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Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1974-03-11 to 1974-03-11
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study not conducted according to GLP or OECD guidelines. However, the study is a well documented in a 20 page Unilever Research Report and the test item (Sodium Lauryl Isethionate) is identified.
Objective of study:
absorption
excretion
metabolism
Qualifier:
no guideline followed
Principles of method if other than guideline:
Six experiments were conducted on radiolabelled sodium [14C] lauryl isethionate (SLI): two in vivo metabolism studies, two in vivo skin absorption studies and two in vitro skin absorption studies. The test item was applied as an aqueous solution to the skins of rats in vivo and the amounts penetrating the skin was measured. The turnover of the test item administered by subcutaneous and intraperitoneal injection in rats in vivo was also studied. Finally, the in vitro penetration of the test item through rat skin and human epidermis was also examined.
GLP compliance:
no
Radiolabelling:
yes
Species:
rat
Strain:
other: Colworth-Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Colworth
- Age at study initiation: no data
- Weight at study initiation: 120g
- Fasting period before study: no data
- Housing: no data
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data


IN-LIFE DATES: no data
Route of administration:
other: dermal, intraperitoneal, subcutaneous
Vehicle:
water
Details on exposure:
Dermal: Hair on backs clipped off 24 hours before topical applications made; 0.5mL over 10cm2 skin and massaged gently with a rounded glass rod for 1 minute whilst the rats were lightly anaesthetised with cyclopropane & left for total of 15 minutes. After the sample was removed, a non-occlusive protective patch was applied over the treated area. 6 animals

Further groups of rats were exposed using Silflo silicone cups for up to 12 hours.


Intraperitoneal: 0.5 or 1mL injected intraperitoneally; 3 animals


Subcutaneous: 1mL injected under skin of thorax; 3 animals
Duration and frequency of treatment / exposure:
Dermal: 15 minutes
Remarks:
Doses / Concentrations:
25mM aqueous solution
Dermal: 0.5mL (4.9mg test material in 0.5mL aqueous solution)
Intraperitoneal: 0.5 or 1mL
Subcutaneous: 1mL
No. of animals per sex per dose:
3 animals per route of exposure
Control animals:
no
Positive control:
Not applicable
Details on study design:
- Dose selection rationale: no data
- Rationale for animal assignment (if not random): no data
Details on dosing and sampling:
ABSORPTION, METABOLITE CHARACTERISATION & EXCRETION STUDIES
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, skin, carcass, protective patches, expired air
- Time and frequency of sampling: 24 hours after treatment
- From how many animals: (samples pooled or not) 3
- Method type(s) for identification: no data
- Limits of detection and quantification: 1.5 x 10exp3 dpm/day in urine, 5 x10exp3 dpm/day in faeces, 1 x 10exp4 dpm/day in expired C02 and for most tissues 1x 10exp3 dpm/gm
Statistics:
No data
Preliminary studies:
Not applicable
Type:
absorption
Results:
SLI can be absorbed through skin at low-moderate rate. 2 in vivo rat topical studies showed the penetration rate reached a plateau of 0.6ug/cm2/hour after 3 hours which continued to the end of the experiment
Type:
absorption
Results:
In two in vitro experiments, no penetration was measureable using rat skin. Over the 48 hour exposure period, 30µg/cm2 penetrated into the receptor solution, with approximately 10% of the dose associated with the skin at the end of the experiment
Type:
metabolism
Results:
Both s.c. and i.p. administration resulted in ~80% of the dosed radioactivity being recovered as [14CO2], indicating that breaking of the isethionate/laurate ester bond and oxidation of the resultant lauric acid is the major route of metabolism
Type:
excretion
Results:
major fate is the breaking of isethionate/laurate ester bond and the laurate is oxidised thus 80% of the dose is expired as 14C02 during first 24h after dosing. The urinary and faecal route are only minor excretion routes for test item.
Details on absorption:
Not applicable
Details on distribution in tissues:
Not applicable
Details on excretion:
Not applicable
Metabolites identified:
yes
Details on metabolites:
Both s.c. and i.p. administration resulted in approximately 80% of the dosed radioactivity being recovered as [14CO2], indicating that breaking of the isethionate/laurate ester bond and oxidation of the resultant lauric acid is the major route of metabolism. The other product produced by hydrolysis of the ester bond would be sodium isethionate.
Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results metabolism to sodium isethionate and lauric acid (and its subsequent oxidation is extensive)
From these experiments it can be seen that SLI can be absorbed through skin at a low to moderate rate. Once within the body, metabolism to sodium isethionate, lauric acid (and its subsequent oxidation) is extensive. Major fate is the breaking of isethionate/laurate ester bond and the laurate is oxidised thus 80% of the dose is expired as 14C02 during first 24h after dosing. The urinary and faecal route are only minor excretion routes for test item.
Executive summary:

Six experiments were conducted on sodium lauryl isethionate (SLI): two in vivo metabolism studies, two in vivo skin absorption studies and two in vitro skin absorption studies. 

For the metabolism (turnover) experiments, 0.5ml or 1.0ml of a 25mM aqueous solution of SLI were administered either subcutaneously under the skin of the thorax or intraperitoneally. Bothand i.p. administration resulted in approximately 80% of the dosed radioactivity being recovered as [14CO2], indicating that breaking of the isethionate/laurate ester bond and oxidation of the resultant lauric acid is the major route of metabolism. The other product produced by hydrolysis of the ester bond would be sodium isethionate; from this study, it cannot be determined whether this metabolite was further metabolised nor its route of excretion.

 

Two in vivo rat topical experiments were carried out, one with 15 minutes exposure to 0.5ml of 25mM aqueous SLR spread over 10cm2, end time point of 24 hours, and one with the same dose applied for 12 hours, end time point 12 hours. In the 15 minute exposure experiment, levels of parent/metabolites in excreta were below the limits of detection. In the 12 hour exposure experiment, the penetration rate reached a plateau of 0.6µg/cm2/hr after 3 hours, which continued until the end of the experiment. This indicated that material remaining associated with the skin at the end of the experiment would have been available for absorption.

 

In the in vitro rat skin absorption experiment, 0.25ml 25mM aqueous solution of SLI was applied to full thickness rat skin mounted in 2.5cm penetration cells. Over the 24 hour period of exposure, no penetration into the receptor solution was measurable, although 622µg were recovered from the skin itself. Extrapolating from the results of the in vivo 12 hour rat experiment, it would seem likely that the material in the skin would eventually penetrate, and that maybe something in the experimental design prevented detection of SLI in the receptor solution (too small aliquots being taken for scintillation counting is one possibility).

 

In the in vitro human skin absorption experiment, 0.25ml 25mM aqueous solution of SLI was applied to human epidermal membranes mounted in 1cm penetration cells. Over the 48 hour exposure period, 30µg/cm2penetrated into the receptor solution, with approximately 10% of the dose associated with the skin at the end of the experiment. The material remaining in the skin would have been bioavailable as indicated by the ever increasing rate of absorption over the 48hrs. 

 

From these experiments it can be seen that SLI can be absorbed through skin at a low to moderate rate. Once within the body, metabolism to sodium isethionate, lauric acid (and its subsequent oxidation) is extensive.

Description of key information

From the studies it can be seen that Sodium [14C] lauryl isethionate can be absorbed through skin at a low to moderate rate. Once within the body, metabolism to sodium isethionate, lauric acid (and its subsequent oxidation) is extensive. 
It is clear that Sodium lauryl isethionate [85408-62-4] when administered via the oral route would be rapidly hydrolyzed in the stomach and gastrointestinal tract, and when absorbed completely metabolized in the liver the single radiolabelled metabolite being lauric acid, the other metabolite being sodium isethionate. The toxicokientic experiments showed that administration by routes that avoid the hydrolysis in the gastrointestinal tract, still resulted in rapid metabolism in the liver to lauric acid (which is subsequently further oxidized to be excreted as CO2) and sodium isethionate.
This information is directly applicable also to SLMI [156572-81-5], which has the same carbon chain distribution, but with no proportion of the less easily metabolized C16 and C18 fatty acid. Therefore the SLMI would be expected to be very rapidly hydrolyzed and metabolized, more rapidly and completely than the Sodium lauryl isethionate in the studies above.

Key value for chemical safety assessment

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

Additional information

In a hydrolysis study with Sodium [14C]lauryl isethionate it was found that the material degraded by approximately 30% in simulated gastric fluid, which was considered to be probably due to acid hydrolysis, producing a single major 14C labeled metabolite. In simulated intestinal fluid degradation was approximately 10% in 6 hours. Degradation was almost complete in the presence of porcine liver esterase over 6 hour with apparently the same14C labeled metabolite being produced. It was concluded that Sodium [14C]lauryl isethionate was shown to be unstable in conditions likely to be met in the stomach, small intestine and that when subsequently absorbed would probably be completely metabolized in the liver before entering the systemic bloodstream.

In a hydrolysis study with sodium [14C]stearyl isethionate, hydrolysis in the simulated gastric juice was 40% with 10% in simulated intestinal fluid. But degradation was only 20% with the porcine esterase after 6 hours. This indicates that sodium [14C]stearyl isethionate, would be more slowly metabolized than the Sodium [14C]lauryl isethionate. This slower metabolism for the sodium [14C]stearyl isethionateis considered to be due to it having predominantly C18 fatty acid linked to the isethionate, rather than C12. The C18 fatty acid present in the sodium [14C]stearyl isethionate being expected to be more slowly metabolized than fatty acids with shorter carbon chains such as C12.

 

In the 12 hour in vivo rat dermal penetration toxicokinetic study the penetration rate plateaued at 0.6µg/cm2/h indicating that the material remaining associated with the skin would have been available for absorption.  In the in-vitro dermal penetration study in rat skin penetration was not detected over the 24 hour period, but this was considered due to limitation in the experiment.

In the in vitro dermal penetration study with human skin over 48 hours 30µg/cm2penetrated with approximately 10% of the dose associated with the skin at the end of the experiment which was considered to have been bioavailable for absorption.

 

In the metabolism experiments the Sodium [14C]lauryl isethionate [85408-62-4) was administered as aqueous solution either subcutaneously under the skin of the thorax or intraperitoneally. Both subcutaneous and intraperitoneal administration resulted in approximately 80% of the dosed radioactivity being recovered as [14CO2], indicating that breaking of the isethionate/laurate ester bond and oxidation of the resultant lauric acid is the major route of metabolism. This was demonstrated by measurement of expired14CO2in the first 24hours. The urinary and faecal routes of excretion were only minor. The other product produced by hydrolysis of the ester bond was sodium isethionate; from this study, it cannot be determined whether this metabolite was further metabolized nor its route of excretion.

From these experiments it can be seen that Sodium [14C] lauryl isethionate can be absorbed through skin at a low to moderate rate. Once within the body, metabolism to sodium isethionate, lauric acid (and its subsequent oxidation) is extensive.

 

It is clear that Sodium lauryl isethionate [85408-62-4] when administered via the oral route would be rapidly hydrolyzed in the stomach and gastrointestinal tract, and when absorbed completely metabolized in the liver the single radiolabelled metabolite being lauric acid, the other metabolite being sodium isethionate. The toxicokientic experiments showed that administration by routes that avoid the hydrolysis in the gastrointestinal tract, still resulted in rapid metabolism in the liver to lauric acid (which is subsequently further oxidized to be excreted as CO2) and sodium isethionate.

 

This information is directly applicable also to SLMI [156572-81-5], which has the same carbon chain distribution, but with no proportion of the less easily metabolized C16 and C18 fatty acid. Therefore the SLMI would be expected to be very rapidly hydrolyzed and metabolized, more rapidly and completely than the Sodium lauryl isethionate in the studies above. This would give the same primary metabolites of fatty acid predominantly lauric acid and sodium isethionate. The resulting lauric or dodecanoic acid would be absorbed in the same way as the dietary derived equivalent.Dodecanoic acid is predicted to be processed via the b-oxidation pathway in the same way as dodecanoic acid from dietary sources and be excreted as CO2. The likely high polarity of sodium 2-hydroxypropane-1-sulfonate would facilitate direct and rapid urinary elimination. Ester cleavage within the gut lumen by intestinal microflora prior to absorption is possible.  Sodium 2-hydroxypropane-1-sulfonate could be absorbed and rapidly eliminated via urine.This strongly supports the use of read across to SLMI from both the Sodium lauryl isethionate [85408-62-4] to SCI [61789-32-0] and from the sodium 2-hydroxyethanesulfonate [1562-00-1] (sodium isethionate), the common metabolite from these substances.

 

There are no oral toxicity studies using SLMI. The toxicological assessment of SLMI is based upon a read across from toxicology data obtained from a close analogues; sodium lauryl isethionate (SLI), and sodium cocoyl isethionate (SCI) (prepared from coconut acid). The structures of SLI/SCI is such that read across is also applicable for toxicokinetic assessment. The studies summarised in sections 5.2 to 5.9 have been considered:

There were no systemic toxicological effects, macroscopic findings or histopathology observed in the oral acute and repeat dose studies with SCI/SLI. In the absence of other toxicological findings the mild and transient effects noted for some animals are considered not to be definitive evidence of systemic absorption. Hence it is not possible to draw any conclusions regarding the toxicokinetic behaviour of this compound from these studies. 

No systemic toxicological effects were seen following repeated oral or dermal dosing, despite the occlusion of the site which would tend to promote absorption. The presence of slight irritancy indicates some dermal penetration, and would enhance absorption, but the lack of systemic toxicity observed means it is not possible to draw any further toxicokinetic conclusions.

In two skin irritation studies SCI was applied to either intact or abraded dorsal surface of rabbits. SCI was found to be slightly to moderately irritating. The presence of slight irritancy indicates some dermal penetration, and would facilitate absorption, but the lack of systemic toxicity observed means it is not possible to draw any further toxicokinetic conclusions.

In an eye irritation study SCI applied in water was found to be irritating to the eye. No toxicokinetic information could be concluded from this study.

Three mutagenicity assays were carried out on SCI using salmonella typhimurium, mouse lymphoma L517Y cells and Chinese hamster ovary cells. Each assay gave negative results in the presence and absence of S9. Therefore no toxicokinetic information can be concluded from these findings.