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EC number: 234-759-6 | CAS number: 12031-82-2
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Description of key information
The Local Lymph Node Assay demonstrated that Lithium titanate does not have the potential to cause skin sensitisation and therefore should not be classified and labelled for skin sensitisation according to Regulation (EC) No. 1272/2008 and its subsequent regulations.
Key value for chemical safety assessment
Skin sensitisation
Link to relevant study records
- Endpoint:
- skin sensitisation: in vivo (LLNA)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Experimental Start Date: 07 September 2020
Experimental Completion Date: 29 September 2020 - Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- As an assessment of skin sensitisation potential could not be made using either existing information on lithium titanate, or by conduct of in chemico and in vitro testing according to OECD test guidelines 442C, D and E, it is considered that in vivo testing in accordance with Point 8.3.2 of Annex VII of the REACH regulation is justified, and that if possible, this should be a Local Lympf Node Assay in accordance with the OECD 429.
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.42 (Skin Sensitisation: Local Lymph Node Assay)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Type of study:
- mouse local lymph node assay (LLNA)
- Specific details on test material used for the study:
- Lithium titanate, also known as Dilithium titanate, Lithium metatitanate and Lithium titanium oxide (CAS number 12031-82-2, EC number 234-759-6), batch number SLEA 7084, was a white powder. It was received on 13 August 2020 and stored at 15-25°C, protected from light. Purity was stated as >98% and the expiry date was given as 23 September 2021. The test article information and certificate of analysis provided by the Sponsor are considered an adequate description of the characterisation, purity and stability of the test article. Determinations of stability and characteristics of the test article were the responsibility of the Sponsor.
- Species:
- mouse
- Strain:
- CBA
- Sex:
- female
- Details on test animals and environmental conditions:
- Animal Specifications and Acclimatisation
Nulliparous, non-pregnant female CBA/CaCrl strain mice were obtained from Charles River (UK) Ltd., Margate. All animals were given a clinical inspection for ill health on arrival and a sample was weighed.
Mice were arbitrarily selected from the delivery boxes and allocated to the appropriate number of cages. The condition of the animals was assessed daily throughout the acclimatisation period of 8 to 15 days. A second inspection was performed prior to study commencement to ensure the animals were suitable for the study. Overtly healthy animals were arbitrarily allocated to the study groups on Day 1, prior to the commencement of treatment.
Animals in the main study were in a body weight range of 18 to 22 g on Day 1 of dosing. Individual body weights were within ±20% of the mean body weight for mice on the study. Based on information from the supplier the mice were approximately 9 to 10 weeks old on Day 1.
Environmental Conditions, Diet and Water
The animals were kept in the following conditions except for short periods of time where experimental procedures dictated otherwise.
Housing
The animals were housed in groups of up to five during acclimatisation, in cages that conformed to the 'Code of Practice for the Housing and Care of Animals Bred, Supplied or Used for Scientific Purposes’ (Home Office, London, 2014). From Day 1 the preliminary animal housed individually, while the main study animals were housed in pairs.
Bedding was provided on a weekly basis to each cage by use of clean European softwood bedding (Datesand Ltd., Manchester, UK). The bedding had been analysed for specific contaminants and the results retained on file at Covance.
No contaminants were present in bedding at levels which might have interfered with achieving the objective of the study.
Water
Mains water was provided, ad libitum, via cage-mounted water bottles. The water had been periodically analysed for specific contaminants.
No contaminants were present in water at levels which might have interfered with achieving the objective of the study. Results are retained on file at Covance.
Diet
5LF2 EU Rodent Diet 14% was freely available to the animals at all times. Each batch of diet had been analysed for specific constituents and contaminants by the manufacturer.
No contaminants were present in diet at levels which might have interfered with achieving the objective of the study. Results are retained on file at Covance.
Environment
The animal rooms were designed to permit a minimum of 15 air changes per hour. The temperature and humidity ranges were 19 to 25C and 40 to 70% respectively. Daily recordings of maximum and minimum temperature and humidity were made.
Fluorescent lighting was controlled automatically to give a cycle of 12 hours light and 12 hours dark.
Environmental Enrichment
In order to enrich both the environment and the welfare of the animals, they were provided with wooden Aspen chew blocks and nesting materials. The nesting materials were removed from the cages on Day 1, prior to dosing.
Animal Identification and Assignment to Study
A unique number was inscribed onto the tail with indelible ink on Day 1, prior to dosing, to individually identify the mice. A colour-coded card on each cage gave information including study number, animal number and sex.
Mice were arbitrarily selected from the delivery boxes and allocated to the appropriate number of cages. Overtly healthy animals were arbitrarily allocated to the study groups on Day 1, prior to commencement of treatment. - Vehicle:
- propylene glycol
- Concentration:
- Preliminary screening test: 25 µL of the test article at the maximum suitable concentration (50% w/v in propylene glycol)
Main study: 10% w/v, 25% w/v and 50% w/v - No. of animals per dose:
- Four
- Details on study design:
- Test Article Formulation
Formulations were freshly prepared using propylene glycol on Days 1, 2 and 3. The formulations were stored at room temperature, in sealed, air-tight containers prior to dosing and were used within two hours of preparation.
The formulations were mixed by multiple inversion of the containers prior to administration to ensure homogeneity.
Concentrations of test article were expressed gravimetrically and in terms of test article received (without regard to purity or active content).
Preliminary Screening Test
According to two in vitro skin irritation/corrosion studies, the test substance was considered to have no skin irritation/corrosion potential (Warren, 2020; Lacey, 2020). Furthermore, no mortality was observed in rats during an acute oral toxicity study (LD50 > 2000 mg/kg bw; Ferreira, 2020). A preliminary screening test was conducted with one animal prior to the Main Study.
The mouse was treated by daily application of 25 µL of the test article at the maximum suitable concentration (50% w/v in propylene glycol) to the dorsal surface of each ear for three consecutive days (Days 1, 2 and 3). The mouse was observed daily for any signs of toxicity or irritation at the application site. The body weight was recorded prior to dosing on Day 1 and prior to termination on Day 6. Both ears were observed for erythema and scored
Ear thickness measurements were taken using a thickness gauge on Day 1 (pre-dose), Day 3 (approximately 48 hours after the first dose) and Day 6.
Excessive local irritation is indicated by an erythema score ≥3 and/or an increase in ear thickness of ≥25% on any day of measurement.
Main Study
Groups of four female mice were assigned to study according to the table given below. Doses were selected from the concentration series 50%, 25%, 10%, 5%, 2.5%, 1.0%, 0.5% etc. Three consecutive concentrations were selected on the basis of the preliminary screening test so that the highest concentration maximised exposure whilst avoiding systemic toxicity and/or excessive local irritation. As the vehicle for the test article formulation was different to that used for the positive control formulation, a positive control vehicle group (acetone / olive oil in a ratio of 4:1 v/v) was also included in the study.
Inlife Procedures
Test Article Administration
Each mouse was manually restrained with both auditory pinnae left free. The outer aspect of both pinnae of each mouse was treated by direct application of the appropriate test or control formulation (0.025 mL/pinna) dispensed from an automatic micro pipette.
Treatment Regimen
The six groups of four female mice were subjected to application of the test article vehicle control, positive control vehicle, positive control or one of the test formulations to the outer aspect of the auditory pinnae, once daily on Days 1, 2 and 3.
On Day 6 the mice were placed in a thermacage in order to dilate the peripheral blood vasculature and thus facilitate intravenous dosing. Each mouse was transferred to a cylindrical restrainer. A plastic syringe and fine gauge hypodermic needle were used to administer 0.25 mL phosphate buffered saline incorporating 20 μCi (0.74 MBq) of 3HTdR into a tail vein of each mouse by slow bolus injection. After this treatment, the mice were returned to their cages.
Five hours after intravenous injection of the 3HTdR, all mice were killed by exsanguination under a deep plane of inhalation anesthesia. Killing was organised to minimise the interval between death and the recovery of the auricular lymph nodes to no more than fifteen minutes.
Clinical Signs
Treated mice were observed twice daily on Days 1 to 5 and once on Day 6 for clinical signs of reaction to treatment or for irritation or other changes at the sites of application of the test article.
Routine Health Checks
All animals were examined at the beginning and end of the working day throughout the acclimatisation and study periods to ensure they were in good health.
Body Weights
Mice were weighed on Day 1 (prior to administration) and on Day 6 prior to intravenous administration of 3HTdR.
Terminal Procedures
Recovery of Lymph Nodes
Once death had been confirmed each mouse was placed on a bench lined with paper with its ventral aspect uppermost. A mid-line incision from the lower jaw to the sternum was made and the cervical structures were exposed by reflecting the skin. The auricular lymph nodes were located and removed using curved end forceps. Any connective tissue was removed from the capsule of the nodes. The auricular lymph nodes of all mice from each dose group were placed into a petri dish containing 5 mL phosphate buffered saline.
Preparation for Scintillation Count
The lymph nodes collected into each petri dish were cut open and disaggregated by squashing the fragments with a sharp blade. The resultant liquor was transferred into code-identified conical tubes. The petri dishes were rinsed with an additional 5 mL phosphate buffered saline and the second liquor was added to the first liquor. At each transfer, debris such as fragments of capsule, were retained in the petri dish wherever possible.
After 5 minutes, the pooled liquor was filtered into a second conical tube by transferring the liquor into a 10 mL syringe and passing it through a stainless steel gauze containing a fabric filter, cut to size (Clarcor UK, Lockertex Filtration Products, Warrington, UK). Any visible sediment remaining prior to filtering was left in the conical tube. The liquor was centrifuged at 200 g for 10 minutes. Following centrifugation, the supernatant was discarded and the pellet was resuspended in 5 mL phosphate buffered saline. This was centrifuged at 200 g for 10 minutes. The supernatant was discarded and the pellet resuspended in 3 mL of 5% w/v aqueous trichloroacetic acid. The suspension was stored for 18 hours at 2 to 8C (nominal 4C).
On the following day, the suspension was re-centrifuged at 200 g for 10 minutes and the supernatant was drawn off and discarded. The pellet was resuspended in 1 mL 5% w/v aqueous trichloroacetic acid then subjected to ultrasonic dispersion for 25 minutes to ensure a homogenous suspension. The suspension (1 mL) was transferred to a scintillation vial and scintillation fluid (10 mL) was added.
Scintillation Counting
Once prepared, the scintillation vials were placed in the appropriate carrier racks. Two background vials were prepared, one containing 10 mL of scintillation fluid and the other containing 1 mL of 5% w/v aqueous trichloroacetic acid and 10 mL scintillation fluid. The carrier rack was passed into the scintillation counter. All vials, including the background samples, were submitted for liquid scintillation counting for 10 minutes, using a 3H quench curve.
Incorporation of 3HTdR is measured by ß-scintillation counting as disintegrations per minute (DPM) over a ten-minute period. This value was corrected to account for the background containing 5% w/v aqueous trichloroacetic acid and scintillation fluid. - Positive control substance(s):
- hexyl cinnamic aldehyde (CAS No 101-86-0)
- Positive control results:
- The positive control article produced a Stimulation Index of 4.94, demonstrating adequate performance of the assay.
- Key result
- Parameter:
- SI
- Value:
- 1.13
- Test group / Remarks:
- 50%
- Key result
- Parameter:
- SI
- Value:
- 0.93
- Test group / Remarks:
- 25%
- Key result
- Parameter:
- SI
- Value:
- 1.27
- Test group / Remarks:
- 10%
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- The Local Lymph Node Assay demonstrated that Lithium titanate does not have the potential to cause skin sensitisation and therefore should not be classified and labelled for skin sensitisation according to Regulation (EC) No. 1272/2008 and its subsequent regulations.
- Executive summary:
SUMMARY
This study was conducted to assess the potential of the test article, Lithium titanate, to cause skin sensitisation in the mouse.
Following a preliminary screening test using a 50% w/v formulation, the test article was prepared for administration at 10, 25 and 50% w/v in propylene glycol.
Groups of four female CBA / CaCrl mice were subjected to topical applications of test article vehicle control, positive control vehicle, positive control or of one of the test formulations to the outer aspect of the auditory pinnae once daily on Days 1, 2 and 3. On Day 6, a 20 μCi dose of tritiated 3H-methyl thymidine was injected intravenously into each mouse. Five hours later the auricular lymph nodes were recovered from each animal. The pairs of nodes from each animal of each group were pooled and suspensions of the cellular components of the lymph nodes were prepared in 5% w/v aqueous trichloroacetic acid and processed through a scintillation counter.
Test results are expressed in terms of Stimulation Indices, the ratios of the mean scintillation counts obtained from the test groups relative to the corresponding mean scintillation count obtained from controls. The threshold level for the Stimulation Index to be considered a positive indicator of the potential to cause skin sensitisation is 3.0.
Concentration of Test Article in Applied Formulation (% w/v)
10%
25%
50%
Stimulation Index
1.27
0.93
1.13
The Local Lymph Node Assay demonstrated that Lithium titanate does not have the potential to cause skin sensitisation and therefore should not be classified and labelled for skin sensitisation according to Regulation (EC) No. 1272/2008 and its subsequent regulations.
The positive control article produced a Stimulation Index of 4.94, demonstrating adequate performance of the assay.
Reference
Preliminary Screening Test
Death or signs of systemic toxicity/excessive irritation were not noted.
Based on this information, the dose levels selected for the main test were 10%, 25% and 50% w/v in propylene glycol.
Preliminary Screening Test - Observations, Body Weights and Mortality Data
Concentration (% w/v in propylene glycol) | Animal Number | Body Weight (g) on Day: | Observations (Days) | |||||||
1 | 6 | 1 | 2 | 3 | 4 | 5 | 6 | |||
50 | 527 | 20 | 21 | ü | ü | ü | ü | ü | ü | |
Key
ü No clinical signs seen
Table 10.2 Preliminary Screening Test - Erythema
Concentration | Animal Number | Grade of Erythema on Day: | |||||
1 | 2 | 3 | 4 | 5 | 6 | ||
50 | 527 | 0 | 0 | 0 | 0 | 0 | 0 |
Key
0 No erythema
Table 10.3 Preliminary Screening Test - Ear Thickness Measurements
Concentration | Animal Number | Ear | Thickness (mm) on Day: | ||
1 | 3 | 6 | |||
50 | 527 | Left | 0.21 | 0.21 | 0.25 |
Main Test
Mortality
All animals survived treatment with Lithium titanate.
Clinical Signs
There were no clinical signs indicative of a systemic effect of treatment among mice treated with the test article vehicle, positive control vehicle or with 10, 25 or 50% w/v formulations of the test article.
The vehicle and test formulation application sites remained free of irritation.
Greasy fur behind the ears and on the back of the neck was noted in all Group 2 and Group 6 animals on Days 1 to 5.
Body Weights
There was no indication of a treatment related effect on body weight.
Group DPMs and Stimulation Index (SI)
Concentration | Group Number | Group DPM | Stimulation Index (SI) a | |
Test Article Vehicle | 1 | 981 | NA | |
10 | 3 | 1241 | 1.27 | |
25 | 4 | 917 | 0.93 | |
50 | 5 | 1105 | 1.13 | |
|
|
|
| |
Positive Control Vehicle | 2 | 1250 | NA | |
Positive control | 6 | 6180 | 4.94 | |
a = Stimulation Index of 3.0 or greater indicates a positive result
Body Weights
Concentration | Group Number | Animal Number | Body Weights (g) | |
Day 1 | Day 6 | |||
Test Article Vehicle | 1 | 528 529 530 531 | 21 22 20 20 | 22 24 21 20 |
Positive Control Vehicle | 2 | 532 533 534 535 | 18 21 21 20 | 19 22 21 22 |
10 | 3 | 536 537 538 539 | 19 22 20 22 | 19 23 21 23 |
25 | 4 | 540 541 542 543 | 22 20 21 19 | 24 21 21 21 |
50 | 5 | 544 545 546 547 | 18 18 18 20 | 19 19 20 21 |
Positive control | 6 | 548 549 550 551 | 19 20 19 19 | 20 23 20 21 |
NA = Not applicable
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (not sensitising)
Justification for classification or non-classification
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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