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

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented study in peer-reviewed publication conducted by experienced testing laboratory.

Objective of study:

metabolism

Principles of method if other than guideline:

The absorption, distribution, metabolism and elimination of LAS (radioactively labeled with 35S) were studied in male Charles River rats. LAS was administered as an aqueous solution.

GLP compliance:

not specified

Radiolabelling:

yes

Remarks:

(radioactively labeled with 35S)

Species:

rat

Strain:

other: Charles River albino

Sex:

male

Details on test animals or test system and environmental conditions:

The animals were housed in individual cages which permitted the separate collection of urine and feces. Food and water were provided ad libitum after dosing.

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

Male rats (150-200 g) were fasted for 16 hours and given orally an aqueous solution containing LA35S. The dose was given in 1.0 mL volume. 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 the study, the animals were killed and selected organs and tissues were taken for radioassay.

Also, the route of absorption was determined by oral feeding of 40 mg of LAS to thoracic duct-cannulated rats. The lymph was collected from each animal in a single 42-hour fraction.

The enterohepatic ciruclation of the sufactant was quantifed by oral feeding of 1.2 mg of LAS to bile duct-cannulated rats and to rats prepared in a manner similar to the dual rat study described by Boquet and Fromageot. A cannula was inserted into the proximal end of the bil deuct of Rat A and into the distal end of the bile duct in Rat B such that the bile from Rat A could flow through the cannula into the bile duct, and finally into the intestin of Rat B. A second cannula was inserted into the proximal end of the bile duct of Rat B so that is bile could be collected. LA35S was 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.

Duration and frequency of treatment / exposure:

See details of exposure section

Remarks:

Doses / Concentrations:
0.6, 1.2, 8.0 and 40.0 mg (averages of three animals for the two lower doses and five animals for the two higher doses) for the excretion test, 1.2 mg/rat for the absorption and enterohepatic circulation tests.

No. of animals per sex per dose / concentration:

Three or five males per dose for the excretion test, six males for the absorption and enterohepatic tests.

Control animals:

not specified

Details on absorption:

The compound was readily absorbed from the gastrointestinal tract (80-90% of the dose).

Details on distribution in tissues:

Primarily excreted in the urine.

Details on excretion:

Most of the absorbed 35S was eliminated within 72 hours and 60-65% of the absorbed dose was eliminated in the urine, 35% of the absorbed 35S was excreted in the bile and was reabsorbed completely from the gastrointestinal tract. Very little was found in the lymph, so transport of LAS is probably by way of portal venous blood.

Metabolites identified:

yes

Details on metabolites:

Urine - sulfophenyl butanoic and sulfophenyl pentatonic acid. These metabolites were sufficiently polar to avoid being reabsorbed from the kidney tubules. Although the metabolites in the bile were not identified, it was shown that no unchanged LAS was eliminated via this pathway.

Conclusions:

Interpretation of results: no bioaccumulation potential based on study results
LAS is readily absorbed by the gastrointestinal track and rapidly excreted with its metabolites, primarily in the urine.

Executive summary:

The absorption, distribution, metabolism and elimination of LAS (radioactively labeled with 35S) were studied in male Charles River rats. LAS was readily absorbed by the gastrointestinal tract and rapidly metabolized and excreted in the urine.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented peer-reviewed publication of contract laboratory study.

Objective of study:

metabolism

Principles of method if other than guideline:

The disposition of radioactivity was studied in single and repeated oral doses of [14C]LAS to rhesus monkeys.

GLP compliance:

not specified

Radiolabelling:

yes

Remarks:

[14C]LAS

Species:

monkey

Strain:

other: Macaca mulatta

Sex:

male/female

Details on test animals or test system and environmental conditions:

Four (2 male, 2 female; 5 kg average body weight) adult rhesus monkeys (Macaca mulatta)

Route of administration:

other: single or repeated oral or subcutaneous

Remarks:

Doses / Concentrations:
single or repeated oral (30, 150 or 300 mg/kg) or subcutaneous (0.1, 0.5 or 1 mg/kg) doses of 14C-LAS

No. of animals per sex per dose / concentration:

2 males and 2 females

Control animals:

not specified

Details on dosing and sampling:

Blood samples were collected for the excretion and plasma studies.

Details on distribution in tissues:

When 14C-LAS was injected into the skin, most of the radioactivity remained at the site of injection. No localization of radioactivity in any tissue occurred

Details on excretion:

After single 30 mg/kg oral doses the radioactivity was rapidly excreted, mostly during the first 24 hours. Means of 71.2% and 23.1% of the dose were excreted in the urine and feces, respectively, during 5 days. Similarly, after single 1 mg/kg subcutaneous doses, means of 64.1% and 10.9% were excreted in urine and feces, respectively, during 5 days, mostly during the first 24 hours. During the 120 hours after single oral (30 mg/kg) or subcutaneous doses (1 mg/kg) the average rate of excretion was between 63 and 74% in the urine and between 9 and 26% in the feces. No unchanged LAS was detected in urine samples after oral or subcutaneous doses (either single or repeated).

Metabolites identified:

no

Details on metabolites:

Five metabolites were excreted but they were not identified. Incubations with beta-glucuronidase/sulfatase did not affect the metabolites, indicating that the metabolites were probably not present as the corresponding conjugates.

Conclusions:

Interpretation of results: no bioaccumulation potential based on study results

Executive summary:

The disposition of radioactivity was studied in single and repeated oral or subcutaneous doses of [14C]LAS to rhesus monkeys. Results show that LAS is rapidly absorbed, then rapidly metabolized and excreted, primarily in the urine but also in the bile and feces. No accumulation or localization of radioactivity or change in elimination was observed. LAS does not bioaccumulate in the tissues.

Reference 3

Endpoint:

dermal absorption in vivo

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented study in peer-reviewed publication.

Justification for type of information:

Test material is radiolabeled sodium 2-dodecylbenzene sulfonate, the 2 phenyl isomer of C12-LAS; C12-LAS is a major constituent of the sponsored material; the 2-phenyl isomer is a major constituent of C12-LAS.

Qualifier:

no guideline followed

Principles of method if other than guideline:

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

GLP compliance:

not specified

Radiolabelling:

yes

Species:

rat

Strain:

other: Colworth-Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

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

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

Type of coverage:

open

Vehicle:

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

Duration of exposure:

15 min

Doses:

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

No. of animals per group:

no data

Control animals:

no

Details on study design:

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

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

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

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

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

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

Signs and symptoms of toxicity:

not specified

Dermal irritation:

not specified

Absorption in different matrices:

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

Dose:

250 micrograms

Parameter:

percentage

Absorption:

< 0.3 %

Remarks on result:

other: 24 hrs after exposure

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

Conclusions:

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

Executive summary:

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

Reference 4

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented study in peer-reviewed publication.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

GLP compliance:

not specified

Radiolabelling:

yes

Species:

human

Sex:

female

Duration of exposure:

48 hrs

Doses:

0.1 ml of 3 mM solution

No. of animals per group:

four skin samples

Details on study design:

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

Details on in vitro test system (if applicable):

SKIN PREPARATION
- Source of skin: human cadavers
- Ethical approval if human skin:
- Type of skin: abdominal
- Preparative technique: Epidermal samples were heated at 58 degrees C for 2 min. Samples were placed in 1 cm diameter penetration cells, and saline with 0.012% penicillin, 0.01% streptomycin was placed on both surfaces of the cells. The cells were equilibrated at 37 degrees C for 24 hrs.
- Membrane integrity check: Only cells with electrical resistance greater than 50,000 ohms were used.
- Storage conditions: -70 degree C

Signs and symptoms of toxicity:

not examined

Dermal irritation:

yes

Remarks:

some swelling was seen after 48 hrs of contact

Absorption in different matrices:

Only 30% of the test substance was removed by rinsing, with 70 % remaining associated with the skin.

Dose:

152.9 micrograms/cm^2

Parameter:

percentage

Absorption:

< 0.07 %

Remarks on result:

other: 2 hrs

Dose:

152.9 micrograms/cm^2

Parameter:

percentage

Absorption:

< 0.07 %

Remarks on result:

other: 6 hrs

Dose:

152.9 micrograms/cm^2

Parameter:

percentage

Absorption:

< 0.07 %

Remarks on result:

other: 24 hrs

Dose:

152.9 micrograms/cm^2

Parameter:

percentage

Absorption:

< 0.07 %

Remarks on result:

other: 48 hrs

Conclusions:

The in vitro penetration through human skin after a 48 hr exposure was < 0.07%.

Executive summary:

Radiolabelled test substance was applied (0.1 ml of a 3 mM solution) to samples of human abdominal skin from four female cadavers. Exposure time was 48 hrs. Analysis by liquid scintillation counting was done at 0.5, 1, 2, 3, 4, 6, 7, 8, 24, and 48 hrs. Penetration through human skin was negligible, with < 0.07% absorbed in 48 hrs.

Description of key information

In the key oral study (Michael 1968), the absorption, distribution, metabolism and elimination of LAS (radioactively labeled with ³⁵S) were studied in male Charles River rats. LAS was administered as an aqueous solution. The urine and faeces were collected and removed daily for analysis. At the termination of the study, the animals were killed and selected organs and tissues were taken for radioassay. In addition, the route of absorption was determined by oral feeding of 40 mg of LAS to thoracic duct-cannulated rats. The lymph was collected from each animal in a single 42-hour fraction. The enterohepatic ciruclation of the surfactant was quantified by oral feeding of 1.2 mg of LAS to bile duct-cannulated rats and to rats prepared in a manner similar to the dual rat study described by Boquet and Fromageot. Three or five males per dose were used for the excretion test, and six males for the absorption and enterohepatic tests. The compound was readily absorbed from the gastrointestinal tract (80-90% of the dose), and rapidly excreted with its metabolites, primarily in the urine. Specifically, most of the absorbed ³⁵S was eliminated within 72 hours and 60-65% of the absorbed dose was eliminated in the urine, 35% of the absorbed ³⁵S was excreted in the bile and was reabsorbed completely from the gastrointestinal tract. Very little was found in the lymph, so transport of LAS is probably by way of portal venous blood. The authors suggested that metabolism proceeded via omega oxidation with subsequent catabolism through a beta-oxidation mechanism to form the metabolites that were excreted in the urine. Retention of radioactivity was not observed in any organ, so LAS has very low bioaccumulation potential.

In a supporting study (Cresswell et al. 1978), the disposition of radioactivity was studied in single and repeated oral or subcutaneous doses of ¹⁴C-LAS to rhesus monkeys. Four adult rhesus monkeys (2 male and 2 female) of body weight approximately 5 kg each were used for all experiments. For excretion studies, single oral doses of 30 mg/kg ¹⁴C-LAS (at 28 µCi) were administered by oral intubation as aqueous solutions. For the plasma level studies the same animals were administered single oral doses (¹⁴C-LAS of 150 mg/kg at 26 µCi and 300 mg/kg at 28 µCi) at intervals of 2 -3 weeks. About 2-3 weeks after the last single dose each animal received 7 consecutive daily oral doses of ¹⁴C-LAS (30 mg/kg/day at 28 µCi/day) in water. Blood samples were taken and animals were sacrificed at a different time after the last dose. Results show that LAS is rapidly absorbed, then rapidly metabolized and excreted, primarily in the urine but also in the bile and faeces. No accumulation or localization of radioactivity or change in elimination was observed. LAS does not bioaccumulate in the tissues.

In the key dermal study (Howes 1975), the dermal absorption of a C₁₂LAS homologue, sodiump-1 [1-¹⁴C]dodecolybenzenesulfonate (read across), was studied in rats and in isolated human epidermis. In the first part of the study, female Colworth-Wistar rats (n = 6) received a single dose (0.2 ml) of an aqueous suspension of the test material (250 μg) applied to a 7.5 cm²clipped area of the back. The contact time was 15 minutes, after which the test material was rinsed off. The ¹⁴C levels in the skin and protective patch were determined 24 hours after application and the penetration results based on levels of ¹⁴C excreted in urine, faeces and expired CO₂during the 24 hours after application plus levels of ¹⁴C in the carcass of the animals at 24 hours. No LAS was detected in skin (<0.1 μg/cm²), indicating that less than 0.04% of applied dose was disposed in the skin. In the second part of the study, isolated human epidermis (0.78 cm², n = 4) was exposed to 0.1 ml of a 1.2 mg/ml solution of the test substance. Penetration of ¹⁴C was measured at 2, 6, 24 and 48 hours. No LAS was detected (<0.1 μg/cm²), indicating that less than 0.065% of the applied dose penetrated the skin in 48 hours.

Summary

An in vitro model of penetration through human epidermis reported <0.065% penetration of a 48 hour applied dose, while dermal exposure to rats for 15 minutes resulted in skin penetration of <0.04% of the applied dose. Oral exposure in rats indicated that the compound was readily absorbed from the gastrointestinal tract (80 -90% of the dose), and rapidly excreted with its metabolites, primarily in the urine. Specifically, most of the absorbed dose was eliminated within 72 hours; 60 -65% in the urine, and 35% was excreted in the bile and was reabsorbed completely from the gastrointestinal tract. Results from a study using oral and subcutaneous exposure to 14C-LAS show that LAS is rapidly absorbed, then rapidly metabolized and excreted, primarily in the urine but also in the bile and faeces. No accumulation or localization of radioactivity or change in elimination was observed. No long-term inhalation toxicity data are available.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

90

Absorption rate - dermal (%):

0.065

Additional information

In the first key study (Michael 1968), the absorption, distribution, metabolism and elimination of LAS (radioactively labeled with ³⁵S) were studied in male Charles River rats. LAS was administered as an aqueous solution. The urine and faeces were collected and removed daily for analysis. At the termination of the study, the animals were killed and selected organs and tissues were taken for radioassay. In addition, the route of absorption was determined by oral feeding of 40 mg of LAS to thoracic duct-cannulated rats. The lymph was collected from each animal in a single 42-hour fraction. The enterohepatic circulation of the surfactant was quantified by oral feeding of 1.2 mg of LAS to bile duct-cannulated rats and to rats prepared in a manner similar to the dual rat study described by Boquet and Fromageot. Three or five males per dose were used for the excretion test, and six males for the absorption and enterohepatic tests. The compound was readily absorbed from the gastrointestinal tract (80-90% of the dose), and rapidly excreted with its metabolites, primarily in the urine. Specifically, most of the absorbed ³⁵S was eliminated within 72 hours and 60-65% of the absorbed dose was eliminated in the urine, 35% of the absorbed³⁵S was excreted in the bile and was reabsorbed completely from the gastrointestinal tract. Very little was found in the lymph, so transport of LAS is probably by way of portal venous blood. The authors suggested that metabolism proceeded via omega oxidation with subsequent catabolism through a beta-oxidation mechanism to form the metabolites that were excreted in the urine. Retention of radioactivity was not observed in any organ, so LAS has very low bioaccumulation potential.

In the second key study (Cresswell et al. 1978),the disposition of radioactivity was studied in single and repeated oral or subcutaneous doses of ¹⁴C-LAS to rhesus monkeys. Four adult rhesus monkeys (2 male and 2 female) of body weight approximately 5 kg each were used for all experiments. For excretion studies, single oral doses of 30 mg/kg ¹⁴C-LAS (at 28 µCi) were administered by oral intubation as aqueous solutions. For the plasma level studies the same animals were administered single oral doses (¹⁴C-LAS of 150 mg/kg at 26 µCi and 300 mg/kg at 28 µCi) at intervals of 2 -3 weeks. About 2-3 weeks after the last single dose each animal received 7 consecutive daily oral doses of ¹⁴C-LAS (30 mg/kg/day at 28 µCi/day) in water. Blood samples were taken and animals were sacrificed at a different time after the last dose. Results show that LAS is rapidly absorbed, then rapidly metabolized and excreted, primarily in the urine but also in the bile and faeces. No accumulation or localization of radioactivity or change in elimination was observed. LAS does not bioaccumulate in the tissues.

In the third key study (Howes 1975), the dermal absorption of a C₁₂LAS homologue, sodiump-1 [1-¹⁴C]dodecolybenzenesulfonate, was studied in rats and in isolated human epidermis. In the first part of the study, female Colworth-Wistar rats (n = 6) received a single dose (0.2 ml) of an aqueous suspension of the test material (250 μg) applied to a 7.5 cm²clipped area of the back. The contact time was 15 minutes, after which the test material was rinsed off. The ¹⁴C levels in the skin and protective patch were determined 24 hours after application and the penetration results based on levels of ¹⁴C excreted in urine, faeces and expired CO₂ during the 24 hours after application plus levels of ¹⁴C in the carcass of the animals at 24 hours. No LAS was detected in skin (<0.1 μg/cm²), indicating that less than 0.04% of applied dose was disposed in the skin. In the second part of the study, isolated human epidermis (0.78 cm², n = 4) was exposed to 0.1 ml of a 1.2 mg/ml solution of the test substance. Penetration of ¹⁴C was measured at 2, 6, 24 and 48 hours. No LAS was detected (<0.1 μg/cm²), indicating that less than 0.065% of the applied dose penetrated the skin in 48 hours.