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Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
not specified
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]LABS Na 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-LABS Na
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-LABS Na 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 LABS Na 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.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
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 LABS Na (radioactively labeled with 35S) were studied in male Charles River rats. LABS Na 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
Dose / conc.:
0.6 other: mg
Remarks:
averages of three animals, for the excretion test
Dose / conc.:
1.2 other: mg
Remarks:
averages of three animals, for the excretion test
Dose / conc.:
8 other: mg
Remarks:
averages of five animals, for the excretion test
Dose / conc.:
40 other: mg
Remarks:
averages of five animals, for the excretion test
Dose / conc.:
1.2 other: mg
Remarks:
per 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 LABS Na 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 LABS Na 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.

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 cadavars
- 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 diamter 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 cadavars. 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.

Endpoint:
dermal absorption 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.
Reason / purpose for cross-reference:
reference to same study
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%.

Description of key information

No experimental data (animal or human studies) on the toxicokinetic behaviour of the target substance is available. A read across evaluation was developed to fill the data gaps with LABS Na as source substance.

The absorption factors were set as follows: oral 50%, inhalation 100% and dermal 10%.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
100

Additional information

Toxicokinetic assessment of HIMO LABS Na

HIMO LABS Na (no CAS or EC number; Benzenesulfonic acid, 4-C20-24 (even numbered) sec-alkyl derivs., sodium salts), is a light brown liquid with the molecular weight of 516.8 g/mol. The physical chemistry values were determined via QSAR and in a test. The QSAR value is used for water solubility, resulting in a very low water solubility of 1.65 x 10 -5mg/L, and supported by the unbounded <10 mg/L in the test. The QSAR resulted in a high log Pow (8.82 at 20 °C), supported by an unbounded value in the test: >1.7. The QSAR resulted in a very low vapour pressure (8.57 x 10-18Pa), while the test showed a vapour pressure of 13.9 Pa at 20°C. The highest value for vapour pressure was considered key as this represents the worst case.

No experimental data (animal or human studies) on the toxicokinetic behaviour of the target substance HIMO LABS Na is available. A read-across evaluation was developed to fill data gaps (according to scenario 2 of ECHA’s RAAF, 2017) with LABS Na (CAS number 68411-30-3) as the source substance. The justification for this read-across approach is included in IUCLID section 13.

LABS Na (CAS number 68411-30-3; EC number 270-115-0; Benzenesulfonic acid, C10-13-alkyl derivs., sodium salts), is a solid compound with a moderate molecular weight (334 g/mole), a high water-solubility (>250 g/L, miscible), a high log Pow (3.32) and a very low vapour pressure (3.0 x 10-13Pa, calculated using the Lyman method).

The data presented in this dossier are based on physico-chemical and toxicological parameters and will allow a qualitative assessment of the toxicokinetic behavior of LABS NA and thus also of HIMO LABS Na.

Pharmacokinetics of LABS Na

The following publications on the pharmacokinetic behavior and bioavailability of LABS Na are considered relevant:

·      The disposition of radioactivity was studied in single and repeated oral and subcutaneous doses of [14C]LABS Na to rhesus monkeys (publication, K2, WoE, Creswell et al., 1978). After single oral doses of 30, 150 and 300 mg/kg, peak plasma concentrations (at 4 hours in all cases) were very similar, with levels of 34, 41 and 36 µg/mL, respectively.  Concentrations declined during the period of 6-24 hours, with a biological half-life of about 6.5 hours. After single subcutaneous doses of 0.1, 0.5 and 1 mg/kg, peak plasma concentrations increased almost proportionately, with levels of 0.16, 0.72 and 1.13 µg/mL, respectively.  During 7 consecutive daily oral (30 mg/kg/day) or subcutaneous (1 mg/kg/day) doses, there was no accumulation of radioactivity in plasma.  Mean peak concentrations and biological half-lives were similar after the first and seventh doses.  Two hours after the last dose, the highest radioactivity was observed in the stomach.  Radioactivity was also observed in the intestinal tract, kidneys, liver, lung, pancreas, adrenals and pituitary. At 24 hours, concentrations were highest in the intestinal tract, probably indicating biliary excretion. Since the concentrations in the tissues in general were lower than in plasma, no specific accumulation of LABS Na occurred. Results show that LABS Na 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. LABS Na does not bioaccumulate in the tissues.

·      The absorption, distribution, metabolism and elimination of LABS Na (radioactively labeled with35S) were studied in male Charles River rats (publication, K2, WoE, Michael, 1968). Three or five animals were dosed via oral administration with 0.6, 1.2, 8.0 or 40.0 mg for the excretion test; or 1.2 mg/rat in the absorption or enterohepatic tests. LABS Na was readily absorbed by the gastrointestinal tract and rapidly metabolized and excreted in the urine.

 

Absorption

Differences in toxicity between different alkylbenzene sulfonic acid derivatives can be partially explained by differences in bioavailability. Water solubility can be considered as the preferred parameter to get an indication of differential bioavailability. In general, water soluble compounds will give rise to a relatively higher bioavailability compared to insoluble compounds such as the target substance. Testing data for water soluble compounds (such as LABS Na) can be used as indicators in read across to less soluble compounds, provided that the difference in water solubility is considered.

Both HIMO LABS Na and LABS Na have high log Pow values >0 (8.82 and 3.32 (estimated), resp.). In addition, a molecular weight below 500 makes LABS Na favourable for absorption (Mw 334 g/mol). Nevertheless, a substance with such a log P value can be poorly soluble in lipids and hence not readily absorbed with its low water solubility (as is the case for HIMO LABS Na). The substance LABS Na has a high water-solubility and is thus more readily absorbed.

 

Oral/GI absorption:

Since alkylbenzene sulfonic acids such as the target substance are strong acids, they are completely ionized and thus expected to not readily diffuse across biological membranes leading to low oral absorption. Furthermore, since the target substance is considered insoluble in water due to its long apolar alkyl chain, it is not expected that this substance will dissolve into the gastrointestinal fluids and thus not be absorbed through passive diffusion. On one hand, absorption of surfactants may be enhanced due to damage to cell membranes but it is expected to be small due to its long apolar chain and its moderate hydrophobic character. On the other hand, the target substance is considered a lipophilic substance due to its high logPow value and may therefore be taken up by micellular solubilisation. This is especially the case for poorly water-soluble substances which would otherwise be poorly absorbed.

Oral absorption from the gastrointestinal tract was observed in the toxicokinetic study carried out with the structural analogue LABS Na (see above). However, this compound is a lot more water soluble, which is an important parameter that favours oral absorption.

No repeated dose toxicity studies are available with the target substance. Though, a reliable chronic oral toxicity study of LABS Na is available and can be used to estimate the oral absorption behaviour of the target substance. In this study, male and female rats were exposed to LABS Na in the diet daily for 6 months. Diarrhea, suppressed growth, increased cecal weight and degeneration of renal tubes characterized the highest dose (115 mg/kg) group. Therefore, it is expected that the target substance is absorbed to some extent after oral intake.

Based on the physicochemical properties of the test substance and the repeated dose oral toxicity study of LABS Na, the oral absorption factor of the test substance is considered 50%.

 

Respiratory absorption:

Based on its low volatility (vapour pressure < 0.5kPa), the availability of the test substance for inhalation as a vapour is limited. Since it is a liquid, the test substance has the potential to readily diffuse/dissolve into the mucus lining of the respiratory tract. The lipophilic character of the test substance implies that the substance has limited potential to be absorbed directly across the respiratory tract epithelium. Lipophilic substances are taken up by micellular solubilisation particularly when the water solubility is so low that the substance would otherwise be poorly absorbed, as is the case for the test substance. Furthermore, penetration of the test substance to the lower respiratory tract is enhanced due to its low water solubility.

No repeated dose inhalation studies are available for the target substance.

Based on the observations described above, the inhalation absorption factor of the test substance is considered 100%.

 

Dermal absorption:

Due to its low water solubility (< 1 mg/L), dermal uptake of the test substance is expected to be low because the substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Furthermore, based on its high log Pow value, the transfer fate between the stratum corneum and the epidermis will be slow and limit absorption across the skin.

Acute dermal toxicity of LABS Na was determined in 5 male and 5 female rats, according to OECD guideline 402. LABS Na was administered via dermal application at 2000 mg/kg bw and exposure lasted 24hrs, after which the test substance LABS Na was removed by washing. During a 14-day observation period, no mortality was observed. There were no signs of systemic toxicity, but reversible signs of slight erythema and slight edema were noted.

Two dermal absorption studies with LABS Na are performed:

·      The radiolabeled test substance sodium 2-dodecylbenzene sulfonate was applied (0.1 ml of a 3mM solution) in an ex vivo dermal absorption study to samples of human abdominal skin from four female cadavers (publication, K2, Howes, 1975). 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.

·      In an in vivo dermal absorption study, the radiolabeled sodium 2-dodecylbenzenesulfonate test substance (3mM solution) was applied to the shaved skin of female rats. The exposure lasted 15 min, after which it was rinsed off. After a 24 hrs observation period, during which 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%.

Based on the physicochemical properties and the results of toxicity studies, the dermal absorption factor is set to 10%.

 

Distribution

The low water solubility and the relatively high molecular weight (>500 g/mol) predict that the test substance will probably not distribute through the body by diffusion through aqueous channels and pores. The substance is lipophilic (logKow>0) and therefore likely to distribute into cells. Target organs cannot be specified based on toxicological studies.

 

Accumulation

The test substance has a low water solubility and is lipophilic. Accumulation is expected within the body if exposures would be continuous. This accumulation will mainly take place in the adipose tissue since this accumulation site is prone to concentrate lipophilic substances. Once exposure stops, the substance will be eliminated at a rate dependent on the half-life of the product.

Based on the physicochemical properties (low water solubility, log Pow of 8.82) of the test substance, no (or little) accumulation is expected within the lungs, bones or stratum corneum. This can also be confirmed by the toxicokinetic study carried out with the water soluble structural analogue LABS Na (see above), where no accumulation took place.

 

Metabolism

Based on the structure, the test substance might undergo phase I biotransformation such as hydroxylation followed by conjugation reactions (phase II) such as glucuronidation (by the enzyme glucuronosyltransferase) and sulphation (by the enzyme sulfotransferase). The Phase II conjugation reactions largely increase the hydrophilic character of the product. Metabolism can take place in the liver, gastrointestinal (GI) flora or within the GI tract epithelia (mainly in the small intestine), respiratory tract epithelia (in the nasal cavity, trachea-bronchial mucosa and alveoli and skin), etc.

Metabolism mainly takes place in the liver, causing route specific presystemic (or first pass) effects, especially after oral intake, which is deemed to be limited. Other metabolic changes may take place in the gastrointestinal flora or within the GI tract epithelia (mainly in the small intestine), respiratory tract epithelia (in the nasal cavity, trachea-bronchial mucosa and alveoli and skin), etc.

 

Excretion

The toxicokinetic study with LABS Na described above also indicated that the primary route of excretion of this structurally similar compound is the urine. The substances that will be excreted in the urine are most likely conjugated metabolites from Phase II biotransformation. This is most likely the case for the test substance since the metabolites will be more water soluble and thus favourable for urinary excretion in comparison to the compound itself. Most of the metabolites are filtered out of the blood by the kidneys though a small amount may enter the urine directly by passive diffusion.

Another route of excretion of conjugated derivatives is the bile which involves active secretion rather than passive diffusion. The excretion via the bile is highly influenced by hepatic function since metabolites formed in the liver may be excreted directly into the bile without entering the bloodstream. Products in the bile pass through the intestine before excretion in the faeces and can thus undergo enterohepatic recycling which will prolong their half-life.