorption
Results:
Plasma concentrations from animals receiving 0.1, 0.5 or 1 mg/kg were 0.16 (2 hrs), 0.72, (4 hrs) or <0.5 (30 hrs) ug/mL, respectively.
Type:
excretion
Results:
Most of the dose was excreted within 48 h. During 5 days after administration, means of 63.8% (males) and 64.3% (females) of the dose were excreted in the urine and means of 12.5% (males) and 9.2% (females) in the faeces
Details on absorption:
- Plasma concentrations of radioactivity in samples taken from animals receiving 1 mg/kg at 30, 48, 72 and 96 h were less than 0.5 ug/mL. Mean concentrations declined from 0.3 ug/mL at 30 h to 0.1 ug/mL at 9.6 h.
- Mean plasma concentrations at a nominal dose level of 0.1 mg/kg reached a maximum of 0.0298% dose/mL (0.16 ug/mL) at 2 h. These levels declined rapidly in the period 7.5-24 h with a mean half life of about 8 hrs. Mean concentrations at 24 h were 0.0052% dose/mL (0.03 ug/mL). Radioactivity could still be detected at 72 hrs at a mean concentration of 0.0019% dose/mL (0.01 ug/mL).
-After single subcutaneous doses to the same monkeys at a nominal dose level of 0.5 mg/kg, plasma concentrations of radioactivity reached a maximum mean concentration of 0.0304% dose/mL (0.72 ug/mL) at 4 hrs. These levels declined rapidly in the period 7.5-24 hrs with a mean half life of about 8.5 hrs. Mean concentrations at 24 hrs were 0.0056% dose/mL (0.15 ug/mL). Radioactivity could still be detected at 120 hrs at a mean concentration of 0.0011% dose/mL (0.03 ug/mL).
Details on distribution in tissues:
N/A
Details on excretion:
- After single subcutaneous doses of [14C]LAS to rhesus monkeys at a nominal dose level of 1 mg/kg, most of the dose was excreted within 48 h. During 5 days after administration, means of 63.8% (males) and 64.3% (females) of the dose were excreted in the urine (55.1% and 50.3%, respectively, during the first 24 h) and means of 12.5% (males) and 9.2% (females) in the faeces (4.9% and 1.6%, respectively, during the first 24 h).
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: A mean half life of about 8 hrs at a nominal dose level of 0.1 mg/kg
Test no.:
#1
Toxicokinetic parameters:
Cmax: 0.16 mg/mL at a nominal dose level of 0.1 mg/kg
Test no.:
#2
Toxicokinetic parameters:
half-life 2nd: A mean half life of about 8.5 hrs at a nominal dose level of 0.5 mg/kg
Test no.:
#2
Toxicokinetic parameters:
Cmax: 0.72 ug/mL (4 hrs) at a nominal concentration of 0.5 mg/kg
Metabolites identified:
no
Details on metabolites:
Radioactive components in urine:
- TLC of urine extracts after subcutaneous doses (1 mg/kg) of [14C]LAS showed that no more than trace amounts of the unchanged compound 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 subcutaneous doses.
- In some instances, some of the components were insufficiently resolved to enable their separate quantitation.
- In all of 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.
Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
After single 1 mg/kg subcutaneous doses, means of 64.1% and 10.9% were excreted in urine and faeces, respectively, during 5 days, mostly during the first 24 h. After single subcutaneous doses, peak plasma concentrations increased almost proportionately. No unchanged LAS was detected in urine samples after subcutaneous 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:

After single 1 mg/kg subcutaneous doses, means of 64.1% and 10.9% were excreted in urine and faeces, respectively, during 5 days, mostly during the first 24 h. After single subcutaneous doses, peak plasma concentrations increased almost proportionately. No unchanged LAS was detected in urine samples after subcutaneous 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.

Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is similar to OECD Test Guidelines with acceptable deviations. However as this study is used in the context of a read across, Klimisch 2 is assigned.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
(1) Only focused on plasma, urine and feces.
GLP compliance:
no
Radiolabelling:
yes
Remarks:
[14C]
Species:
monkey
Strain:
other: Macacca mulatta
Sex:
male/female
Details on test animals 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.
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:
Single dose
Remarks:
Doses / Concentrations:
30 mg/kg for excretion studies, and 150 mg/kg or 300 mg/kg for plasma concentration studies
No. of animals per sex per dose:
Two/sex/dose
Control animals:
no
Positive control:
no
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
Preliminary studies:
N/A
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
Type:
excretion
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
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 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%.
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: Mean half life of about 6.5 hrs at nominal dose level of 150 mg/kg
Test no.:
#1
Toxicokinetic parameters:
Cmax: 41.2 (4 hrs) at nominal dose level of 150 mg/kg
Test no.:
#2
Toxicokinetic parameters:
half-life 2nd: Mean half time of about 5.5 hrs at nominal dose level of 300 mg/kg
Test no.:
#2
Toxicokinetic parameters:
Cmax: 36.3 (4 hrs) at a nominal dose level of 300 mg/kg
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.
Conclusions:
Interpretation of results (migrated information): 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:

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.

Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is similar to OECD Test Guidelines with acceptable deviations. However as this study is used in the context of a read across, Klimisch 2 is assigned.
Objective of study:
absorption
distribution
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
(1) Only focused on plasma levels and tissue distribution..
GLP compliance:
no
Radiolabelling:
yes
Remarks:
[14C]
Species:
monkey
Strain:
other: Macacca mulatta
Sex:
male/female
Details on test animals and environmental conditions:
- Body weight: approx. 5 kg
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.
- Each animal received 7 consecutive daily doses of [14C]LAS (30 mg/kg/day, about 28 uCi/day) in water (6 mL).
Duration and frequency of treatment / exposure:
Single daily doses for 7 consecutive days
Remarks:
Doses / Concentrations:
30 mg/kg
No. of animals per sex per dose:
Two/sex/dose/timepoint
Control animals:
no
Positive control:
no
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: plasma, liver, kidneys, brain, spinal cord, pituitary, thyroid, eyes, lungs, gonads, heart, adrenals, pancreas, spleen, stomach, small and large intestine, omentum, mesentery, and samples of adipose tissue and muscle
- Time and frequency of sampling: Blood samples were withdrawn at predose and at 0.5, 1, 2, 4, 6 and 7.5 h after the first dose and immediately before administration of the following 6 doses. After the 7th and last dose, blood samples were taken at different times until sacrifice for the measurement of plasma concentrations. Single animals were sacrificed at 2, 4, 24 and 48 h and tissues were taken.
Statistics:
N/A
Preliminary studies:
N/A
Type:
absorption
Results:
After the first of 7 consecutive daily oral doses of 30 mg/kg, concentrations reached a maximum mean concentration of 33.6 ug/mL at 4-hrs.
Type:
distribution
Results:
High levels were found in the stomach at 2 h. Concentrations were also high in liver, kidneys, lungs, pancreas, and adrenals after 2 hrs.
Details on absorption:
After the first of 7 consecutive daily oral doses of 30 mg/kg, concentrations reached a maximum mean concentration of 33.6 ug/mL at 4-hrs. These levels declined to 1.8 ug/mL at 24 hrs with a mean elimination half-life of about 5 hrs. The predose concentrations for both males and females on the succeeding 5 days did not increase significantly, and at 24 hrs after the sixth dose was a mean of 2.2 ug/mL.

After the seventh and final dose, mean plasma concentrations reached a peak of 43.5 ug/mL at 4 hrs and declined until 24 hrs, with a mean half life of about 6 hrs. Concentrations in the male and female animals sacrificed at 24 and 48 hrs were 2.4 and 1.0 ug/mL, respectively.
Details on distribution in tissues:
Tissue concentrations of radioactivity in the monkeys after the last of 7 repeated oral doses (30 mg/kg/day) of [14C]LAS were high in the stomach at 2 h , which subsequently declined, although concentrations in the intestinal tract were highest in the animal sacrificed at 24 h (255 ug/g). At 2 h, concentrations were also high in liver (64.8 ug/g), kidneys (135.6 ug/g), lungs (19.8 ug/g), pancreas (17.7 ug/g), adrenals (20.6 ug/g) and pituitary (17.0 ug/g). At 4 h, concentrations in these tissues were lower but had increased in some other tissues, such as heart (12.2 ug/g), brain (2.0 ug/g), gonads (25.8 ug/g), eyes (3.9 ug/g), spleen (5.5 ug/g), thyroid (6.2 ug/g), pituitary (21.3 ug/g) and subcutaneous fat (6.2 ug/g). At 24 h, concentrations were less than 2 ug/g in all tissues except the intestinal tract (255.4 ug/g) and liver (10.5 ug/g). Concentrations in the tissues of the animal sacrificed at 48 h were generally lower. Concentrations of radioactivity in most tissues were lower than those in plasma indicating that there was no specific accumulation or localization of LAS and/or its metabolites in these tissues
Details on excretion:
N/A
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: After the seventh and final dose, mean plasma concentrations reached a peak of 43.5 ug/mL at 4 hrs and declined until 24 hrs, with a mean half life of about 6 hrs
Test no.:
#1
Toxicokinetic parameters:
Cmax: After the first of 7 consecutive daily oral doses of 30 mg/kg, concentrations reached a maximum mean concentration of 33.6 ug/mL at 4-hrs
Metabolites identified:
no
Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
During seven consecutive daily oral doses, there was no accumulation of radioactivity from [14C]LAS in plasma. Mean peak concentrations and biological half-lives were similar after the first and seventh doses. After 7 doses, there was no localization of radioactivity in any tissue.
Executive summary:

During seven consecutive daily oral doses, there was no accumulation of radioactivity from [14C]LAS in plasma. Mean peak concentrations and biological half-lives were similar after the first and seventh doses. After 7 doses, there was no localization of radioactivity in any tissue.

Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is similar to OECD Test Guidelines with acceptable deviations. However as this study is used in the context of a read across, Klimisch 2 is assigned.
Objective of study:
absorption
distribution
excretion
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
GLP compliance:
not specified
Radiolabelling:
yes
Remarks:
[35S]
Species:
guinea pig
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
N/A
Route of administration:
dermal
Vehicle:
other: white petrolatum
Details on exposure:
N/A
Duration and frequency of treatment / exposure:
Single dermal application of [35S]-LAS in white petrolatum to a 4cm2 area of the dorsal skin for 24 hours
Remarks:
Doses / Concentrations:
29mg [35S]-LAS in 0.3ml white petrolatum
No. of animals per sex per dose:
N/A
Control animals:
not specified
Positive control:
N/A
Details on study design:
N/A
Details on dosing and sampling:
N/A
Statistics:
N/A
Preliminary studies:
N/A
Type:
absorption
Results:
24 hrs after application, 0.01% of the dose was found in the blood and organs, and 0.1% in the urine
Type:
excretion
Results:
24 hrs after application, 0.1% of the dose was found in the urine
Type:
distribution
Results:
24 hrs after application, 0.01% of the dose was found in the blood and organs
Details on absorption:
24 hrs after application, 0.01% of the dose was found in the blood and organs, and 0.1% in the urine
Details on distribution in tissues:
24 hrs after application, 0.01% of the dose was found in the blood and organs.
Details on excretion:
24 hrs after application, 0.1% of the dose was found in the urine
Metabolites identified:
no
Details on metabolites:
N/A
Bioaccessibility testing results:
N/A

N/A

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
24 hrs after application, 0.01% of the dose was found in the blood and organs, and 0.1% in the urine
Executive summary:

[35S]-LAS in 0.3ml white petrolatum was applied to the dorsal skin of guinea pigs. Twenty four hours after application, 0.01% of the dose was found in the blood and organs, and 0.1% in the urine. An additional group of rats and guinea pigs were treated with the same procedure. After 24 hours, [35S] equal to 9.7ug/g and 0.4ug/g LAS was found in the rat and guinea pig livers respectively.

Endpoint:
basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is similar to OECD Test Guidelines with acceptable deviations. However as this study is used in the context of a read across, Klimisch 2 is assigned.
GLP compliance:
not specified
Radiolabelling:
yes
Remarks:
[14C]
Species:
rat
Strain:
other: Colworth-Wistar Strain
Sex:
female
Route of administration:
dermal
Vehicle:
water
Duration and frequency of treatment / exposure:
Single dose; 15 minutes
Remarks:
Doses / Concentrations:
A single dose of the [14C]-labelled DOBS was applied (0.2 mL) as a 3 mM aqueous suspension over 7.5 cm² of skin for 15 min. The applied dose
resulted in 250 µg per test site. Then the test solution was rinsed off with distilled water and the animals were fitted with either restraining collars or
non-occlusive protection patches and placed in the metabolism cages
No. of animals per sex per dose:
N/A
Control animals:
no
Preliminary studies:
N/A
Type:
absorption
Results:
Autoradiography of the skins showed heavy deposition of the surfactant on the skin surface and in the upper regions of the hair follicles.
Type:
excretion
Results:
All the tissue and excreta samples examined did not contain quantifiable amounts of 14C.
Details on absorption:
The excised skin was monitored for 14C and examined by autoradiography. Autoradiography of the skins showed heavy deposition of the
surfactanton the skin surface and in the upper regions of the hair follicles. 11± 4 µg/cm² was recovered in the excised skin of rats, 135 µg in the
rinsing and < 2 µg in the protection patches, so the total recovery was complete. All the tissue and excreta samples examined did not contain
quantifiable amounts of 14C. The penetration of the DOBS was below the limit of detection (<0.1 µg/cm²). Based on the amount applied (250 µg) and the penetration of 0.1 µg/cm², rat skin absorption would result in 0.3%.
Details on distribution in tissues:
All the tissue and excreta samples examined did not contain quantifiable amounts of 14C.
Details on excretion:
Limit of detection (LOD): 2.0, 5.0 and 10.0x 10E3 dpm for urine, faeces and expired CO2, respectively. For analysis of whole carcass a limit of
accurate measurement of 1 x 10E4 dpm is possible
Metabolites identified:
not specified
Details on metabolites:
N/A
Bioaccessibility testing results:
N/A
Executive summary:

N/A

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
24 hours
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is similar to OECD Test Guidelines with acceptable deviations. However as this study is used in the context of a read across, Klimisch 2 is assigned.
Objective of study:
absorption
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Principles of method if other than guideline:
N/A
GLP compliance:
not specified
Radiolabelling:
yes
Remarks:
[14C]
Species:
rat
Strain:
other: Colworth-Wistar
Sex:
female
Route of administration:
dermal
Vehicle:
water
Duration and frequency of treatment / exposure:
Dose volume: 0.25 mL of each test solution was applied to the rat skin (4.9 cm²). Frequency: 2, 6, 24 hours
Remarks:
Doses / Concentrations:
Dose volume: 0.25 mL of each test solution was applied to the rat skin (4.9 cm²).
No. of animals per sex per dose:
N/A
Control animals:
no
Preliminary studies:
N/A
Type:
absorption
Results:
The results show no measurable penetration (<0.1 µg/cm²) of DOBS through the rat skin up to 24 hours.
Type:
excretion
Results:
The 14C level in urine was calculated to be equivalent to a penetration of 0.26 µg/cm2 per 24 h
Details on absorption:
The results show no measurable penetration (< 0.1 μg/cm²) of DOBS through the rat skin up to 24 h after exposure.

Total recovery: - Total recovery (rat skin): 30 % [14C] DOBS was recovered in the rinsings and 70 % remained associated with the skin of rats.
- Limit of detection (LOD): 0.1 μg/cm².

Percutaneous absorption rate:
0.16 % at 2, 6, 24 hours (rat) (based on the applied amount of 0.25 mL DOBC (concentration in vehicle 1.2 mg/mL) to the rat skin of 4.9 cm² and penetration of 0.1 μg/cm² (lower limit of detection was taken as worst-case)
Details on distribution in tissues:
The results show no measurable penetration (<0.1 µg/cm²) of DOBS through the rat skin up to 24 hours. 30% [14C] DOBS was recovered in
the rinsings and 70% remained associated with the skin of rats.
Details on excretion:
N/A
Metabolites identified:
not specified
Details on metabolites:
n/a
Bioaccessibility testing results:
N/A

N/A

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
Executive summary:

N/A

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
48 hours
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is similar to OECD Test Guidelines with acceptable deviations. However as this study is used in the context of a read across, Klimisch 2 is assigned.
Objective of study:
absorption
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Principles of method if other than guideline:
N/A
GLP compliance:
no
Radiolabelling:
yes
Remarks:
[14C]
Species:
human
Strain:
other:
Sex:
not specified
Route of administration:
dermal
Vehicle:
water
Duration and frequency of treatment / exposure:
Dose volume: 0.1 mL applied to the human epidermal samples (0.78 cm²). Frequency: 2, 6, 24 and 48 hours (human)
Remarks:
Doses / Concentrations:
Dose volume: 0.1 mL was applied to the human epidermal samples (0.78 cm²).
No. of animals per sex per dose:
N/A
Control animals:
no
Preliminary studies:
N/A
Type:
absorption
Results:
DOBS did not penetrate human epidermis (<0.1 µg/cm²).
Type:
excretion
Results:
The 14C level in urine was calculated to be equivalent to a penetration of 0.26 µg/cm2 per 24 h
Details on absorption:
The results show DOBC did not penetrate through the human epidermis until 48 hours after application (< 0.1 μg/cm²). Permeability constant of 0.1 μcm/min (= 1.0E-7cm/min) was calculated for the isolated human epidermis 6 and 24 hours after skin contact.

Total recovery: - Total recovery (human epidermis): 30-50 % of [14C] DOBC retained in the human epidermis after rinsing;
- Limit of detection (LOD): 0.1 μg/cm².


Details on distribution in tissues:
The results show DOBS did not penetrate human epidermis (<0.1 µg/cm²). 30-50% of [14C] DOBS retained in the human epidermis after rinsing.
Details on excretion:
N/A
Metabolites identified:
not specified
Details on metabolites:
n/a
Bioaccessibility testing results:
N/A

N/A

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
Executive summary:

N/A

Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is similar to OECD Test Guidelines with acceptable deviations. However as this study is used in the context of a read across, Klimisch 2 is assigned.
Objective of study:
metabolism
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Principles of method if other than guideline:
N/A
GLP compliance:
no
Radiolabelling:
yes
Remarks:
[35S]
Species:
rat
Strain:
other: Charles River Strain
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Fasting period before study: 16 hours before dosing
- Housing: The animals were housed in individual cages which permitted the separate collection of urine and feces.
- Diet (e.g. ad libitum): ad libitum after dosing
- Water (e.g. ad libitum): ad libitum after dosing
Route of administration:
oral: unspecified
Duration and frequency of treatment / exposure:
- The animals were administered a single oral dose.
Remarks:
Doses / Concentrations:
N/A
No. of animals per sex per dose:
N/A
Control animals:
no
Positive control:
N/A
Details on study design:
N/A
Details on dosing and sampling:
- The urine was collected under toluene, removed daily, and refrigerated until it could be examined; the feces were removed each day and allowed to dry at room temperature.
- At the termination of each study, the animals were killed and selected organs and tissues were taken for radioassay.

Route of absorption of the two compounds:
- Determined by oral feeding of 40 mg of either surfactant to thoracic duct-cannulated rats.
- The lymph was collected from each animal in a single 42-hour fraction.

Ability of the rat to absorb these surfactants:
- Determined in bile duct-ligated rats.
- Each rat received orally 1.2 mg of either labelled compound.
- The urine and feces of each animal were collected for 90 hours after dosing.

The enterohepatic circulation of the two surfactants:
- Quantified by oral feeding of 1.2 mg of the surfactants to bile duct-cannulated rats and to rats prepared in a manner similar to Boquet and Fromageot (1952).
- In the latter experiment, a cannula was inserted into the proximal end of the bile duct of Rat A and into the distal end of the bile duct of Rat B.
- The bile from Rat A could then flow through the cannula into the bile duct, and finally into the intestine of Rat B. In addition, a second cannula was inserted into the proximal end of the bile duct of Rat B so that its bile could be collected.
- The 35S-labelled surfactants were fed orally to Rat A.
- Urine and feces of Rats A and B and bile of Rat B were collected for 90 hours after dosing.

Determination of inorganic-35S04 in the urine of rats fed LA35S:
- A measured quantity of Na2S04 (2.0 g) was added to urine which was known to contain 35S equivalent of 20 mg of LA35.
- The sulfate was then precipitated with ethanol.
- The precipitate was filtered, washed with ethanol and then redissolved in water; this procedure was repeated three times before the final product was assayed for 35S.
- None of the radioactivity was precipitated with the Na2S04.

Assay for cationic-SO3 in the urine:
- The urine was assayed for cationic-SO3 by the method recommended by the ABSM-SAC Committee (1957).

Identification of metabolic products:
- The urine from rats that were fed LAS was pooled as were the bile samples from rats that were fed ABS.
- The urine or bile was then passed through a column packed with Dowex 1 x 4 anion exchange resin in the chloride form.
- Sulfonic acid-containing compounds were then selectively removed from the resin.
- The sulfonates were then esterified using diazomethane and the esters were purified by repeated chromatography on columns packed with acid-washed Florisil.
- The sulfonate-containing compounds were removed from the feces by means of continuous extraction with methanol in a Soxhlet apparatus.
- The methanol extract was then passed through a column containing Dowex 1 x 4 and the sulfonates were separated and purified in the same manner as described for the metabolites isolated from the urine and bile.
- To quantify the amount of unchanged LAS or ABS that was present in the extract of the feces, a measured quantity of W-labeled surfactant was added to one-third of the extract.
- The latter mixture was then separated on the Dowex 1 x 4 resin, esterified, and then chromatographed on Florisil.
- The specific activity of the purified ester was then determined, and the quantity of unchanged surfactant was calculated.
- The infrared, nuclear magnetic resonance (NMR), and mass spectra of the metabolites isolated from the urine of rats that were fed LAS and from the bile of rats that were fed ABS were obtained.
- From these spectra and the spectra of authentic reference compounds, the structural features of the metabolites were deduced.
- Materials other than the unchanged surfactants isolated from the feces were not characterized, nor were the metabolites of LAS excreted in the bile.
Statistics:
N/A
Preliminary studies:
N/A
Type:
absorption
Results:
Findings indicate that both surfactants are absorbed from the gastrointestinal tract.
Type:
excretion
Results:
LAS was excreted primarily in the urine, and ABS was excreted primarily in the feces. Both LA35S and AB35S were excreted primarily in the urine, indicating that both surfactants are absorbed from the GI tract.
Details on absorption:
Absorption of Bile Duct-Ligated Rats
- Both surfactants were excreted primarily in the urine; these findings indicate that both surfactants, Linear Alkylate Sulfonate and Alkyl Benzene Sulfonate, are absorbed from the gastrointestinal tract.

Route of Absorption
- There was 1.6 % of the LA35S and 1.6 % of the AB35S detected in the lymph of the animals during the 42-hour collection period.
- Both surfactants appeared to be absorbed from the gastrointestinal tract and transported by some route other than the lymphatic system.
Details on distribution in tissues:
- At the end of 3 days, no 35S residue (< 1.0% of the dose) could be detected in the carcasses of the rats that received the 40 mg dose of either surfactant.

Enterohepatic Circulation:
- The urine appears to be the primary route for the excretion of absorbed 35S from administered LA35S, while the bile into the feces appears to be the primary route for the excretion of 35S from AB35S.
- The 35S-containing compounds from LA35S that were absorbed from the gastrointestinal tract, and nearly two-thirds of this activity was excreted in the bile. The 35S from AB35S was excreted primarily in the rat feces.
- Approximately 27 % of the 35S from the AB35S was absorbed from the intestinal tract, and it in turn was excreted primarily in the bile.
Details on excretion:
- LAS was excreted primarily in the urine, and ABS was excreted primarily in the feces.
- Both LA35S and AB35S were excreted primarily in the urine, indicating that both surfactants are absorbed from the GI tract.
- No explanation could be found for the unusually low recovery of S35 in animals fed 0.6 mg of AB35S.

Quantification of LA35S and AB35S Excreted in the Feces:
- Isotopic dilution with authentic LAS or ABS showed that, of the total dose, 19% of the LA35S and 10% of the AB35S were excreted in the feces without being metabolized.
Metabolites identified:
yes
Details on metabolites:
Chemical Nature of 35S in the Urine of Rats Fed La35S:
- The 35S in the urine was not precipitated by ethanol along with added carrier Na2SO3; in addition, it was not extracted from the urine along with the added carrier LAS when the method recommended by the ABSM-SAC (1957) for assay of cationic-SO3 was used.
- The 35S was thus assumed to be present in the urine as a metabolite of LAS.

Identification of Urinary Metabolites of LAS:
- The 35S-containing methyl esters of the components of the urine of rats that were fed LA35S were separated by column chromatography on Florisil as one major fraction.
- The metabolites were eluted with a solvent mixture containing 8 parts benzene and 1 part hexane.
- The infrared and NMR spectra were virtually identical to those obtained from methyl 4-(4’-methylsulfophenyl)pentanoate.
- The mass spectra obtained nearly equal intensities for the molecular ions and for those at m/e 213, 199, fraction; one at 286 m/e and the other at 272 m/e.
- The peaks at M-59 (227 and 213) were more intense for the isolated mixture.
- These findings suggest that the methylsulfo- phenyl moiety could be attached to the carbon atom alpha to the carboxyl group.

Identification of Biliary Metabolites of ABS:
- The methyl esters of the metabolites in the bile of rats that were fed ABS were separated into two fractions by column chromatography on Florisil.
- The esters of fraction ABS-I, representing 13% of the total 35S detected in the bile were washed from the column with a 4 to 1 (v: v) mixture of hexane and benzene.
- Fraction ABS-II contained 36 % of the total 35S detected in the bile; it was washed from the column with a 1 to 1 mixture of hexane and benzene.
- The methyl esters of ABS-I metabolites were shown by infrared and NMR spectroscopy to contain the following functional groups: methyl ester of both a carboxylic and a sulfonic acid; two double bonds, probably cis configuration with one of the double bonds alpha to an activating group; and a disubstituted benzene moiety with substitution primarily l-4.
- The mass spectrum showed that this fraction contained a mixture of homologs that had molecular weights of 394, 380, and 366.
- These weights are 4 mass units less than what would be expected for a molecule containing no double bonds other than those in the benzene moiety of the molecule.
- Since there was insufficient material available to establish firmly by chemical means the exact positions of the double bonds, spectra data alone were used.
- The peaks at m/e 307, 293, and 279 in the mass spectrum, corresponding to loss of 87 mass units from the three isomers, suggest that one of the double bonds was not in a position m-/3 to the ester group.
- The ultraviolet (peaks at 208, 211, 222, 258, 260 ,268 and 272 rnp) and NMR spectra showed peaks which suggest that at least one of the double bonds was adjacent to an activating group.
- The infrared and NMR spectra for the methyl ester of ABS-II showed peaks which would be expected for a molecule containing methyl esters of carboxylic and sulfonic acids, as well as those for a 1-4 disubstituted benzene moiety.
-The mass spectrum showed only one molecular peak and it was at m/e 370; the structure that best represents the data is ABS-II.

Table I. Distribution of LA35S in Urine and Feces After Administration of a Single Dose of Various Quantities by Stomach Tube

Quantity administered (mg)

Day

Percent of dose excreted

Urine

Feces

Total

0.6a

1

31.6

36.6

68.2

2

7.8

18.1

25.9

3

0.8

1.4

2.2

Total

40.2

56.1

96.3

1.2a

1

53.7

22.5

76.2

2

3.3

15.5

18.8

3

0.7

0.9

1.6

Total

57.7

38.9

96.6

8.0b

1

38.0

37.4

75.4

2

1.3

2.0

3.3

3

0.9

1.7

2.6

Total

40.2

41.1

81.3

40.0b

1

38.2

31.0

69.2

2

2.7

11.9

14.6

3

0.8

0.6

1.4

Total

41.7

43.5

85.2

a Average of 3 animals

b Average of 5 animals

.

Table II. Distribution of AB35S in Urine and Feces After Administration of a Single Dose of Various Quantities by Stomach Tube

Quantity administered (mg)

Day

Percent of dose excreted

Urine

Feces

Total

0.6a

1

8.7

31.6

40.3

2

0.5

17.1

17.6

3

0.3

4.0

4.3

Total

9.5

52.7

62.2

1.2a

1

7.0

40.0

47.0

2

0.6

34.5

35.1

3

0.2

4.1

4.3

Total

7.8

78.6

86.4

40.0b

1

5.0

46.2

51.2

2

1.5

28.0

29.5

3

0.3

4.8

5.1

Total

6.8

79.0

85.8

a Average of 3 animals

b Average of 5 animals

Executive summary:

N/A

Endpoint:
basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Limited information available
GLP compliance:
not specified
Radiolabelling:
yes
Remarks:
two radiolabelled LAS isomers (chain length, C12) with the benzene sulfonate moieties at the 2 and 6 positions
Species:
rat
Route of administration:
other: oral or intravenous
Remarks:
Doses / Concentrations:
1 mg per 200 g body weight
Details on study design:
Doses of 1 mg per 200 g body weight of two radiolabelled LAS isomers were administered orally and intravenously to rats; the same dose was also administered to anaesthetized rats with bile-duct cannulas by intravenous or intraduodenal injection.
Type:
excretion
Details on absorption:
Studies of absorption after intraduodenal administration showed that both isomers were extensively absorbed within 6 h
Details on excretion:
Forty-eight hours after oral or intravenous administration, there were marked differences in the disposition of the isomers in the urine and faeces: most of the radiolabel associated with the 2 isomer (75.3%) was in the urine, whereas most of that on the 6 isomer (77.9%) was present in the faeces. After intravenous administration to bile duct-cannulated rats, 88.6% of the 2 isomer was recovered in the urine, whereas 83.1% of the 6 isomer was in the bile. Studies of absorption after intraduodenal administration showed that both isomers were extensively absorbed within 6 h.
Executive summary:

Rats were exposed to doses of 1 mg/200g bw of two radiolabelled LAS isomers (chain length C12), resulting in differential excretion was observed in urine and faeces depending on the position of sulfonate moieties on the benzene ring (position 2 or 6). For either route of administration, after 48 hours around 75% of position 2 isomer was found in the urine, whereas 78% of the position 6 isomer was found in the faeces. In bile duct cannulated rats following intravenous administration, 89% of the 2 isomer was recovered in the urine whilst 83% of the 6 isomer was found in the bile.

Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is similar to OECD Test Guidelines with acceptable deviations. However as this study is used in the context of a read across, Klimisch 2 is assigned.
Objective of study:
absorption
distribution
excretion
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Principles of method if other than guideline:
N/A
GLP compliance:
not specified
Radiolabelling:
yes
Remarks:
[14C]
Species:
rat
Strain:
Wistar
Sex:
not specified
Details on test animals and environmental conditions:
N/A
Route of administration:
oral: unspecified
Vehicle:
not specified
Details on exposure:
N/A
Duration and frequency of treatment / exposure:
Single oral administration
Remarks:
Doses / Concentrations:
2mg/animal
No. of animals per sex per dose:
N/A
Control animals:
not specified
Positive control:
N/A
Details on study design:
N/A
Details on dosing and sampling:
N/A
Statistics:
N/A
Preliminary studies:
N/A
Type:
absorption
Results:
Radiolabel was detected in plasma at 0.25 hours after oral administration. Maxima was reached at 2 hours, with 0.86ug/g detected. The half life of the calcium salt was calculated to be 10.9 hours.
Type:
distribution
Results:
4 hour distribution of C-LAS and metabolites respectively (ug/g): stomach (22.56, 31.67), intestine (43.24, 27.26), bladder (34.89, 16.58), liver (2.73, 2.13), kidney (1.19, 1.35), testis (0.08, 0.11), spleen (1.63, 0.16), lung (0.49, 0.44)
Type:
excretion
Results:
Over the test period of 168 hours, 51% of the radiolabel was excreted in the feces, and 50% in the urine.
Details on absorption:
Radiolabel was detected in plasma at 0.25 hours after oral administration. Maxima was reached at 2 hours, with 0.86ug/g detected. The half life of the calcium salt was calculated to be 10.9 hours.
Details on distribution in tissues:
4 hour distribution of C-LAS and metabolites (ug/g): stomach (22.56, 31.67), intestine (43.24, 27.26), bladder (34.89, 16.58), liver (2.73, 2.13), kidney (1.19, 1.35), testis (0.08, 0.11), spleen (1.63, 0.16), lung (0.49, 0.44)
Details on excretion:
Over the test period of 168 hours, 51% of the radiolabel was excreted in the feces, and 50% in the urine.
Metabolites identified:
yes
Details on metabolites:
After oral administration of the calcium or sodium salt of 14C-LAS to rats, two metabolites were detected in urine and four in faeces by thin-layer chromatography. The two urinary and two of the faecal metabolites were believed to be compounds similar to metabolites sulfophenyl butanoic and sulfophenyl pentanoic acids.
Bioaccessibility testing results:
N/A

N/A

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
Executive summary:

Radiolabel was detected in plasma at 0.25 hours after oral administration. Maxima was reached at 2 hours, with 0.86ug/g detected. The half life of the calcium salt was calculated to be 10.9 hours. At 4 hours, the following distribution of C-LAS and metabolites was observed repsectively: stomach (22.56 and 31.67 ug/g), large intestine (43.24 and 27.26ug/g), urinary bladder (34.89 and 16.58ug/g), liver (2.73 and 2.13ug/g), kidney (1.19 and 1.35ug/g), testis (0.08 and 0.11ug/g), spleen (1.63 and 0.16ug/g), and lung (0.49 and 0.44ug/g). During the test period of 168 hours, 51% of the radiolabel was excreted in the feces and 50% in the urine.

Description of key information

The toxicokinetic profile of benzene, mono-C10-13-alkyl derivatives, distillation residues, sulfonated, sodium salt (registered substance) was not determined by actual absorption, distribution, metabolism or excretion (ADME) measurements. Instead, read across substances were used to predict toxicokinetic behavior of the registered substance. The registered substance is produced, supplied and marketed in the presence of a liquid mineral oil solvent. The primary route of exposure to the registered substance is therefore anticipated to be via the dermal, primarily in the professional/consumer use as lubricant additives. Given that the registered substance is distributed as 68-71%/26-27% in separable mixtures of registered substance/diluent oil, it is not clear what role the diluent oil contributes to the dermal absorption of the aforementioned registered substance. Whilst there exists no specific ADME studies to this registered substance, this category of substances was subject to an evaluation by the WHO (World Health Organisation) in 1996, and is covered extensively in the paper “Linear alkylbenzene sulfonates and related compounds, Environmental Health Criteria 196, Geneva. International Program on Chemical Safety. World Health Organisation.” Information on short chain alkaryl benzene sulfonates (ABS) is primarily considered within this report; however, this data is considered relevant as longer chain ABS are likely to be oxidized to shorter chain length species in vivo (reported by Michael, 1968). It is likely that the registered substance, being a longer chain ABS, will be absorbed generally to a lesser extent than shorter chain ABS.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
50

Additional information

The toxicokinetic profile of benzene, mono-C10-13-alkyl derivatives, distillation residues, sulfonated, sodium salt (registered substance) was not determined by actual absorption, distribution, metabolism or excretion (ADME) measurements. Instead, read across substances were used to predict toxicokinetic behavior of the registered substance.

Absorption, distribution metabolism and excretion

WHO (1996) reports that in experimental animals, Alkyl Benzene Sulfonates (ABS) are readily absorbed via the gastrointestinal tract. In Wistar rats following oral administration, radiolabeled calcium and sodium salts of ABS with chain length of C12 were detected in plasma after 0.25 hours, with levels reaching a maximum at 2 hours. Biological half-lives were calculated at 10.9 and 10.8 hours respectively. Excretion occurred equally via urine and feces (Sunakawa et al, 1979, as cited in WHO, 1996). A rat study of ABS isomers of similar chain length (C12) given orally or intravenously showed differential excretion in urine and feces depending on the position of sulfonate moieties on the benzene ring (position 2 or 6). For either route of administration, after 48 hours around 75% of position 2 isomer was found in the urine, whereas 78% of the position 6 isomer was found in the feces. In bile duct cannulated rats following intravenous administration, 89% of the 2 isomer was recovered in the urine whilst 83% of the 6 isomer was found in the bile (Rennison et al, 1987, as cited in WHO, 1996).

In an earlier series of rat studies of radiolabeled ABS of alkyl chain lengths C10-14, 40-58% was excreted in urine and 39-56% in feces within 72 hours of oral (gavage) administration. Orally administered radiolabeled ABS in bile duct cannulated rats showed 46% recovered in urine, 29% in feces and 25% in bile after 90 hours. Lymph levels (< 2%) in thoracic duct cannulated rats indicated little absorption of ABS via the lymphatic system (Michael, 1968).

In contrast, dermally applied ABS of chain length C10-14 are not well absorbed. Of radiolabeled ABS applied to dorsal skin of rats for 15 minutes, none was detected in urine or feces 24 hours after application. An accompanying in vitro study showed no measurable penetration of ABS through isolated human epidermis or rat skin 24 or 48 hours after application (Howes, 1975, as cited in WHO (1996). Similarly, of radiolabeled ABS applied in white petrolatum to the dorsal skin of guinea-pigs, only 0.1% was found in urine and 0.01% in blood and main organs after 24 hours (Hasegawa and Sato, 1978, as cited in WHO, 1996).

This conclusion is further endorsed by three dermal repeat dose studies (28 day) in rats using various ABS products (CAS no. 70024-69-0; 68783-96-0; 71786-47-5). These materials showed a consistently low pattern of subchronic toxicity with NOELs ranging from 500-1,000 mg/kg; NOAEL=1,000 mg/kg respectively, suggesting either low systemic toxicity or lack of appreciable dermal transfer. Corroboration for lack of systemic toxicity is partially supported by a corresponding repeat oral dose study (28 day) in rats using 115733-09-0 in which a similarly low toxicity outcome (NOAEL=150 mg/kg for females; 1,000 mg/kg for males was noted).

Three metabolism studies in rhesus monkeys by Cresswell et al. (1978) were reported in WHO (1996). After a single oral administration of radiolabeled ABS with a mean molecular weight of 349 (150 mg/kg bw), plasma concentrations peaked at 41.2 μg/mL at 4 hours. Concentrations declined during the period of 6-24 hours with a biological half-life reported to be approximately 6.5 hours. Concentrations were below the limit of detection at 48 hours.

Similar results for peak plasma levels and half-life were found following 7 consecutive daily oral doses of ABS at 30 mg/kg bw. In the monkeys, the highest concentration of radiolabeled ABS 2 hours after the last dose was found in the stomach (239 μg/g). At this time, high concentrations were found also in the intestinal tract, kidney and liver. Moderate levels were seen in the lungs, pancreas, adrenal and pituitary glands. At 24 hours, high levels seen in the intestinal tract (256 μg/g) and liver were the only levels that exceeded that of plasma. Levels in other tissues lower than plasma indicated no specific tissue-specific accumulation or localization of ABS and/or metabolites (Cresswell et al, 1978).

After 7 subcutaneous doses of radiolabeled ABS (1 mg/kg bw/day) highest levels were seen at injection sites (114 μg/g) after 2 hours. At this time, levels between 1 and 2.45 μg/g were seen in the lungs, intestinal tract, spleen, kidney, thyroid and pituitary gland. At 4 hours, tissue levels were generally lower than at 2 hours except for the intestinal tract, kidney and liver, these latter two organs associated with biotransformation and excretion. Levels in the intestinal tract were attributable to biliary excretion. At 24 hours, skin injection sites were the only tissue sites for which levels exceeded that of plasma (Cresswell et al, 1978).

A study of the excretion of single oral or subcutaneous doses of radiolabeled ABS in the rhesus monkey showed almost all but approximately 6% of the oral ABS and around 25% of the subcutaneous ABS excreted via urine or feces within 120 hours. In both instances, excretion occurred predominantly (up to 74%) via the urine (Cresswell et al, 1978).

For three additional metabolism studies identified in the open literature, a five-week oral study using 14C labeled dodecylbenzene sulfonate (DoDBS) in rats is also relevant to assess the potential ADME characteristics of ABS. In this study, 81.8% of administered DoDBS was excreted during the dosing period; 52.4 and 29.4 % in the feces and urine respectively. Low levels of DoDBS were detected in all tissues on termination of the study. A tangential study using a single i.p. injection resulted in the total elimination of 94.5% within 10 days with 84.7% being eliminated in the first 24 hours.

According to Michael (1968), the main metabolites from an orally administered radiolabeled mixture of C10-14 ABS in rats were sulfophenyl butanoic acid and sulfophenyl pentanoic acid, formed via ω-oxidation and ß-oxidation of the parent ABS molecules. From thin layer chromatography, these two molecules were also claimed to be the two metabolites found in urine and two of the four metabolites found in feces in a subsequent test of oral administration of radiolabeled calcium or sodium salts of ABS in rats (Sunakawa et al, 1979, as cited in WHO, 1996).

In rhesus monkeys, thin layer chromatography of urine samples following oral (30 mg/kg bw) or subcutaneous (1 mg/kg bw) administration of radiolabeled ABS showed 5 metabolites (unidentified) and only trace quantities of the original parent compound (Cresswell et al, 1978).

Overall, given the relatively increased hydrophobicity of the higher chain commercial ABS substances, expected low transdermal penetration based on low dermal subchronic toxicity and high levels of metabolism followed by excretion of metabolites, there is little support for significant systemic bioaccumulation of this substance within the body.