Silicate(2-), hexafluoro-, disodium, reaction products with lithium magnesium sodium silicate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

other: discussion in comparison with naturally occurring structurally related hectorite

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to other study

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1973-4

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Work carried out by recognised toxicology laboratory by qualified laboratory personnel using calibrated equipment and recognised methods of test. But the work was done in 1974 and not to GLP standards at that time

Justification for type of information:

See Document "Laponite Analog justification-BL_6_30_2020.pdf" in Section 13.2 - Toxicokinetic assessment for Synthetic fluorohectorites for justification of read-across.

Qualifier:

no guideline available

Principles of method if other than guideline:

100 rats, 50 of each gender divided into four groups, were orally dosed by intubation with a dispersion concentration of 10ml/kg of the test material in deionised water over a period of 100 consecutive days. The rats were grouped by weight and dosed according to a recorded schedule. Group 1 was the control group and had just distilled water administered. Group 2 had a low dose (5mg/kg), group 3 had a medium dose (50mg/kg) and group 4 had a high dose (500mg/kg). The rats were observed daily for signs of toxicity and mortality. All rats were weighed on day 1 and weekly thereafter and at sacrifice. Blood analysis was carried out after 6 weeks and at the end of the test period. All organs were examined after sacrifice

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

CD-1

Sex:

male/female

Details on test animals or test system and environmental conditions:

The rats were 28 days old when received for the start of the testing.

Route of administration:

oral: gavage

Vehicle:

water

Analytical verification of doses or concentrations:

not specified

Sacrifice and pathology:

Opthalmology, blood analysis, hematology, biochemistry and urinalsysis testing were carried out

Other examinations:

Rats were weighed at day 1 and then weekly thereafter and at sacrifice

Key result

Dose descriptor:

dose level:

Effect level:

>= 50 - <= 500 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

Remarks on result:

not determinable due to absence of adverse toxic effects

Critical effects observed:

yes

Lowest effective dose / conc.:

500 mg/kg bw/day (actual dose received)

System:

gastrointestinal tract

Organ:

oesophagus

stomach

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

no

Executive summary:

This study, carried out in 1973, was designed to evaluate the repeat dose oral toxicity of Laponite on rats over a period of 3 months. The material was dispersed in deionised water and the rats were fed by intubation. The rats were split into four groups, even numbers of male/female. Group 1 was the control group, (just water), group 2 was low dose (5mg/kg bw), group 3 was medium dose (50mg/kg bw) and group 4 was high dose (500mg/kg bw). The high dose group saw some premature deaths and these were found to be due to the fact that the Laponite forms a gel at high dose and this had accumulated in the animals digestive system and had not been digested. This level of dosing would not be permitted under today's controls. For surviving rats at necropsy, there were no signs of abnormalities relating to the oral dosing of the Laponite. The high dosage group resulted in half of the rats failing to survive to completion of the test but all rats in the other two groups (with the exception of 1 in the low dose group whose death was not attributed to the treatment) all survived. No systemic toxic effect as ascertained by blood analysis and histopathological examination were observed, even in the high dose rats

Cross-reference 2

Reason / purpose for cross-reference:

other: see Remarks

Remarks:

general substance background and toxicokinetics summary

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Biodegradable polymer-nanoclay composites as intestinal sleeve implants installed in digestive tract for obesity and type 2 diabetes treatment

Author:

Hsu, Wei-Hsin; Lee, Ya-Lun; Prasannan, A.; Hu, Chien-Chieh; Wang, Jun-Shen

Year:

2020

Bibliographic source:

Hsu, Wei-Hsin, et al., Biodegradable polymer-nanoclay composites as intestinal sleeve implants installed in digestive tract for obesity and type 2 diabetes treatment. 2020/05/01 Materials Science and Engineering: C 10.1016/j.msec.2020.110676

Reference 2

Reference Type:

publication

Title:

Silicon and bone health

Author:

Jugdaohsingh R.

Year:

2007

Bibliographic source:

Jugdaohsingh R. Silicon and bone health. J Nutr Health Aging. 2007;11(2):99–110.

Reference 3

Reference Type:

publication

Title:

STUDIES ON THE SIZE AND SHAPE OF CLAY PARTICLES IN AQUEOUS SUSPENSION

Author:

Kahn, A.

Year:

1957

Bibliographic source:

Kahn, A. Clays Clay Miner. (1957) 6: 220

Reference 4

Reference Type:

publication

Title:

Machado-VThe role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis

Author:

Machado-Vieira R, Manji HK, Zarate CA Jr.

Year:

2009

Bibliographic source:

Machado-Vieira R, et. al. The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis. Bipolar Disord. 2009;11 Suppl 2(Suppl 2):92–109. doi:10.1111/j.1399-5618.2009.00714.x

Reference 5

Reference Type:

publication

Title:

National InstitutMagnesium Fact Sheet for Health Professionals

Author:

National Institute of Health (NIH)

Year:

2019

Bibliographic source:

National Institute of Health (NIH) Magnesium Fact Sheet for Health Professionals https://ods.od.nih.gov/factsheets/Magnesium-HealthProfessional/ 10.11.2019

Reference 6

Reference Type:

publication

Title:

Injectable nanoclay gels for angiogenesis.

Author:

Page DJ, Clarkin CE, Mani R, Khan NA, Dawson JI, Evans ND.

Year:

2019

Bibliographic source:

Page DJ, Clarkin CE, Mani R, Khan NA, Dawson JI, Evans ND. (2019) Injectable nanoclay gels for angiogenesis. Acta Biomater. 2019 Dec;100:378-387. doi: 10.1016/j.actbio.2019.09.023. Epub 2019 Sep 19.

Reference 7

Reference Type:

publication

Title:

Critical review of any new evidence on the hazard profile, health effects, and human exposure to fluoride and the fluoridating agents of drinking water.

Author:

Scientific Committee on Health and Environmental Risks (SCHER).

Year:

2011

Bibliographic source:

Scientific Committee on Health and Environmental Risks (SCHER). Critical review of any new evidence on the hazard profile, health effects, and human exposure to fluoride and the fluoridating agents of drinking water. Report date: 16.5.2011

Reference 8

Title:

Bentonite, kaolin, and selected clay minerals

Author:

World Health Organization (WHO)

Year:

2005

Bibliographic source:

World Health Organization (WHO). Bentonite, kaolin, and selected clay minerals. Environmental Health Criteria 231, 2005

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

discussion in comparison with naturally occurring structurally related hectorite

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Silicate(2-), hexafluoro-, disodium, reaction products with lithium magnesium sodium silicate

EC Number:

285-349-9

EC Name:

Silicate(2-), hexafluoro-, disodium, reaction products with lithium magnesium sodium silicate

Cas Number:

85085-18-3

Molecular formula:

Na0.7[Mg5.3Li0.7Si8O20(OH)0.0F4.0]

IUPAC Name:

Synthetic fluorohectorite

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

Laponite Type Type 1
Date of manufacture 31/05/2009
Batch Number 09-2151-1

Test animals

Species:

rat

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Remarks on result:

other: see Remarks

Remarks:

see Any Other Information on Results

Results (fetuses)

Effect levels (fetuses)

Remarks on result:

other: see Remarks

Remarks:

see Any Other Information on Results

Overall developmental toxicity

Developmental effects observed:

no

Any other information on results incl. tables

There is no evidence that the substance is absorbed through ingestion, dermal contact or inhalation None of the ions present are known to have effects on fertility or reproduction.No effects were observed in the 90-day study on a similar read-across material (Laponite type 2) to indicate effects on gonads. It is not considered justified to perform further animal testing on this class of substance.

Laponite is a synthetically manufactured layered silicate similar to a naturally occurring smectite clay: Hecotorite. Laponite, a Silicate(2-), hexafluoro-, disodium, reaction products with lithium magnesium sodium silicate, (EC no 285-349-9) is a monoconstituent substance and is an inorganic layered silicate structure with a unit cell of the following composition: Na_0.7[Mg_5.3Li_0.7Si₈O₂₀(OH)_0.0F_4.0]. Hectorite is a trioctahedral, magnesium based smectite clay with a unit cell of the following composition: H₂LiMgNaO₁₂Si4^-2. The unique properties of the naturally occurring hectorite active mineral are very small platelet size, an elongated platelet structure with an inherent negative charge counterbalanced by exchangeable sodium (Na+) ions, light color with low iron content and high viscosifying ability in water.

Na, Mg, Li and Si are already widely found in the environment both in waters and soils / sediments. If released to the environment, the substance is expected to combine indistinguishably with the soil or sediment due to its similarity with inorganic soil/sediment matter and will be subjected to natural processes under environmental conditions (cation exchange, dissolution, sedimentation). Furthermore the potential human exposure to laponite is negligible in comparison to the release by natural deposits or alteration of naturally occurring clays with similar compositions.

Laponite is not expected to pose serious risk via the systemic absorption route. Lithium is the only metal that is less common from natural exposures. A review of publicly available information has indicated that lithium is not expected to bioaccumulate and its human and environmental toxicity are 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 and has been utilized as a pharmacological treatment for over 60 years (Machado-Vieira et al. 2009). Excreted lithium from human use will find its way into the environment naturally. Accumulating evidence over the last 30 years strongly suggest that dietary silicon is beneficial to bone and connective tissue health and there are strong positive associations between dietary silica intake and bone mineral density. Dietary intake of silica is between 20-50 mg Si/day for most Western populations (Jugdaohsingh, 2007). Mg and Na are abundant minerals in the body, they are naturally present in many foods, added to other food products, available as a dietary supplement, and present in some medicines (such as antacids and laxatives). Magnesium is a cofactor in more than 300 enzyme systems that regulate diverse biochemical reactions in the body, including protein synthesis, muscle and nerve function, blood glucose control, and blood pressure regulation (NIH 2019). In humans and animals, ingested fluoride occurs as hydrogen fluoride (HF) in the acidic environment of the stomach and is effectively absorbed from the gastrointestinal tract, although there is no proved absorption from the oral cavity. Once absorbed, fluoride is rapidly distributed throughout the body via the blood. Approximately 99% of the fluoride in the human body is found in bones and teeth. Renal excretion is the major route of fluoride removal from the body.

None of the ions present are known to have effects on fertility or reproduction. No effects were observed in the 90 day study to indicate effects on gonads. No significant differences we observed in the contents of magnesium, sodium in the brain, kidney, liver, or tibia from pregnant SD rats dosed with 2% sodium montmorillonite or calcium montmorillonite clay compared with animals fed the basal diet. (WHO, 2005)

Laponite exhibited no toxicity in acute testing (oral, dermal, inhalation), mutagenicity and cytogenicity (See submitted studies) or any other toxicological relevant pathway. In addition Laponite is currently being explored as a potential drug delivery mechanism for angiogenesis (Page DJ., 2019), in implantable medical devices (Hsu, 2020). Laponite is a synthetic clay based on hectorite a naturally occurring clay mineral. There have been no epidemiological or toxicologically relevant studies on hectorite that found potential risk from hectorite exposure. Laponite is a synthetic clay with the same functional chemical composition as hectorite. Any nanoform exposures from laponite would be comparable to background exposure from the nanoform compartment of hectorite (Kahn, 1957).

Applicant's summary and conclusion

Conclusions:

There is no evidence that the substance is absorbed through ingestion, dermal contact or inhalation
None of the ions present are known to have effects on fertility or reproduction so further animal testing is not warranted based on animal welfare reasons.

Executive summary:

There is no evidence that the substance is absorbed through ingestion, dermal contact or inhalation

None of the ions present are known to have effects on fertility or reproduction so further animal testing is not warranted based on animal welfare reasons.