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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1967
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Cross-reference
Reason / purpose:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1968
Report Date:
1967
Reference Type:
publication
Title:
Unnamed
Year:
1965
Report Date:
1964

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
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 orally as an aqueous solution.

GLP compliance:
no

Test material

Reference
Name:
Unnamed
Test material form:
not specified
Details on test material:
Name of test material: C10-13, LAS (CAS# 68411-30-3); alkyl chain length predominately C11, C12 and C13; phenyl ring fairly randomly distributed between carbons 2 through 6 of the alkyl chains.
Radiolabelling:
yes
Remarks:
(radioactively labeled with 35S)

Test animals

Species:
rat
Strain:
other: Charles River albino
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 150-200 g
- Housing: The animals were housed in individual cages which permitted the separate collection of urine and feces.
- Diet: ad libitum
- Water: ad libitum

No further details on test animals and environmental conditions were provided in the source.

Administration / exposure

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.

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

-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.

- The excretion was measured after oral administration of 1.2 mg of radiolabeled LAS to bile duct-ligated rats. In another set of animals, LAS was also determined after single dose via stomach tube of 0.6, 1.2, 8.0 and 40.0 mg and excretion was estimated over a 3- day period.
Duration and frequency of treatment / exposure:
Excretion and distribution studies: Single oral dose of 0.6, 1.2, 8 or 40 mg
Absorption, enterohepatic circulation and excretion studies: Single oral dose of 1.2 mg
Route of absorption study: Single oral dose of 40 mg
Doses / concentrations
Remarks:
0.6, 1.2, 8.0 and 40.0 mg for the excretion test, 1.2 mg/rat for the absorption and enterohepatic circulation tests, 40 mg for route of absorption study
No. of animals per sex per dose:
Excretion and distribution studies: Average of 5 animals for 0.6 and 1.2 mg dose levels and average of 3 animals for 8.0 and 4.0 mg dose levels
Route of absorption study: Six male rats
Enterohepatic circulation study: Three bile duct-cannulated rats connected to dual rat (total 6 rats)
Control animals:
no
Positive control:
No positive control was included in the study.
Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: Urine, feces, bile and lymph
- Time and frequency of sampling:
- For route of absorption study: The lymph was collected from each animal in a single 42-hour fraction
- For evaluation of absorption of test substance: Urine and feces were collected for 90 hours after dosing.
- For evaluation of disposition: Urine and feces were removed daily.
- For quantification of enterohepatic circulation of test substance: Urine, bile and feces were collected for 90 hours after dosing.
- For evaluation of excretion: Urine was collected daily

METHOD OF ANALYSIS FOR TISSUES AND BODY FLUIDS: Urine, lymph, and bile were each assayed directly by liquid scintillation counting while the feces and tissues were wet ashed with HNOJ/HC104 followed by direct counting of an aliquot of the solution.

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: Urine and feces
- Time and frequency of sampling: Daily
- From how many animals: The urine from rats that were fed LAS was pooled.
- Method type(s) for identification: The column chromatography, infrared, nuclear magnetic resonance (NMR), and mass spectra of the metabolites isolated from the urine of rats were obtained and analysed.
- Limits of detection and quantification: not specified
Statistics:
No details were provided

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
80-90% of the administered dose was readily absorbed from the gastrointestinal tract.
Type:
metabolism
Results:
60-65 % of the absorbed dose was excreted in urine as a mixture of two polar metabolites i.e.sulfophenyl butanoic and sulfophenyl pentatonic acid.
Type:
excretion
Results:
LAS was primarily excreted in the urine.

Toxicokinetic / pharmacokinetic studies

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

Route of absorption: There was 1.6 % of the LAS detected in the lymph of the animals during the 42-hour collection period. LAS appeared to be absorbed from the gastrointestinal tract and transported by other than the lymphatic system, probably by way of portal venous blood.
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 as a mixture of two polar metabolites i.e.sulfophenyl butanoic and sulfophenyl pentatonic acid. These compounds were probably formed from LAS by ω-oxidation followed by catabolism through a ß-oxidation mechanism to form the metabolites that were excreted in the urine. The polar nature of metabolites resisted reabsorption from the kidney tubule and as the result were excreted primarily 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.
Chemical nature of 35S in the urine of rats fed LAS: The 35S in the urine was not precipitated by ethanol along with added carrier Na2SO4. In addition, it was not extracted from the urine along with the added carrier LAS when the assay of cationic-SO3 was used. The 35S was thus assumed to be present in the urine as a metabolite of LAS. At the end of the 3 days, no 35S residue (<1% of the dose) could be detected in the carcasses of the rats that received the 40 mg dose of either surfactant. No explanation could be found for the unusually low recovery of 3% in animal.

Metabolite characterisation studies

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.

Any other information on results incl. tables

Table 1: Distribution of LA35S in urine and feces after administration of single dose of various quantities by stomach tube (Michael, 1968)

Quantities administered in mg  Percentage of dose excreted
Day Urine Feces Total
0.6a 1 31.6 36.6 68.2
2 7.8 18.1 25.9
3 0.8 1.4 2.2
Total 40.2 56.1 96.3
1.2a 1 53.7 22.5 76.2
2 3.3 15.5 18.8
3 0.7 0.9 1.6
Total 57.7 38.9 96.6
8.0b 1 38 37.4 75.4
2 1.3 2 3.3
3 0.9 1.7 2.6
Total 40.2 41.1 81.3
40.0b 1 38.2 31 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 2: Disposition of 3% in bile duct ligated rats 90 hours after a single dose of LAS (Michael, 1968).

  Percentage of recovered 35S activity
Urine 89
Feces 11
Total recovery of 35S  83

Applicant's summary and conclusion

Conclusions:
Based on the results, C10-13 LAS is readily absorbed by the gastrointestinal tract and rapidly excreted with its metabolites, primarily in the urine.
Executive summary:

The purpose of the study was to determine the absorption, distribution and metabolic fate of test substance, C10-13 LAS in rats.

 

Charles river male rats (150-200 g) were used in this study. The rats were housed in individual cages which permitted the separate collection of urine and feces. For the determination of disposition profile of chemical, rats were fasted for 16 hours and given orally an aqueous solution containing LA35S. The dose was given in 1.0 mL volume. The urine and feces were collected daily for examination. At the termination of the study, the animals were killed, and selected organs and tissues were taken for radioassay.

 

The absorption, route of absorption and enterohepatic circulation of test substance were also quantified in the study. 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. For absorption study, each rat received orally 1.2 mg of test substance. The urine and feces of each animal were collected for 90 hours after dosing for analysis.

 

The enterohepatic circulation of the surfactant was quantified by using a dual rat study. In this, Rat A of one pair received 1.2 mg of LAS by stomach tube, while Rat A of second pair received another chemical. The 35S containing compounds from LA35S that were excreted in bile of Rat A and transferred by cannula to Rat B were completely absorbed from the gastrointestinal tract of Rat B, and nearly two-thirds of this activity was excreted in the bile of Rat B.

 

For the excretion study, the cumulative excretion of LA35S, at dose levels 0.6, 1.2, 8.0 and 40.0 mg over a 3- day period following a single administration is determined.

 

Urine and feces samples were also analyzed for the identification of metabolites. Various analytical techniques like column chromatography, infrared, nuclear magnetic resonance (NMR), and mass spectra were used for the determination of metabolites.

 

The results revealed 80-90% of the administered dose was readily absorbed from the gastrointestinal tract and excreted primarily through urine. Of the absorbed LA35S, 60-65 % was excreted in the urine as a mixture of sulfo - phenyl butanoic and sulfophenyl pentanoic acids. 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.

 

Based on the above, LAS was readily absorbed by the gastrointestinal tract, rapidly metabolized and excreted in the urine.