Benzenesulfonic acid, di-C10-14-alkyl derivs., sodium salts

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

The study is similar to OECD Test Guidelines with acceptable deviations.

Justification for type of information:

REPORTING FORMAT FOR THE CATEGORY APPROACH
1. HYPOTHESIS FOR THE CATEGORY APPROACH
The read across follows Scenario 5 - Qualitatively and quantitatively similar effects are caused by a common compound, which is formed from all category members (as described in the 2017 Read-Across Assessment Framework document).
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
TARGET: Benzenesulfonic acid, di-C10-14-alkyl derivs., sodium salts
SOURCE: Sodium 4-undecylbenzenesulfonate
3. CATEGORY APPROACH JUSTIFICATION

Linear and non-linear or branched alkylbenzene sulfonates are anionic surfactants with molecules characterized by a hydrophobic (apolar) and a hydrophilic (polar) group. As a group of chemicals, they are generally mixtures of closely related isomers and homologues. Each molecule contains an aromatic ring sulfonated at the para position and attached to either a linear or a branched alkyl chain at any position except the terminal carbons. The sulfonate group is a common functional group present in each of the category members, and is expected to exhibit similar biological activities with little influence from the length of carbon chain. The cation components of the chemicals (e.g. calcium, magnesium, sodium, or barium) are not expected to contribute significantly to the toxicity.
4. DATA MATRIX
See Read Across document attached to CSR

Qualifier:

equivalent or similar to guideline

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 or test system 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 / concentration:

Two/sex/dose/timepoint

Control animals:

no

Positive control reference chemical:

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

Key result

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

Key result

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.

Reference 2

Endpoint:

basic toxicokinetics

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

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.

Justification for type of information:

REPORTING FORMAT FOR THE CATEGORY APPROACH
1. HYPOTHESIS FOR THE CATEGORY APPROACH
The read across follows Scenario 5 - Qualitatively and quantitatively similar effects are caused by a common compound, which is formed from all category members (as described in the 2017 Read-Across Assessment Framework document).
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
TARGET: Benzenesulfonic acid, di-C10-14-alkyl derivs., sodium salts
SOURCE: Sodium 4-undecylbenzenesulfonate
3. CATEGORY APPROACH JUSTIFICATION

Linear and non-linear or branched alkylbenzene sulfonates are anionic surfactants with molecules characterized by a hydrophobic (apolar) and a hydrophilic (polar) group. As a group of chemicals, they are generally mixtures of closely related isomers and homologues. Each molecule contains an aromatic ring sulfonated at the para position and attached to either a linear or a branched alkyl chain at any position except the terminal carbons. The sulfonate group is a common functional group present in each of the category members, and is expected to exhibit similar biological activities with little influence from the length of carbon chain. The cation components of the chemicals (e.g. calcium, magnesium, sodium, or barium) are not expected to contribute significantly to the toxicity.
4. DATA MATRIX
See Read Across document attached to CSR

Qualifier:

equivalent or similar to guideline

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 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.

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 / concentration:

Two/sex/dose

Control animals:

no

Positive control reference chemical:

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).

Key result

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

Key result

Test no.:

#1

Toxicokinetic parameters:

Cmax: 0.16 mg/mL at a nominal dose level of 0.1 mg/kg

Key result

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

Key result

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.

Reference 3

Endpoint:

basic toxicokinetics

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

The study is similar to OECD Test Guidelines with acceptable deviations.

Justification for type of information:

REPORTING FORMAT FOR THE CATEGORY APPROACH
1. HYPOTHESIS FOR THE CATEGORY APPROACH
The read across follows Scenario 5 - Qualitatively and quantitatively similar effects are caused by a common compound, which is formed from all category members (as described in the 2017 Read-Across Assessment Framework document).
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
TARGET: Benzenesulfonic acid, di-C10-14-alkyl derivs., sodium salts
SOURCE: sodium 4-undecylbenzenesulfonate
3. CATEGORY APPROACH JUSTIFICATION

Linear and non-linear or branched alkylbenzene sulfonates are anionic surfactants with molecules characterized by a hydrophobic (apolar) and a hydrophilic (polar) group. As a group of chemicals, they are generally mixtures of closely related isomers and homologues. Each molecule contains an aromatic ring sulfonated at the para position and attached to either a linear or a branched alkyl chain at any position except the terminal carbons. The sulfonate group is a common functional group present in each of the category members, and is expected to exhibit similar biological activities with little influence from the length of carbon chain. The cation components of the chemicals (e.g. calcium, magnesium, sodium, or barium) are not expected to contribute significantly to the toxicity.
4. DATA MATRIX
See Read Across document attached to CSR

Qualifier:

equivalent or similar to guideline

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 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.

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 / concentration:

Two/sex/dose

Control animals:

no

Positive control reference chemical:

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%.

Key result

Test no.:

#1

Toxicokinetic parameters:

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

Key result

Test no.:

#1

Toxicokinetic parameters:

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

Key result

Test no.:

#2

Toxicokinetic parameters:

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

Key result

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.

Reference 4

Endpoint:

basic toxicokinetics

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

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

Justification for type of information:

REPORTING FORMAT FOR THE CATEGORY APPROACH
1. HYPOTHESIS FOR THE CATEGORY APPROACH
The read across follows Scenario 5 - Qualitatively and quantitatively similar effects are caused by a common compound, which is formed from all category members (as described in the 2017 Read-Across Assessment Framework document).
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
TARGET: Benzenesulfonic acid, di-C10-14-alkyl derivs., sodium salts
SOURCE: Sodium 4-undecylbenzenesulfonate
3. CATEGORY APPROACH JUSTIFICATION

Linear and non-linear or branched alkylbenzene sulfonates are anionic surfactants with molecules characterized by a hydrophobic (apolar) and a hydrophilic (polar) group. As a group of chemicals, they are generally mixtures of closely related isomers and homologues. Each molecule contains an aromatic ring sulfonated at the para position and attached to either a linear or a branched alkyl chain at any position except the terminal carbons. The sulfonate group is a common functional group present in each of the category members, and is expected to exhibit similar biological activities with little influence from the length of carbon chain. The cation components of the chemicals (e.g. calcium, magnesium, sodium, or barium) are not expected to contribute significantly to the toxicity.
4. DATA MATRIX
See Read Across document attached to CSR

Objective of study:

absorption

distribution

Qualifier:

equivalent or similar to guideline

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 or test system 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 / concentration:

Two/sex/dose/timepoint

Control animals:

no

Positive control reference chemical:

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.

Reference 5

Endpoint:

basic toxicokinetics

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Study period:

1978

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

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.

Justification for type of information:

REPORTING FORMAT FOR THE CATEGORY APPROACH
1. HYPOTHESIS FOR THE CATEGORY APPROACH
The read across follows Scenario 5 - Qualitatively and quantitatively similar effects are caused by a common compound, which is formed from all category members (as described in the 2017 Read-Across Assessment Framework document).
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
TARGET: Benzenesulfonic acid, di-C10-14-alkyl derivs., sodium salts
SOURCE: Linear Alkylbenzene Sulfonates
3. CATEGORY APPROACH JUSTIFICATION

Linear and non-linear or branched alkylbenzene sulfonates are anionic surfactants with molecules characterized by a hydrophobic (apolar) and a hydrophilic (polar) group. As a group of chemicals, they are generally mixtures of closely related isomers and homologues. Each molecule contains an aromatic ring sulfonated at the para position and attached to either a linear or a branched alkyl chain at any position except the terminal carbons. The sulfonate group is a common functional group present in each of the category members, and is expected to exhibit similar biological activities with little influence from the length of carbon chain. The cation components of the chemicals (e.g. calcium, magnesium, sodium, or barium) are not expected to contribute significantly to the toxicity.
4. DATA MATRIX
See Read Across document attached to CSR

Objective of study:

absorption

distribution

excretion

Qualifier:

equivalent or similar to guideline

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 or test system 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 / concentration:

N/A

Control animals:

not specified

Positive control reference chemical:

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 (or Bioavailability) 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.

Reference 6

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

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.

Justification for type of information:

REPORTING FORMAT FOR THE CATEGORY APPROACH
1. HYPOTHESIS FOR THE CATEGORY APPROACH
The read across follows Scenario 5 - Qualitatively and quantitatively similar effects are caused by a common compound, which is formed from all category members (as described in the 2017 Read-Across Assessment Framework document).
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
TARGET: Benzenesulfonic acid, di-C10-14-alkyl derivs., sodium salts
SOURCE: Sodium 2-dodecylbenzenesulfonate
3. CATEGORY APPROACH JUSTIFICATION

Linear and non-linear or branched alkylbenzene sulfonates are anionic surfactants with molecules characterized by a hydrophobic (apolar) and a hydrophilic (polar) group. As a group of chemicals, they are generally mixtures of closely related isomers and homologues. Each molecule contains an aromatic ring sulfonated at the para position and attached to either a linear or a branched alkyl chain at any position except the terminal carbons. The sulfonate group is a common functional group present in each of the category members, and is expected to exhibit similar biological activities with little influence from the length of carbon chain. The cation components of the chemicals (e.g. calcium, magnesium, sodium, or barium) are not expected to contribute significantly to the toxicity.
4. DATA MATRIX
See Read Across document attached to CSR

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:

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 / concentration:

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 (or Bioavailability) testing results:

N/A

Executive summary:

N/A

Reference 7

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Study period:

24 hours

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

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.

Justification for type of information:

REPORTING FORMAT FOR THE CATEGORY APPROACH
1. HYPOTHESIS FOR THE CATEGORY APPROACH
The read across follows Scenario 5 - Qualitatively and quantitatively similar effects are caused by a common compound, which is formed from all category members (as described in the 2017 Read-Across Assessment Framework document).
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
TARGET: Benzenesulfonic acid, di-C10-14-alkyl derivs., sodium salts
SOURCE: Sodium 2-dodecylbenzenesulfonate
3. CATEGORY APPROACH JUSTIFICATION

Linear and non-linear or branched alkylbenzene sulfonates are anionic surfactants with molecules characterized by a hydrophobic (apolar) and a hydrophilic (polar) group. As a group of chemicals, they are generally mixtures of closely related isomers and homologues. Each molecule contains an aromatic ring sulfonated at the para position and attached to either a linear or a branched alkyl chain at any position except the terminal carbons. The sulfonate group is a common functional group present in each of the category members, and is expected to exhibit similar biological activities with little influence from the length of carbon chain. The cation components of the chemicals (e.g. calcium, magnesium, sodium, or barium) are not expected to contribute significantly to the toxicity.
4. DATA MATRIX
See Read Across document attached to CSR

Objective of study:

absorption

Qualifier:

equivalent or similar to guideline

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 / concentration:

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 (or Bioavailability) testing results:

N/A

N/A

Conclusions:

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

Executive summary:

N/A

Reference 8

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Study period:

48 hours

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

The study is similar to OECD Test Guidelines with acceptable deviations.

Justification for type of information:

REPORTING FORMAT FOR THE CATEGORY APPROACH
1. HYPOTHESIS FOR THE CATEGORY APPROACH
The read across follows Scenario 5 - Qualitatively and quantitatively similar effects are caused by a common compound, which is formed from all category members (as described in the 2017 Read-Across Assessment Framework document).
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
TARGET: Benzenesulfonic acid, di-C10-14-alkyl derivs., sodium salts
SOURCE: Sodium 2-dodecylbenzenesulfonate
3. CATEGORY APPROACH JUSTIFICATION

Linear and non-linear or branched alkylbenzene sulfonates are anionic surfactants with molecules characterized by a hydrophobic (apolar) and a hydrophilic (polar) group. As a group of chemicals, they are generally mixtures of closely related isomers and homologues. Each molecule contains an aromatic ring sulfonated at the para position and attached to either a linear or a branched alkyl chain at any position except the terminal carbons. The sulfonate group is a common functional group present in each of the category members, and is expected to exhibit similar biological activities with little influence from the length of carbon chain. The cation components of the chemicals (e.g. calcium, magnesium, sodium, or barium) are not expected to contribute significantly to the toxicity.
4. DATA MATRIX
See Read Across document attached to CSR

Objective of study:

absorption

Qualifier:

equivalent or similar to guideline

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 / concentration:

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 (or Bioavailability) testing results:

N/A

N/A

Conclusions:

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

Executive summary:

N/A

Reference 9

Endpoint:

basic toxicokinetics

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

The study is similar to OECD Test Guidelines with acceptable deviations.

Justification for type of information:

REPORTING FORMAT FOR THE CATEGORY APPROACH
1. HYPOTHESIS FOR THE CATEGORY APPROACH
The read across follows Scenario 5 - Qualitatively and quantitatively similar effects are caused by a common compound, which is formed from all category members (as described in the 2017 Read-Across Assessment Framework document).
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
TARGET: Benzenesulfonic acid, di-C10-14-alkyl derivs., sodium salts
SOURCE: Sodium 4-undecylbenzenesulfonate
3. CATEGORY APPROACH JUSTIFICATION

Linear and non-linear or branched alkylbenzene sulfonates are anionic surfactants with molecules characterized by a hydrophobic (apolar) and a hydrophilic (polar) group. As a group of chemicals, they are generally mixtures of closely related isomers and homologues. Each molecule contains an aromatic ring sulfonated at the para position and attached to either a linear or a branched alkyl chain at any position except the terminal carbons. The sulfonate group is a common functional group present in each of the category members, and is expected to exhibit similar biological activities with little influence from the length of carbon chain. The cation components of the chemicals (e.g. calcium, magnesium, sodium, or barium) are not expected to contribute significantly to the toxicity.
4. DATA MATRIX
See Read Across document attached to CSR

Objective of study:

metabolism

Qualifier:

equivalent or similar to guideline

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 or test system 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 / concentration:

N/A

Control animals:

no

Positive control reference chemical:

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.
Bioaccessibility

Table I. Distribution of LA^35S 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
0.6^a	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
1.2^a	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
8.0^b	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
40.0^b	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 AB^35S 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
0.6^a	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
1.2^a	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
40.0^b	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

Reference 10

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient for assessment

Remarks:

Limited information available

Justification for type of information:

REPORTING FORMAT FOR THE CATEGORY APPROACH
1. HYPOTHESIS FOR THE CATEGORY APPROACH
The read across follows Scenario 5 - Qualitatively and quantitatively similar effects are caused by a common compound, which is formed from all category members (as described in the 2017 Read-Across Assessment Framework document).
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
TARGET: Benzenesulfonic acid, di-C10-14-alkyl derivs., sodium salts
SOURCE: Linear alkybenzene sulfonate
3. CATEGORY APPROACH JUSTIFICATION

Linear and non-linear or branched alkylbenzene sulfonates are anionic surfactants with molecules characterized by a hydrophobic (apolar) and a hydrophilic (polar) group. As a group of chemicals, they are generally mixtures of closely related isomers and homologues. Each molecule contains an aromatic ring sulfonated at the para position and attached to either a linear or a branched alkyl chain at any position except the terminal carbons. The sulfonate group is a common functional group present in each of the category members, and is expected to exhibit similar biological activities with little influence from the length of carbon chain. The cation components of the chemicals (e.g. calcium, magnesium, sodium, or barium) are not expected to contribute significantly to the toxicity.
4. DATA MATRIX
See Read Across document attached to CSR

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.

Reference 11

Endpoint:

basic toxicokinetics

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Study period:

1979

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

The study is similar to OECD Test Guidelines with acceptable deviations.

Justification for type of information:

REPORTING FORMAT FOR THE CATEGORY APPROACH
1. HYPOTHESIS FOR THE CATEGORY APPROACH
The read across follows Scenario 5 - Qualitatively and quantitatively similar effects are caused by a common compound, which is formed from all category members (as described in the 2017 Read-Across Assessment Framework document).
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
TARGET: Benzenesulfonic acid, di-C10-14-alkyl derivs., sodium salts
SOURCE: Calcium salt of linear alkylbenzene sulfonate, chain length C12
3. CATEGORY APPROACH JUSTIFICATION

Linear and non-linear or branched alkylbenzene sulfonates are anionic surfactants with molecules characterized by a hydrophobic (apolar) and a hydrophilic (polar) group. As a group of chemicals, they are generally mixtures of closely related isomers and homologues. Each molecule contains an aromatic ring sulfonated at the para position and attached to either a linear or a branched alkyl chain at any position except the terminal carbons. The sulfonate group is a common functional group present in each of the category members, and is expected to exhibit similar biological activities with little influence from the length of carbon chain. The cation components of the chemicals (e.g. calcium, magnesium, sodium, or barium) are not expected to contribute significantly to the toxicity.
4. DATA MATRIX
See Read Across document attached to CSR

Objective of study:

absorption

distribution

excretion

Qualifier:

equivalent or similar to guideline

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 or test system 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 / concentration:

N/A

Control animals:

not specified

Positive control reference chemical:

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 (or Bioavailability) 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 benzenesulfonic acid, di-C10-14-alkyl derivs., sodium salts (registered and read across target 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 in 5% w/w (maximum 20% w/w) diluent oil, it is not clear what role the diluent oil contributes to the dermal absorption of the 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.

Absorption

In general, absorption of a chemical is possible, if the substance crosses biological membranes. This process requires a substance to be soluble, both in lipid and in water, and is also dependent on its molecular weight (substances with molecular weights below 500 are favourable for absorption). Generally, the absorption of chemicals which are surfactants or irritants may be enhanced, because of damage to cell membranes. Benzenesulfonic acid, di-C10 -14 -alkyl derivs., sodium salts are not favourable for absorption, due to its molecular weight (500-560g/mol), low water solubility (< 0.1 mg/L) and a logPow of 8.8. Such lipophilic low water-soluble substances are hindered to be absorbed because the dissolving in the gastrointestinal fluids is impaired. On the other hand, any lipophilic compound may be taken up by micellular solubilisation and this mechanism may be of particular importance for benzenesulfonic acid, di-C10-14-alkyl derivs., sodium salts since it is poorly soluble in water. The substance does bear, however, surface activity; therefore, an enhancement of absorption is theoretically possible.

The above-mentioned properties determine the absorption of benzenesulfonic acid, di-C10-14-alkyl derivs., sodium salts to be, rather limited, based on the absorption-hindering properties (molecular weight, slight water solubility and high LogPow) and the observed effects in toxicological experiments.

Oral route

Benzenesulfonic acid, di-C10 -14 -alkyl derivs., sodium salts are not expected to hydrolyse in the stomach due to its low water solubility. In the small intestine absorption occurs mainly via passive diffusion or lipophilic compounds may form micelles and be taken into the lymphatic system. Additionally, metabolism can occur by gut microflora or by enzymes in the gastrointestinal mucosa. However, the absorption of highly lipophilic substances (LogPowof 4 or above) may be limited by the inability of such substances to dissolve into gastrointestinal fluids and hence make contact with the mucosal surface. The absorption of such substances will be enhanced if they undergo micellular solubilisation by bile salts. Substances absorbed as micelles enter the circulation via the lymphatic system, bypassing the liver.

The available data suggest that orally administered benzenesulfonic acid, di-C10 -14 -alkyl derivs., sodium salts will be absorbed to a limited extent, even though micellular solubilisation, pinocytosis and persorption cannot be ruled out. This thesis is supported by the LD50 value of 10000 mg/kg bw available for the calcium sulfonate read across substance CAS 70024-69-0, which shows that the substance is not acutely toxic after oral exposure. After repeated exposures by oral route, the read-across substance produced only minimal clinical signs in treated animals (Bjorn, 2004). Based on these toxicological data and considered the physico-chemical properties of the substance which are not in the range suggestive for significant absorption from the gastrointestinal tract,50% absorption is considered appropriate for the purposes of DNEL derivation for systemic effects.

Inhalation route

Concerning absorption in the respiratory tract, any gas or vapour must be sufficiently lipophilic to cross the alveolar and capillary membranes. Therefore, a moderate log P value (between -1 and 4) would be favourable for absorption. They can be absorbed directly across the respiratory tract epithelium by passive diffusion. The rate of systemic uptake of very hydrophilic gases or vapours may be limited by the rate at which they partition out of the aqueous fluids (mucus) lining the respiratory tract and into the blood. Such substances may be transported out of the lungs with the mucus and swallowed or pass across the respiratory epithelium via aqueous membrane pores. Very hydrophilic substances can be absorbed through aqueous pores (for substances with molecular weights below

and around 200) or be retained in the mucus. Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (log P >4), particularly those that are poorly soluble in water (1 mg/L or less) that would otherwise be poorly absorbed (ECHA guidance R7c, Table R.7.12-2, 2012).

The read-across substance magnesium sulfonate (CAS 231297 -75 -9) has a low vapour pressure (0.01 Pa at25°C), which indicates only low availability for inhalation. The high molecular weight and the high LogPow also indicate no possibility for absorption through aqueous pores. Based on this data, benzenesulfonic acid, di-C10 -14 -alkyl derivs., sodium salts are marginally available in the air for inhalation and if inhaled it is expected not to be absorbed. Considering the fact that there is no experimental data on absorption,50% absorption for the purposes of DNEL derivation is considered appropriate.

Dermal route

To cross the skin, a compound must first penetrate into the stratum corneum and may subsequently reach the epidermis, the dermis and the vascular network. The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the epidermis is most resistant to penetration by highly lipophilic compounds. Substances with a molecular weight below 100 are favourable for penetration of the skin and substances above 500 are normally not able to penetrate. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore, if the water solubility is below 1 mg/L, dermal uptake is likely to be low. LogPow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal; ECHA guidance R7c., TableR.7.12-2, 2012) particularly if water solubility is high. Above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow.

Additionally, vapours of substances with vapour pressures below 100 Pa are likely to be well absorbed and the amount absorbed dermally may be more than 10% of the amount that would be absorbed by inhalation. If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration. During the whole absorption process into the skin, the compound can be subject to biotransformation. In the case of benzenesulfonic acid, di-C10 -14 -alkyl derivs., sodium salts, the molecular weight is above 500, which indicates already a marginal potential to penetrate the skin. This is accompanied by a low hydrophilicity (logPow of8.8) of the substance and even though it will be absorbed into the stratum corneum it is unlikely to be transferred into the epidermis.

Although the substance does show characteristics of a surfactant, benzenesulfonic acid, di-C10 -14 -alkyl derivs., sodium salts are not irritating to skin and eyes, and therefore this does not enhance dermal absorption. In support of this hypothesis (the low dermal absorption), the systemic toxicity of the calcium sulfonate read across substance CAS 70024-69-0 and of 115733-09-0 via the skin is low (acute dermal toxicity, LD50 value of > 2000 and > 5000mg/kg bw for rats, respectively). Repeated applications of the read-across substances to the skin of rats during 28days resulted in NOAEL of 1000 mg/kg bw (no systemic effects were observed). Moreover, a critical assessment of all available data (toxicity effects in the available studies and physicochemical properties) should be taken into account before using default assumptions (ECETOC, TR No. 110). The absorption after dermal exposure is generally more gradual and slower than oral absorption and a lower bioavailability is expected due to the presence of the absorption hindering outer skin layer stratum corneum and a comparatively smaller surface area.

Schuhmacher et al. (2003) recommended that a low dermal penetration (< 10%) can be assumed for substances with a logPow value >5 or for substances with a Kp value <0.0001 (cm/h). A skin permeability constant (Kp) of 1.0E-7 cm/min (= 6.0E-6 cm/h) for human epidermis was obtained experimentally for the related substance dodecyl benzenesulfonate (DOBS, CAS 25155-30-0, Howes, 1975). This substance is structurally like the target benzenesulfonic acid, di-C10 -14 -alkyl derivs., sodium salts. The alkyl chain of DOBS consisting of 12 carbon atoms is in the range of alkyl lengths distribution in the target substance therefore it is of similar lipophilicity. Therefore, the Kp value for the target substance is expected to be like that of DOBS. Based on the high molecular weight, high logPow and on the results of dermal toxicity studies,10% absorption is considered for the purposes DNEL derivation

Reference:

1.Schuhmacher-Wolz U., Kalberlach F., Oppl R., van Hemmen J. J. (2003). A toolkit for dermal risk assessment:toxicological approach for hazard characterization. Ann. Occup. Hyg., Vol 47 No.8, pp. 641 -652.

Distribution

In general, the following principle applies: the smaller the molecule, the wider the distribution. A lipophilic molecule (LogPow >0) is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. Protein binding can limit the amount of a substance available for distribution. Furthermore, if a substance undergoes extensive first-pass metabolism, predictions made on the basis of the physico-chemical characteristics of the parent substance may not be applicable. In case of benzenesulfonic acid, di-C10-14-alkylderivs., sodium salts, no data is available for distribution patterns. Even though the high LogPow would indicate the possibility to reach the intracellular compartment, this seems to be unlikely as the molecular weight of the un-metabolised substance is so high. Therefore, the distribution is expected to be limited.

Accumulation

It is also important to consider the potential for a substance to accumulate or to be retained within the body. Lipophilic substances have the potential to accumulate within the body (mainly in the adipose tissue), if the dosing interval is shorter than 4 times the whole-body half-life. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, substances with high LogPow values tend to have longer half-lives. On this basis, there is the potential for highly lipophilic substances (LogPow >4) to accumulate in biota which are frequently exposed. Highly lipophilic substances (LogPow between 4 and 6) that come into contact with the skin can readily penetrate the lipid rich stratum corneum but are not well absorbed systemically. Although they may persist in the stratum corneum, they will eventually be cleared as the stratum corneum is sloughed off. A turnover time of 12 days has been quoted for skin epithelial cells. Accordingly, the high LogPow and the predicted behaviour concerning absorption and metabolism of benzenesulfonic acid, di-C10 -14 -alkyl derivs., sodium salts might indicate a potential for accumulation in the body. This, however, is limited as the absorption is expected to be low via all routes of exposure and because metabolism of benzenesulfonic acid, di-C10 -14 -alkyl derivs., sodium salts are expected to influence this initial prediction.

Metabolism

Route specific toxicity results from several phenomena, such as hydrolysis within the gastrointestinal or respiratory tracts, also metabolism by gastrointestinal flora or within the gastrointestinal tract epithelia (mainly in the small intestine), respiratory tract epithelia (sites include the nasal cavity, tracheo-bronchial mucosa [Clara cells] and alveoli [type 2 cells]) and skin. As specified above, hydrolysis does not apply for benzenesulfonic acid, di-C10-14-alkylderivs., sodium salts. However, its metabolism is very likely to occur via the Cytochrome P450 group of metabolising enzymes.

Excretion

The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces (via bile and directly from the gastrointestinal mucosa). For non-polar volatile substances and metabolites exhaled air is an important route of excretion. Substances that are excreted favourable in the urine tend to be water-soluble and of low molecular weight (below 300 in the rat) and be ionized at the pH of urine. Most will have been filtered out of the blood by the kidneys though a small amount may enter the urine directly by passive diffusion and there is the potential for reabsorption into the systemic circulation across the tubular epithelium. Substances that are excreted in the bile tend to be amphipathic (containing both polar and nonpolar regions), hydrophobic/strongly polar and have higher molecular weights and pass through the intestines before they are excreted in the faeces and as a result may undergo enterohepatic recycling which will prolong their biological half-life. This is particularly a problem for conjugated molecules that are hydrolysed by gastrointestinal bacteria to form smaller more lipid soluble molecules that can then be reabsorbed from the gastrointestinal (GI) tract. Those substances less likely to recirculate are substances having strong polarity and high molecular weight of their own accord. Other substances excreted in the faeces are those that have diffused out of the systemic circulation into the GI tract directly, substances which have been removed from the gastrointestinal mucosa by efflux mechanisms and non-absorbed substances that have been ingested or inhaled and subsequently swallowed. Non-ionized and lipid soluble molecules may be excreted in the saliva (where they may be swallowed again) or in the sweat. Highly lipophilic substances that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with or without metabolism with skin cells.

For benzenesulfonic acid, di-C10 -14 -alkyl derivs., sodium salts no data is available concerning its elimination. Concerning the fate of the metabolites formed of benzenesulfonic acid, di-C10-14-alkylderivs., sodium salts, the metabolites should be eliminated mainly via the urine and to a smaller extent via the bile.

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

ADME Studies on Related Alkyl/aryl Sulfonates

Linear alkylbenzene sulfonates (LAS), alpha-olefin sulfonates (AOS) and alkyl sulfates (AS). The World Health Organization (WHO assessment of alkyl/aryl sulfates and sulfonates (ISBN 92 4 157169 1,1996), shows that linear alkylbenzene sulfonates, alpha-olefin sulfonates and alkyl sulfonates are readily absorbed by the gastrointestinal tract, widely distributed throughout the body and extensively metabolised. They can undergo omega- and beta-oxidation, which is followed by oxidative scission of the aromatic ring and desulfonation. For LAS, the parent compounds and the metabolites are excreted mainly through the kidneys and via the bile. AOS and AS are mainly excreted via the urine. Only minimal amounts of LAS and AS are absorbed through intact skin.

Dodecyl benzenesulfonate (DOBS)

The percutaneous absorption of DOBS surfactant was studied in in vitro studies in rats and humans (Howes,1975). Two test solutions of the [14C]DOBS were used, the first a 3 mM solution in 25 % v/v Polyethylene Glycol400 in water and a second 3mM suspension in water. 0.25 mL of the test solution was applied to the rat skin (4.9cm²) and 0.1 mL to the human epidermal samples (0.78 cm²). The concentration of the test material in the solutions was 1.2 mg/mL. After 2, 6 and 24 hours (rats) or after 0.5, 1, 2, 3, 4, 6, 7, 8, 24 and 48 hours (human) of exposure, the skin samples were washed with excess of water and the radioactivity was measured in the rinsings and in the tested skin samples to determine the penetration rates. The results show no measurable penetration (<0.1 µg/cm²) of DOBS through the rat skin up to 24 hours. DOBS did not penetrate human epidermis as well (<0.1 µg/cm²).30% [14C] DOBS was recovered in the rinsings and 70% remained associated with the skin of rats. 30-50% of[14C] DOBS retained in the human epidermis after rinsing.

To calculate percutaneous absorption rates, penetration of 0.1 µg/cm², the lower limit of detection, was taken as worst-case. Based on the applied amount of 0.25 mL to the rat skin (4.9 cm²) and 0.1 mL to the human epidermis (0.78 cm²) and ´the concentration of DOBS in vehicle of 1.2 mg/mL, 0.16% and 0.065% absorption was calculated for the rat skin and human epidermis, respectively. Monitoring at 2, 6, and 24 hours after exposure to rat and human skin showed no measurable percutaneous penetration of 14C (< 0.1 µg/cm²) for DOBS.

Howes (1975) also studied the in vivo dermal absorption of DOBS in rats (Howes, 1975). 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 for collection of excreta. The expired CO2, urine, faeces and the carcasses of the animals, after excision of the treated skin, was monitored for 14C at 24 h after treatment. The excised skin was monitored for 14C and examined by autoradiography. Autoradiography of the skins showed heavy deposition of the surfactant on 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%.

The turnover (elimination) of [14C]-labelled DOBS was also measured by injecting three animals intraperitoneally and three animals subcutaneously with 0.1 or 0.5 mL of surfactant solution (Howes, 1975). Two test solutions of the [14C] DOBS were used, the first a 3mM solution in 25% v/v Polyethylene Glycol 400 in water and a second a 3 mM suspension in water. The administered dose resulted in 1.02 mg/kg bw. The animals were placed in sealed metabolism cages where urine, faeces and expired air were collected and monitored for14C. After 6 or 24 h the animals were killed and the radioactivity in their carcasses was measured. The rate and route of excretion of 14C from intraperitoneally administered [14C] surfactant solutions were the same as that from subcutaneously administered solutions. Most of the administered 14C was recovered in the urine at 24 h after dosing (78%). 22% and 1.5% of applied dose were recovered in carcasses and in faeces, respectively. Less than 0.1% radioactivity was measured in the expired air.

The following information is taken into account for any hazard / risk assessment: The toxicology profile for benzenesulfonic acid, di-C10 -14 -alkyl derivs., sodium salts and the calcium sulfonate read across substances indicate that oral and dermal absorption is expected to be limited. The in vitro andin vivostudies with DOBS and other related alkyl/aryl sulfates and sulfonates provide additional evidence that the skin absorption is expected to be low. No measurable skin penetration could be determined in the in vitro and in vivo studies in rats and/or humans. Concerning the absorption after exposure via inhalation, as the chemical is considered to have a low vapour pressure, is highly lipophilic, has a high LogPow, and has a rather high molecular weight, it is clear, that the substance is poorly available for inhalation and will not be absorbed significantly. The distribution of the target substance throughout the body is expected to be limited due to the high lipophilicity.

However, if absorbed, the substance will tend to distribute predominantly into the intracellular compartment. The substance does not indicate a significant potential for accumulation, when considering the predicted behaviour concerning absorption and metabolism. The calcium sulfonate target substance is expected to be extensively metabolised (metabolism by cytochrome P450 enzymes, followed by omega- and beta-oxidation and cleavage of the aromatic ring and desulfonation) and to be eliminated mainly via the urine and via the bile.