Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
from 14-AUG-2012 to 18-JAN-2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was performed according to EU / OECD guidelines and GLP

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report date:
2013

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
Deviations:
yes
Remarks:
the temperatures in the inhalation chamber were slightly increased during the 2d part of the exposure. This deviation had no effect on the purpose and integrity of the study.
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
cerium(3+) lanthanum(3+) terbium(3+) triphosphate
EC Number:
915-152-1
Molecular formula:
(La,Ce,Tb)PO4
IUPAC Name:
cerium(3+) lanthanum(3+) terbium(3+) triphosphate
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder

Test animals

Species:
rat
Strain:
Wistar
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)
- Age at study initiation: approximately 10 weeks old (on Day 0)
- Weight at study initiation: 364-374 g (males) and 240-247 g (females) on Day 0
- Fasting period before study: no
- Housing: group caging (3 animals, by sex, per cage) in polycarbonate solid floor cages (type III) with stainless steel mesh lids. (LxWxH in cm: 38x38x18)
- Diet: ad libitum (ssniff SM R/M-Z+H “Autoclavable Complete Feed for Rats and Mice – Breeding and Maintenance”)
- Water: ad libitum (tap water from the municipal supply, as for human consumption from 500 ml bottles)
- Acclimation period: animals were acclimated to laboratory conditions for 21 days prior to involvement in the study. Animals were also acclimatised to the test apparatus (restrain procedures) for a short period prior to testing in order to lessen the stress during exposure.

ENVIRONMENTAL CONDITIONS
- Temperature: 20.4 – 25.0 °C
- Humidity: 36 - 67 %
- Air changes: at least 15 air exchanges per hour
- Photoperiod: 12 hours of continuous artificial light in each twenty-four hour period (from 6.00 a.m. to 6.00 p.m.)

IN-LIFE DATES: from 23 August 2012 (reception of animals) to 27 September 2012 (necropsy)

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
clean air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 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 of two concentric anodised aluminium chambers and a computer control system incorporating pressure detectors and mass flow controllers. The exposure unit is placed in closed hood in order to avoid cross-contamination and contamination of the laboratory environment. Atmosphere generation was dynamic.
- Exposure chamber volume: no data
- Method of holding animals in test chamber: the animals were held in polycarbonate restraint tubes located around the chamber which allowed only the animal’s nares 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 dust generator. The flow of air through each port was at least 0.5 L/min.
- Method of conditioning air: no data
- System of generating particulates/aerosols: dust particles were produced using a rotating brush dust generator Palas RBG 1000 (Palas GmbH, Karlsruhe, Germany) located at the top of the exposure chamber and compressed air. The dust aerosol produced was then ducted to the exposure system using suitable tubing. In order to improve aerodynamic size distribution, large particles were trapped via impaction in the subsequent simple separator (collision plate).
- The test item was administered after milling the powder to a fine powder.
- 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). 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. 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 4µm (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.
- The following variables were monitored continuously and recorded every minute during each exposure period: chamber airflow rates, test atmosphere temperature, test atmosphere relative humidity, test atmosphere carbon dioxide concentration, test atmosphere oxygen concentration

TEST ATMOSPHERE
- Brief description of analytical method used: the dust aerosol concentration was measured gravimetrically 17 times during the exposure and the particle size distribution of the test aerosol was determined 3 times.
> Samples were taken from an unoccupied exposure port by pulling a suitable volume of test atmosphere through weighed GF10 glass fibre filters (Whatman GmbH, Germany, ref. no. 10370302). 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 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. 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 4µm (considered to be the inhalable portion) was determined.
- Samples taken from breathing zone: yes (samples were taken from an unoccupied exposure port)

TEST ATMOSPHERE
- Particle size distribution: Inhalable Fraction (% < 4µm) = 59.7%
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 3.26 µm / 2.29

CLASS METHOD
- Rationale for the selection of the starting concentration: a limit test was conducted at 5 mg/L, as no toxicity was expected based on inhalation data with similar products. Moreover no toxicity was observed with the test item in other tests (not irritant to eyes and skin, LD50 oral/dermal > 2000 mg/kg bw).
Analytical verification of test atmosphere concentrations:
yes
Remarks:
The dust aerosol concentration was measured gravimetrically 17 times during the exposure and the particle size distribution of the test aerosol was determined 3 times.
Duration of exposure:
4 h
Concentrations:
Target Concentration: 5 mg/L
Mean Achieved Concentration: 5.04 mg/L +/- 0.13mg/L
Nominal Concentration: 8.88 mg/L
(see details and tables below)
No. of animals per sex per dose:
3 males and 3 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
> Morbidity/mortality: hourly during exposure, 1 hour after exposure and twice daily (early and late in the working day) during the observation period.
> Clinical signs: at hourly intervals during exposure, and thereafter 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.
> Bodyweight: individual bodyweights were recorded prior to treatment on the day of exposure (before the exposure on Day 0) and on Days 1, 3, 7 and 14.
- Necropsy of survivors performed: yes
Statistics:
Not applicable (the method used is not intended to allow the calculation of a precise LC50 value)

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.04 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
No animals died during the study.
Clinical signs:
other: In the exposed group, slight laboured respiration was observed in all animals on the day of exposure and persisted in males up to Day 2. In a single male rat, moderately laboured respiration on Day 0 and slight noisy respiration on Day 0-1 were also noted
Body weight:
Slight bodyweight loss (0-4%) or bodyweight retardation was observed in all animals on Day 0-3. All rats returned to the initial values on up to Day 7.
Gross pathology:
No external finding was recorded at necropsy.
Other findings:
No internal finding was recorded at necropsy.

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the experimental conditions of this study, no lethality occurred in rats when exposed to a test atmosphere at 5.04 mg/L (limit test) for 4 hours. The acute inhalation median lethal concentration (LC50) of Reaction Mass of Lanthanum Phosphate and Cerium Phosphate and Terbium Phosphate in rats was therefore considered to be above 5.04 mg/L.
Executive summary:

The acute inhalation toxicity of the test item Reaction mass of lanthanum phosphate and cerium phosphate and terbium phosphate was evaluated in rats according to OECD Guidelines for the Testing of Chemicals No. 436 “Acute Inhalation Toxicity-Acute Toxic Class Method”. The study was conducted in compliance with the principles of Good Laboratory Practice Regulations.

Wistar rats (3 males and 3 females) were exposed to a test atmosphere of the test item at a target concentration of 5 mg/L for 4 hours using a nose-only exposure system. The dust aerosol concentration was measured gravimetrically 17 times during the exposure and the particle size distribution of the test aerosol was determined 3 times. The day of exposure was designated Day 0 and a 14-day observation period followed the exposures.

 

The mean achieved atmosphere concentration was 5.04 mg/L with a standard deviation of 0.13 mg/L. The mass median aerodynamic diameter (MMAD) was 3.26 µm with geometric standard deviation (GSD) 2.29.

No mortality was noted either during the exposure or during the 14-day observation period. No external or internal finding was recorded at necropsy.

Some clinical observations were noted (slight to moderate laboured respiration, noisy respiration, wet fur, red-brown staining and fur stained by test item), but all animals appeared normal within 3 days.

Slight bodyweight loss or bodyweight retardation was observed in all animals on Day 0-3. All rats returned to the initial values on up to Day 7.

 

The acute inhalation median lethal concentration (LC50) of Reaction Mass of Lanthanum Phosphate and Cerium Phosphate and Terbium Phosphate in Wistar rats was considered to be above 5.04 mg/L.

The Reaction Mass of Lanthanum Phosphate and Cerium Phosphate and Terbium Phosphate can be ranked as unclassified according to the UN and EU Globally Harmonized System of Classification and Labelling of Chemicals (GHS).

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