Benzenesulfonic acid, 4-C15-16-sec-alkyl derivs.

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

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 labelled with 35S) were studied in male Charles River rats. LAS was administered as an aqueous solution.

GLP compliance:

not specified

Radiolabelling:

yes

Remarks:

(radioactively labelled 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 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. A cannula was inserted into the proximal end of the bile duct 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 intestine 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 pentanoic 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 (migrated information): 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 labelled 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:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting 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 (migrated information): 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.

Description of key information

A series of toxicokinetic studies in rats and monkeys indicates that LAS (read across) is rapidly absorbed when the exposures are intravenous, oral or dermal, then rapidly eliminated from the body, mostly via the urine and to a lesser extent in the bile and faeces.  A dermal absorption study of a C12 LAS homologue in isolated human epidermis indicated < 1 % of the applied dose penetrated the skin in 48 hours. Benzenesulfonic acid, 4-C15-16-sec-alkyl-derivs. would be expected to show a comparable toxicokinetic profile.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - dermal (%):

1

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 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 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 C12 LAS homologue, sodium p-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 cm2 clipped 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.