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Endpoint:
basic toxicokinetics
Type of information:
calculation (if not (Q)SAR)
Remarks:
Migrated phrase: estimated by calculation
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Assessment based on existing toxicological data
Reason / purpose for cross-reference:
other: see Remarks
Remarks:
general substance background and toxicokinetics summary
Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 428 (Skin Absorption: In Vitro Method)
Version / remarks:
OECD Guideline 428, Skin Absorption: in vitro Method, adopted 13 April 2004
Deviations:
no
Principles of method if other than guideline:
The test item Laponite XLG - Silicic acid, lithium, magnesium, sodium salt was investigated in vitro on its absorption and penetration properties on human skin. For all 12 replicates 7 different donors were used. The analyzed compound was Lithium.
For the determination of the dermal absorption/percutanous penetration properties of the test substance skin pieces were mounted onto Franz chambers and after checking the skin integrity, a finite dose of the test preparation (10 µL) was applied onto the skin and was left on the skin for an exposure period of 24 hours under non-occluded conditions in a practice relevant manner. Afterwards the test preparation was removed by washing the skin with extraction solution.
Benzoic acid and 2-Ethylhexyl trans-4-methoxycinnamate are used as positive and negative control substances known to permeate or not permeate the skin to demonstrate the performance of the system.
GLP compliance:
yes (incl. QA statement)
Specific details on test material used for the study:
Identity: Laponite XLG - Silicic acid, lithium, magnesium, sodium salt
Description: 3 % (w/w) Laponite XLG in deionised water
Batch No.: Bx 11-249
Content of test substance: 809 ng lithium in 10 mg test item
Purity: not applicable, product is a dispersion
Stability in water: > 1 year
Storage: At room temperature
Expiry date: December 2012
Species:
other: human skin taken from the abdoment
Details on test animals or test system and environmental conditions:
Human skin was provided dermatomized by Biopredic, Rennes (France).
Whole skin with a thickness of 425 - 557um and free of any adipose tissue was used. The surface of the skin in contact to the test item was 1.0 cm².
7 donors were used in this study.
A limited amount of the test preparation corresponding to realistic in use conditions was applied to the surface of the skin. According to the guideline cited the application of the test item to the skin should mimic realistic conditions. 10 µL of the test item were applied to the skin. 
Details on in vitro test system (if applicable):
For the determination of the dermal absorption/percutanous penetration properties of the test substance skin pieces were mounted onto Franz chambers and after checking the skin integrity, a finite dose of the test preparation (10 µL) was applied onto the skin and was left on the skin for an exposure period of 24 hours under non-occluded conditions in a practice relevant manner. Afterwards the test preparation was removed by washing the skin with extraction solution.
Signs and symptoms of toxicity:
not examined
Dermal irritation:
not examined
Key result
Time point:
24 h
Dose:
10 µL of the test preparation (3 % (w/w) Laponite XLG in deionised water ) were applied on the skin in the respective donor chamber. The application of the test item to the skin should mimic realistic conditions.
Parameter:
percentage
Absorption:
1.8 %

It is assumed that substances penetrating the stratum corneum of the skin during the exposure time diffuse into the dermis and/or the receptor solution over the 24 h monitoring time since penetration of the outer layer of the skin is considered as the rate limiting step.

The amount of penetrated test substance was determined by its concentration in the collected samples. For a worst case consideration the amounts of test item found in the receptor vials and in the extracts of the remaining skin after tape stripping were considered to have penetrated the skin respectively to be systemically available.

The amounts of test substance measured in the combined washing solutions, in the extracts of the skin areas not in contact with the receptor fluid are considered not to have passed the skin. An overall mass balance of Lithium was calculated.

The various samples solutions from the skin dermal absorption assay were analyzed by AAS for the presence of Lithium. The LLOQ for Lithium was 1.00 ng/mL in receptor solution and extraction solution. Four chambers examined for Lithium did not meet the acceptance criteria (chambers 1, 4 and 5 of experiment 1, and chamber 6 of experiment 2) due to recovery not in the range of 85-115 %. So in total 8 chambers met the requirements of the study. So in total 8 chambers were used for calculation of dermal delivery of Lithium.

Lithium was detected in only two fractions relevant for dermal absorption, which are the extract of the dermis and epidermis, but not in the receptor fluid samples. In the samples where no Lithium was detected for worst case considerations a Lithium concentration of 1.00 ng/mL (LLOQ) was assumed. So a major part of the reported dermal delivery comes only from this calculation.

In conclusion, it can be stated that under the reported conditions, 15.6 ng/cm² (1.80 % of applied dose) had penetrated the skin and are considered as bioavailable portion 

Conclusions:
The test item Laponite XLG - Silicic acid, lithium, magnesium, sodium salt was investigated in vitro on its absorption and penetration properties on human skin. For all 12 replicates 7 different donors were used. The analyzed compound was Lithium.
Two experiments were performed with human skin samples which were stored frozen until use and under static non-occluded conditions. Thus the test substance was analysed in 6 replicates per experiment (12 replicates in total).
The thickness of the skin used was 425 - 557 um. The blank samples (KBL, at 0 hours) were collected immediately after filling the donor chambers at the maximal flow rate of the pump prior to application of the test item. The conductivity across the skin samples of each chamber was determined before treatment and after the last sampling as a measure of skin integrity. The integrity of the skin was demonstrated prior to application and only skin samples within the acceptable range of ≤900 µS/cm were used. In addition, no major impairment on the skin layer was detectable after incubation with the test item.
10 µL (corresponding to approx. 809 ng/cm2 Lithium, theoretical value) of the test preparation were applied on each skin sample, left on the skin for 24 hours and then washed off using 5% HNO3 (extraction solution).
The stratum corneum was removed from the skin by stripping 10 times, and extracted with extraction solution. The epidermis was separated from the dermis using heat separation. Both skin compartments were extracted with extraction solution. Analysis for the presence of Lithium was carried out by means of AAS (atom absorption spectroscopy). The LLOQ was determined as 1.00 ng/mL for Lithium in PBS (receptor solution) and extraction solution.
8 out of 12 chambers met the acceptance criteria and were used for the assessment of the absorption and penetration properties. Four chambers examined for Lithium did not meet the acceptance criteria (chambers 1, 4 and 5 of experiment 1, and chamber 6 of experiment 2) due to recovery not in the range of 85-115 %. So in total 8 chambers met the requirements of the study.
Lithium was detected in only two fractions relevant for dermal absorption, which are the extract of the dermis and epidermis, but not in the receptor fluid samples. In the samples where no Lithium was detected for worst case considerations a Lithium concentration of 1.00 ng/mL (LLOQ) was assumed. So a major part of the reported dermal delivery comes only from this calculation.
Executive summary:

In conclusion, it can be stated that under the reported conditions, 15.6 ng/cm² (1.80 % of applied dose) had penetrated the skin and are considered as bioavailable portion. It is assessed from this anlysis that a negligible amount of Laponite XLG in dispersed (nano) form has penetrated the skin barrier and as such should not be considered as being bioavailable via dermal exposure.

Description of key information

The test material has a low potential for any absorption by oral ingestion and dermal absorption.

Since the test material has a low potential for absorption by any route it means that the test material will not be readily bioavailable. The majority of any test material that is ingested orally is likely to pass through the gastrointestinal (GI) tract unchanged and be excreted in the faeces. Any small amount of constituents from the test material that are absorbed by the gut will enter the essential elemental pool along with those that are absorbed from the daily nutritional requirement of elements and therefore are not considered to be of any toxicological significance. Na, Mg and Si are found naturally in the human body. Lithium is the only metal that is less common. A review of publicly available information has indicated that lithium is not expected to bioaccumulate and its human toxicity is low. Large doses of lithium (up to 10 mg/L in serum) are given to patients with bipolar disorder. A provisional recommended daily intake of 14.3 μg/kg body weight lithium for an adult has been suggested. Lithium does not accumulate in the body since daily doses are required to maintain effect.

No bioaccumulation potential based on study results

For dermal absorption or penetration of this substance in nano form once totally dispersed in aqueous medium, it can be stated that under the reported conditions, 15.6 ng/cm² (1.80 % of applied dose) had penetrated the skin and are considered as bioavailable portion. It is assessed from this anlysis that a negligible amount of Laponite XLG in dispersed (nano) form has penetrated the skin barrier and as such should not be considered as being bioavailable via dermal exposure.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - dermal (%):
1.8

Additional information

The test material silicic acid, lithium magnesium sodium salt (EC no 258-476-2) is a monoconstituent substance and is an inorganic layered silicate structure with a unit cell of the following composition

Na0.7+ [(Si8Mg5.5Li0.3)O20(OH)4]0.7-  

It is an inorganic synthetic version of hectorite clay, which is smectite clay that commonly occurs in nature.

LAPONITE Type 2 products are placed on the market in the form of a finely divided granular powder and also in the form of a ready-to-use concentrated dispersion in water.

 

The powder granules are composed of aggregates of nano-sized particles. The powder granules are micro-sized particles. Hence Laponite Type 2 is supplied to downstream users as a powder product with micro-sized particles.

During use in most application fields the user will add LAPONITE Type 2 powderproduct intowaterwithmixing. The aggregates willwet out, hydrate anddisperseintoindividual primary particles, givinga clear, colourless and stable dispersion of nanoparticles, also called a colloidal dispersion.

In some application fields, LAPONITE Type 2 powder is wetted out into non-aqueous fluids, such as mineral or silicone oils or polyols. In such cases LAPONITE Type 2 does not disperse into individual primary particles and a colloidal dispersion is not formed.

The LAPONITE Type 2 products supplied as a ready-to-use concentrated dispersion in water are already in the form of a stable dispersion of nanoparticles.

 

Measurementsbyanalyticaltechniquessuchas AFM,TEM, SAXS and comparisons made with similar materials, naturally occurring layered silicates, hectorite and montmorillonite indicatethatLAPONITE Type 2primary particles havealayerstructure,and aredisc-shaped. According to the CommissionRecommendationof18October, 2011,onthedefinitionofnanomaterial (2011/696/EU), 100% of the synthetic silicate component of LAPONITE Type 2 is classified as a nanomaterial.

Some grades of LAPONITE Type 2 contain additives; these are either water soluble salts or polymer materials, which are not nanomaterials.

 

Typical particlesizemeasurementsofLAPONITE Type 2materialsinthesetwodifferentphysicalstates,powderas supplied and dispersed colloid, are shown below:

 

Powder as supplied (D50)

D10 = 4.6µm, D50 = 48.2µm, D90 = 124.3µm, D99 = 167.0µm(1)

(1)Sympatec particle size analyser, Helos H0399, incorporating a Retsch Vibri feeder, Rodos and venturi(laser deflection on powder dispersed in air)

 

Dispersed colloid (Z Ave.)

Z Ave. = 25.4nm(2)

Typically, the disc shaped LAPONITE Type 2 primary particle is 0.9-1.0nm in thickness (x Dimension) and 4.0-73.0nm in diameter (y and z Dimensions)

(2) Malvern Zetasizer Nano ZS (Dynamic Light Scattering – DLS – on 1% solids dispersion in deionized water)

The dispersed particles have a negative charge on the surface and a positive charge on the edge of the disc. When LAPONITE Type 2 is dispersed in water and used in a formulation, such as a paint, drilling fluid or cosmetic product, the oppositely charged edges and faces form electrostatic associations with each other. The charged sections of the LAPONITE Type 2 discs can also form associations with oppositely charged sections of other particles, such as dispersion resins and pigments and also molecules, such as polymers that are present in the formulation. These associations form a single continuous network that extends throughout the whole of the container that is holding the formulation. It is this network of particle-particle and particle-polymer associations which develops the very high levels of viscous structure that is typical of formulations containing LAPONITE Type 2. These viscous structures are micro-sized. The viscous structure can be reduced under shear forces, such as mixing or pumping and will build up again when shear forces are removed.

 

Typical use levels of LAPONITE Type 2 in a formulation can range from 0.1% up to 5% or higher.

 

In a water solubility study with silicic acid, lithium magnesium sodium salt (carried out by means of dialysis because of the unusual nature of this material) the nominal loading rate of 0.1 g/l confirmed that this substance was essentially insoluble in water at its natural pH of 10 and whilst not dissolving in water it disperses to form a clear sol (McCarthy & Doyle 2010a)

 

In addition a hydrolysis study, again using a dialysis method to determine the release of component ions from the structure, confirmed that no hydrolysisof lithium and magnesiumoccurred at pH values from 4 – 10. Results indicated dissociation of lithium and magnesium at pH below 4 and significant dissociation at pH 1. (McCarthy & Doyle 2010b)

 

Particle size analysis of a typical sample showed that 80% of particles were smaller than 100µm and ~ 16% of particles were smaller than 10 µm in the respirable fraction (Doyle 2010c).  

 

In the acute inhalation study the 1 hr LC50of Optigel SH (silicic acid, lithium magnesium sodium salt) was calculated to be >200 mg/L (Nitka 1988). As such although silicic acid, lithium magnesium sodium salt has the potential to be inhaled due to its particle size distribution it doesn’t exhibit inhalation toxicity at a high dose in the rat. Since the test material would have virtually no solubility in alveolar fluid at a pH of around 6, it is considered the inhaled test material will not be absorbed. 

 

The acute oral median lethal dose (LD50) of the test material was estimated to be > 2000 mg/kg bw (A Pooles, 2010). As such, the test material has a very low potential for toxicity by oral absorption.

 

The LD50 in the dermal toxicity study was > 2000 mg/kg (Nitka 1988).