Dilutetium oxide silicate

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2 February 2017 - 1 August 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

adopted: 07 September 2009

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)

Version / remarks:

adopted: 07 September 2009

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Version / remarks:

August 1998

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Version / remarks:

2008

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

traditional method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Dilutetium oxide silicate

EC Number:

235-337-4

EC Name:

Dilutetium oxide silicate

Cas Number:

12168-86-4

Molecular formula:

Lu2O5Si

IUPAC Name:

Dilutetium oxide silicate

Test material form:

solid: particulate/powder

Details on test material:

- Name of test material (as cited in the test report): dilutetium oxide silicate
- Physical state: solid
- Appearance: light grey powder
- Further information on test material is reported in confidential details on test material

Specific details on test material used for the study:

Treatment of test material prior to testing: The test item was used as supplied.

Test animals

Species:

rat

Strain:

Wistar

Remarks:

Crl:WI from SPF colony

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Model and Services, Germany GmbH (Sandhofer Weg 7, D-97633, Sulzfeld, Germany)
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation:
• Sighting exposure (Group 0.1): approximately 10 weeks old
• Main study (Group 1): approximately 8 weeks old
- Weight at study initiation:
• Sighting exposure (Group 0.1): 380 g (male) and 228 g (female)
• Main study (Group 1): 401-416 g (males) and 237-258 g (females)
- Fasting period before study: no data
- Housing: Group caging (5 animals, by sex, per cage), individual caging during the sighting study; polycarbonate solid floor cages (type II or type III) with stainless steel mesh lids
- Diet (e.g. ad libitum): ad libitum, the animals were provided with ssniff SM R/M “Autoclavable Complete Feed for Rats and Mice – Breeding and Maintenance” (ssniff Spezialdiäten GmbH, D-59494 Soest Germany)
- Water (e.g. ad libitum): ad libitum, tap water fit for human consumption
- Acclimation period: 22 days (sighting group), 5 days (main study)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.5 – 26.5°C
- Humidity (%): 23 – 79%
- Air changes (per hr): at least 15 air exchanges per hour
- Photoperiod (hrs dark / hrs light): 12 hours of continuous artificial light in each twenty-four hour period (from 6.00 a.m. to 6.00 p.m.)

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

3.52 µm

Geometric standard deviation (GSD):

2.4

Remark on MMAD/GSD:

inhalable fraction (% < 4 µm): 58.1%

Details on inhalation exposure:

TECHNICAL TRIALS
- Prior to animal exposures, test material atmospheres were generated within the exposure chamber. During these technical trials, air-flow settings, test material input rates and test item formulation of the material were varied to achieve the required aerosol concentration of particles with a mass median aerodynamic diameter (MMAD) between 1 to 4 µm and a geometric standard deviation (GSD) in the range of 1.5 to 3.0. Measurements of aerodynamic particle size were performed from the animal’s breathing zone using a cascade impactor.
After the technical trials, a new batch was used in the in-life phase, as the amount of the first batch was not enough to perform the study.

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- The animals were exposed, nose-only, to an atmosphere of the test item using a TSE Rodent Exposure System (TSE Systems GmbH, Bad Homburg, Germany). This system comprises two concentric anodised aluminium chambers and a computer control system incorporating pressure detectors and mass flow controllers.
- Fresh aerosol from the generation system was constantly supplied to the inner plenum (distribution chamber) of the exposure system from where, under positive pressure, it was distributed to the individual exposure ports.
- Method of holding animals in the test chamber: The animals were held in polycarbonate restraint tubes located around the chamber which allowed only the animal’s nostrils to enter the exposure port.
- Source and rate of air: Compressed air was supplied by means of an oil-free compressor and passed through a suitable filter system prior to introduction to the nebuliser. The flow of air through each port was at least 0.5 L/min. This flow rate was considered adequate to minimise re-breathing of the test atmosphere as it is approximately twice the respiratory minute volume of a rat.
- System of generating particulates/aerosols: The test item was aerosolised using PALAS RBG1000 (Palas GmbH, Karlsruhe, Germany; Serial Number: 1717) located at the top of the exposure chamber. Compressed air was supplied by means of an oil-free compressor passed through a suitable filter system prior to introduction to the aerosol generator.
- Method of particle size determination: The particle size of the test atmosphere was determined three times during the exposure period using a 7-stage impactor of Mercer style (TSE Systems GmbH, Bad Homburg, Germany). Such devices employ an inertial separation technique to isolate particles in the discrete aerodynamic size ranges. Samples were taken from an unoccupied exposure port (representing the animal’s breathing zone). The collection substrates and the backup filter were weighed before and after sampling and the weight of test item, collected at each stage, calculated by this difference. The total amount collected for each stage was used to determine the cumulative amount below each cut-off point size. In this way, the proportion (%) of aerosol less than < 0.550, 0.550, 0.960, 1.550, 2.105, 3.555, 6.655 and 10.550 µm was calculated. From these data, using the software supplied with the impactor (TSE Systems GmbH, Bad Homburg, Germany), the Mass Median Aerodynamic Diameter (MMAD), and Geometric Standard Deviation (GSD) were calculated. In addition, the proportion (%) of aerosol less than 4 µm (considered to be the inhalable portion) was determined.
- Treatment of exhaust air: After passing through the animal’s breathing zone, used aerosol entered the outer cylinder from where it was exhausted through a suitable filter system. Atmosphere generation was therefore dynamic.
- Temperature in test chamber: 19.8-22.4°C (mean: 21.4°C).

TEST ATMOSPHERE
- The test atmosphere was sampled at regular intervals during the exposure period. Samples were taken from an unoccupied exposure port (representing the animal’s breathing zone) by pulling a suitable volume of test atmosphere through weighed GF10 glass fibre filters (Whatman®, Whatman GmbH, Germany, Ref./Lot no.: A10256986, A10058746).
- The difference in the pre and post sampling weights, divided by the volume of atmosphere sampled, was equal to the actual achieved test atmosphere concentration. The nominal concentration was calculated by dividing the mass of test material disseminated into the chamber by the total volume of air that flowed through the chamber during the same period.

CLASS METHOD
- Rationale for the selection of the starting concentration: maximal technically achievable concentration

Analytical verification of test atmosphere concentrations:

yes

Remarks:

gravimetrical determination

Duration of exposure:

4 h

Concentrations:

A sighting exposure was performed first, where a maximum achievable test atmosphere of dilutetium oxide silicate at a 4.62 mg/L concentration was tested on single animals of both sexes (Group 0.1).
As both animals survived the treatment, the main study group (Group 1) of 5 male and 5 female Crl:WI Wistar strain rats were exposed to an aerosol atmosphere of dilutetium oxide silicate at the maximum feasible concentration of 4.03 mg/L.

No. of animals per sex per dose:

sighting exposure: 1 male and 1 female
main study: 5 males and 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
*Morbidity/mortality: Animals were checked hourly during exposure, 1 hour after exposure and twice daily (early and late in the working day) during the 14-day observation period for morbidity and/or mortality.
*Clinical signs: All animals were observed for clinical signs at hourly intervals during exposure whilst the animals were still restrained. Following exposure, clinical observations were performed twice on the day of exposure (following removal from the restrainer and approximately one hour after completion of the exposure) and subsequently once daily for 14 days.
Observations included changes in the skin and fur, eyes and mucous membranes and also respiratory, circulatory, autonomic and central nervous system, somato-motor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.
*Body weight: Individual body weights were recorded prior to treatment on the day of exposure (on Day 0) and on Days 1, 3, 7 and 14.
- Necropsy: At the end of the 14-day observation period, the surviving animals were sacrificed by exsanguination under anaesthesia (intra-peritoneal injection of pentobarbital solution – Euthanimal 40%; Lot No.: 1609291-03; Expiry: October 2019; Produced by Alfasan International B. V., Woerden, Netherlands) and gross macroscopic examination was performed.
All rats were subject to a gross necropsy which included a detailed examination of the abdominal and thoracic cavities. Special attention was given to the respiratory tract for macroscopic signs of irritancy or local toxicity.

Statistics:

No statistics performed.

Results and discussion

Preliminary study:

A sighting exposure was performed first, where a maximum achievable test atmosphere of dilutetium oxide silicate at a 4.62 mg/L concentration was tested on single animals of both sexes (Group 0.1). Both animals survived the treatment.
The mean achieved atmosphere concentrations in this sighting study was 4.62 mg/L. The mass median aerodynamic diameter (MMAD) was 3.39 µm with a geometric standard deviation (GSD) of 2.22.

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 4.03 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: 4.03 mg/L was the maximum achievable test concentration

Mortality:

There was no mortality in the study.

Clinical signs:

other: Red-brown staining was commonly recorded on the day of the exposure, which was considered to be related to the restraint and exposure procedures but not to be toxicologically significant. The following observations were considered to be related to exposur

Body weight:

In Group 0.1, no or minimal body weight loss (1.3%) was recorded on the day of treatment. In the observation period, normal body weight gain was recorded in both animals.
In Group 1, no or slight body weight loss (max. of 8.8%) was recorded after the treatment. In the observation period from Day 3, normal body weight gain was recorded in all animals.

Gross pathology:

A single four hours nose-only exposure of dilutetium oxide silicate to Wistar Crl:WI rats dosed at 4.62 mg/L (sighting exposure) or 4.03 mg/L (main study) was associated with test item-related enlargement of lung-associated lymph nodes.

Other findings:

No data

Any other information on results incl. tables

Test atmosphere concentration:

The test atmosphere concentration was sampled in the breathing zone during the 4-hour exposure period 17 times at approximately equal intervals during both parts of the study.

The mean achieved actual concentrations based on the analysis of these filter samples and nominal concentrations are presented in the table below.

Mean achieved actual and nominal aerosol concentration

Part of Study	Target Concentration (mg/L)	Mean Achieved Concentration (mg/L)	Standard Deviation of Achieved Concentration (mg/L)	Nominal Concentration (mg/L)
Sighting exposure: Group 0.1	Maximum attainable	4.62	0.33	61.97
Main study: Group 1	Maximum attainable	4.03	0.55	65.26

Particle size analysis:

Analysis of the particle size distribution of the aerosol at the animals’ breathing zone demonstrated that during both parts of the study (sighting exposure and main study) the test atmosphere was respirable to the animals. The mean values of the particle size distribution parameters calculated from three samples of each exposure are presented in the following table.

Mean achieved particle size distribution data (MMAD and GSD)

Part of Study	Target Concentration (mg/L)	Mean Mass Median Aerodynamic Diameter (MMAD) (mm)	Geometric Standard Deviation (GSD)	Inhalable Fraction (% < 4 mm)
Sighting exposure: Group 0.1	Maximum attainable	3.39	2.22	58.1
Main study: Group 1	Maximum attainable	3.52	2.40	55.7

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Under the experimental conditions of this study, no death occurred in a group of 10 Wistar Crl:WI rats (main study) that were exposed to a maximum achievable test atmosphere concentration of 4.03 mg/L for 4 hours. The acute inhalation median lethal concentration (LC50) of dilutetium oxide silicate in Wistar Crl:WI rats was therefore considered to be above 4.03 mg/L. Based on these results and on relevant experimental data from other rare earth compounds, the test substance is considered not to be classified as acute toxicant via inhalation according to the CLP Regulation.