Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2015-11-03 to 2016-01-12
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report date:
2016

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
2009
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
traditional method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
lutetium(3+) yttrium(3+) cerium oxidandiide silicate
EC Number:
941-731-3
Molecular formula:
Lu2(1-x)Y2xSiO5:Ce, 0
IUPAC Name:
lutetium(3+) yttrium(3+) cerium oxidandiide silicate
Test material form:
solid
Specific details on test material used for the study:
- Name: Lyso
- Batch: C14-193
- Storage: at room temperature
- Composition: 100%
- EC number: 941-731-3
- Physical description: Crystal odorless
- Stability: stable
- Expiration date: not applicable

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
The test substance, as received, was a solid. Prior to aerosolization, the test substance was ground in a ball mill for 506 hours. The ground material was removed from the grinding media using a 3/8" polyethylene separator and then ground using a mortar and pestle.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Received from SAGE® Labs on October 28, 2015
- Number of animals: 10 (5 male/5 female)
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 9-10 weeks
- Weight at study initiation: males 274-326 grams and females 177-230 grams
- Housing: animals were singly housed in suspended stainless steel caging, which conforms to the size recommendations in the most recent Guide for the Care and Use of Laboratory Animals (Natl. Res. Council, 2011). Enrichment (e.g., toy) was placed in each cage. Litter paper was placed beneath the cage and was changed at least three times per week.
- Diet (e.g. ad libitum): Envigo Teklad Global 16% Protein Rodent Diet® #2016. The diet was available ad libitum, except during the exposure.
- Water (e.g. ad libitum): Filtered tap water was supplied ad libitum
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23
- Relative Humidity (%): 49-61
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
clean air
Mass median aerodynamic diameter (MMAD):
2.23 µm
Geometric standard deviation (GSD):
2.12
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure chamber: ADG Developments LTD (Nose-only Inhalation Chamber)
- Exposure chamber volume: 28 liter
- Method of holding animals in test chamber: Animals were individually housed in polycarbonate holding tubes which seal to the chamber with an "O" ring during exposure. The base unit terminates the chamber with a 0.5-inch diameter tube for discharged air.
- Air supply: Filtered generator air was supplied to the spray atomization nozzle by an air compressor (Powerex Air Compressor), and measured with a Mass Flow Controller (Omega Mass Flow Controller). Additional filtered mixing air from the same air compressor, measured with a Mass Flow Controller, was introduced into the chamber to help uniformly distribute the test atmosphere by creating a vortex at the chamber inlet. Chamber airflow (Aalborg Mass Flow Controller) was monitored throughout the exposure period and recorded periodically. The exposure was conducted under slight negative pressure.
- System of generating particulates/aerosols: The test substance was aerosolized using a Jet-Mill. The test substance was delivered from the hopper using a variable speed motor and a 3/8- nch, closed pitch inch helix into the Jet-Mill. Compressed generator and mixing air were both supplied. The aerosolized dust was then fed directly into the chamber through the dust outlet assembly.

- Method of particle size determination: An eight-stage 1 ACFM Andersen Ambient Particle Sizing Sampler was used to assess the particle size distribution of the test atmosphere. Samples were withdrawn from the breathing zone of the animals at two intervals. The filter paper collection stages were weighed before and after sampling to determine the mass collected upon each stage. The mass median aerodynamic
diameter (MMAD) and geometric standard deviation (GSD) were calculated using two-cycle logarithmic probit axes.

- Temperature, humidity, pressure in air chamber: The temperature and relative humidity within the exposure chamber as well as the room were monitored continuously during exposure, and were measured with a temperature-humidity monitor. Temperature and relative humidity values were recorded every 15 minutes for the first hour of exposure and approximately every 15 or 30 minutes thereafter.

TEST ATMOSPHERE
- Brief description of analytical method used: Gravimetric samples were withdrawn at 6 intervals from the breathing zone of the animals. Samples were collected using 37 mm glass fiber filters (Whatman™ GF/B) in a filter holder attached by 1/4 inch Tygon® tubing to a vacuum pump. Filter papers were weighed before and after collection to determine the mass collected. This value was divided by the total volume of air sampled to determine the chamber concentration. Sample airflows were measured using a Mass Flow Controller.
- Samples taken from breathing zone: yes
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
Chamber concentration: 5.19 mg/L
Nominal chamber concentration: 19.22 mg/L
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: All animals were observed for mortality during the exposure period. The animals were examined for signs of gross toxicity and behavioural changes upon removal from the exposure tube and at least once daily thereafter for 14 days.
- Frequency of weighing: Individual body weights of the animals were recorded prior to test substance exposure and gain on days 1, 3, 7 and 14.
- Necropsy of survivors performed: Yes. all rats were euthanized via CO2 inhalaion on day 14. Gross necropsies were performed on all animals. Tissues and organs of the thoracic and abdominal cavities were examined.

Statistics:
Statistical analysis was limited to the calculation of the mean and standard deviation.

Results and discussion

Preliminary study:
pre-test trial to establish the desired generation procedures
Effect levels
Key result
Sex:
female
Dose descriptor:
LC50
Effect level:
> 5.19 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Mortality:
There were no unscheduled deaths.
Clinical signs:
other: Following exposure, all rats exhibited irregular respiration. However, all animals recovered by Day 1 and appeared active and healthy for the remainder of the 14-day observation period.
Body weight:
All animals gained body weight during the study.
Gross pathology:
No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.

Any other information on results incl. tables

Particle Size and Test item concentrations:

The chamber and nominal chamber concentrations were 5.19 mg/L and 19.22 mg/L, respectively. The average mass median areodynamic diameter was estimated to be 2.23 µm based on graphic analysis of the particle size distribution as measured with a 1 ACFM Anderson Ambient Particle Sizing Sampler with an average geometric standard deviation of 2.12.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Based on the results from an acute inhalation toxicity study, the LC50 can be considered to be greater than 5.19 mg/L.
Executive summary:

In an acute inhalation toxicity study conducted according to OECD 403, groups of young adult Sprague-Dawley rats (5 males/5 females) were exposed nose only to 5.19 mg/L Cerium doped Lutetium Yttrium Orthosilicate (100%) in clean air for 4 hours. Animals then were observed for 14 days. No mortality occurred. Following exposure, all rats exhibited irregular respiration. However, all animals recovered by Day 1 and appeared active and healthy for the remainder of the 14-day observation period. No effects were observed during gross pathology and on the body weight development. Based on the results, the LC50 can be considered to be greater than 5.19 mg/L.

Categories Display