Yttrium oxide

Endpoint summary

Description of key information

Oral: In the two available studies (and reliable studies), the LD50 was determined to be > 5000 mg/kg bw.
Inhalation: In the only available (and reliable study), the LD50 was determined to be >5.09 mg/m3
Therefore, the test substance has no acute toxicity.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

data not available

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was performed according to EU guidelines and GLP

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS:
- Source: IFFA CREDO (Saint- Germain sur l'Arbresle, France)
- Age at study initiation: 6 - 7 weeks
- Weight at study initiation: 160 - 200 g (males), 140 - 180 g (females)
- Fasting period before study: yes (16 - 20 hr)
- Housing: 2 or 5 animals in stainless steel cages (342 x 252 x 180 mm)
- Food consumption: UAR entretien AO4, ad libitum
- Water consumption: ad libitum
- Acclimation period: data not available

ENVIRONMENTAL CONDITIONS:
- Temperature: 22 +/- 3 °C
- Humidity: 30 - 70 %
- Air changes: 10 per hour
- Photoperiod: data not available

In-life dates: data not available

Route of administration:

oral: gavage

Vehicle:

other: 10% arabic gum aqueous dispersion

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 50 g test item / 100 mL
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: no data
- Lot/batch no.: no data
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

Doses:

0, 5000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
> behaviour and mortality: 1h, 2h, 4h, and on days 1, 2, 4, 7 and 14 after treatment
> weighing: one day before treatment, and on days 0, 7 and 14 after treatment
- Necropsy of survivors performed: yes

Statistics:

no statistical analysis was used

Preliminary study:

3 doses (1000, 2500 and 5000 mg/kg bw) were tested. The vehicle was an aqueous dispersion of 10% arabic gum. 2 males and 2 females were used per dose. Mortality checks were performed at 1, 2, 4h, and then on days 1, 2, 4, 7 and 14.
No mortality was observed.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Mortality:

No mortality was observed in rats dosed with 0 or 5000 mg/kg bw yttrium oxide.

Clinical signs:

other: No clinical signs was observed in rats dosed with 0 or 5000 mg/kg bw yttrium oxide.

Gross pathology:

No gross abnormalities were observed at necropsy.

Other findings:

- Organ weights: no data
- Histopathology: no data
- Potential target organs: no data
- Other observations: none

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Yttrium oxide is not classified based on the LD50 in males and females (Oral LD50 Combined (males and females) > 5000 mg/kg bw).

Executive summary:

In an acute oral toxicity study (Guillot & Lheritier, 1986), groups of fasted, 6-7 week old Sprague Dawley rats (5/sex) were given a single oral dose of yttrium oxide (> 99.9 % a.i.) in aqueous dispersion of 10% arabic gum at dose of 5000 mg/kg bw (limit test) and observed for 14 days.

Oral LD50 Combined (males and females) > 5000 mg/kg bw

No clinical signs and no mortality were observed during the study.

Yttrium oxide is not classified based on the result of this acute toxicity study.

This acute oral study is classified as acceptable. It does satisfy the guideline requirement for an acute oral study (EU B.1) in the rat.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Quality of whole database:

Test was performed according to the GLP and international guideline

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2011/01/13 -2012/11/27

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was performed according to EU guidelines and GLP.

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Sex: 3 Males and 3 Females. The females assigned to test were nulliparous and non-pregnant.
- Age/Body weight: Young adult (10-11 weeks)/males 288-309 grams and females 196-209 grams at experimental start.
- Housing: The animals were singly housed in suspended stainless steel caging with mesh floors, which conform to the size recommendations in the most recent Guide for the Care and Use of Laboratory Animals (Natl. Res. Council, 2011). Litter paper was placed beneath the cage and was changed at least three times per week.
- Animal Room Temperature and Relative Humidity Ranges: 19-23ºC and 47-62%, respectively.
- Animal Room Air Changes/Hour: 12. Airflow measurements are evaluated regularly and the records are kept on file at Product Safety Labs.
- Photoperiod: 12-hour light/dark cycle (light period 0500-1700 hours)
- Acclimation Period: 19 days
- Food: Harlan Teklad Global 16% Protein Rodent Diet® #2016. The diet was available ad libitum, except during the exposure.
- Water: Filtered tap water was supplied ad libitum by an automatic water dispensing system except during exposure.
- Contaminants: There were no known contaminants reasonably expected to be found in the food or water at levels which would have interfered with the results of this study. Analyses of the food and water are conducted regularly and the records are kept on file at Product Safety Labs.

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

clean air

Details on inhalation exposure:

A. Pre-Test Trials
Prior to initiation of the full inhalation study, pre-test trials were conducted to establish generation procedures to achieve, to the extent possible, the desired chamber concentration (5.0 mg/L) and desired particle size distribution (mass median aerodynamic diameter between 1 and 4 μm). In these trials, the following adjustments were made in an attempt to achieve these objectives:
Air Pressure: constant
Compressed Generator Airflow: constant
Compressed Mixing Airflow: constant
Total Airflow: constant
Motor Setting: varied
Dust Generating System: constant
Cutting Head: constant
Cutting Blade: constant
Packing Pressure: constant
Material Preparation: constant
The procedures and aerosolization equipment used in the full test were based on the results of pre-test trial number 3. This provided a chamber concentration of 5.13 mg/L and a mass median aerodynamic diameter of 2.88 μm.

B. Inhalation Procedures
The exposure chamber, air supply and equipment used to measure particle size distribution, airflow and chamber concentration were the same as used during the pre-test trials and are described below.

Nose-Only Exposure Chamber: A nose-only inhalation chamber with an internal volume of approximately 6.7 liters (Nose Only Inhalation Chamber, ADG Developments LTD) was used for exposure. 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: Approximately 30.0 liters per minute (Lpm) of filtered air and an additional 6.0 Lpm of compressed mixing air was supplied by an air compressor (Powerex Model: SES05) to the dust generator to help uniformly distribute the test atmosphere by creating a vortex at the chamber inlet. Compressed airflow was measured with a Mass Flowmeter. Chamber airflow was monitored throughout the exposure period and recorded periodically. Total airflow was 36.0 Lpm. Based on the volume of the inhalation chamber, this airflow provided approximately 322 air changes per hour during the study. The exposure was conducted under slightly negative pressure.

Ambient Conditions: The exposure tube temperature and relative humidity ranges during exposure were 21-23ºC and 12-19%, respectively. The room temperature and relative humidity ranges during exposure were 21-23ºC and 37-44%, respectively. In-chamber measurements and room conditions were measured with a Temperature-Humidity Monitor (Fisher Scientific, Model #11-661-18). Temperature and relative humidity values were recorded every 15 minutes for the first hour of exposure and every 30 minutes thereafter.

Dust Generation: The test substance was aerosolized using a modified Wright Dust Generator driven by a variable speed motor D.C. speed control with 0-100 potentiometer. The test substance was packed into the dust container and compressed to 2,000 lbs/in2 using a lab press. The container was then fitted with a stainless steel cutting head and cutting blade. Compressed/mixing air was supplied to the dust generator at 30 psi. The aerosolized dust was then fed directly into the chamber through the dust outlet assembly.

Chamber Concentration Measurements: Gravimetric samples were withdrawn at six intervals from the breathing zone of the animals. Samples were collected using mm glass fiber filters in a filter holder attachedto 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. The collections were carried out for 1 minute at airflows of 4 Lpm. Sample airflows were measured using a Mass Flowmeter.

Particle Size Distribution: An eight-stage ACFM Anderson 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 aerodynamic mass median diameter and geometric standard deviation were determined graphically using two-cycle logarithmic probit axes.

Exposure Period: The animals were exposed to the test atmosphere for 4 hours. The exposure period was extended beyond 4 hours to allow the chamber to reach equilibrium. The times for 90 and 99% equilibration of the chamber atmosphere were 0.4 and 0.9 minutes, respectively. At the end of the exposure period, the generation was terminated and the chamber was operated for a further 24 minutes with clean air. At the end of this period the animals were removed from the exposure tube. Prior to being returned to their cages, excess test substance was removed from the fur of each animal.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

ca. 4 h

Remarks on duration:

one additional minute was necessary to ensure atmosphere equilibration

Concentrations:

5.09 mg/L

No. of animals per sex per dose:

3 animals per sex and per dose

Control animals:

no

Details on study design:

Selection of animals:
On the day of and prior to exposure, the rats were examined for health and weighed. Six healthy, naive rats (three males and three females; not previously tested) were selected for test.

Body Weights
Individual body weights of the animals were recorded prior to test substance exposure (initial) and on Days 1, 3, 7 and 14 (termination) following exposure.


Cage-side observation:
All animals were observed for mortality during the exposure period. The animals were examined for signs of gross toxicity, and behavioral changes upon removal from the exposure tube and at least once daily thereafter for 14 days. Observations included gross evaluation of skin and fur, eyes and mucous membranes, respiratory, circulatory, autonomic and central nervous systems, somatomotor activity and behavior pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhea, and coma.

Necropsy:
All rats were euthanized via CO2 inhalation on Day 14. Gross necropsies were performed on all animals. Tissues and organs of the thoracic and abdominal cavities were examined.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.09 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No mortality observed

Clinical signs:

other: Following exposure, all animals exhibited irregular respiration. However, all animals recovered from this symptom by Day 2 and appeared active and healthy for the remainder of the 14-day observation period.

Body weight:

Although all animals lost body weight by Day 1, all animals showed a continued weight gain thereafter through Day 14.

Gross pathology:

No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.

TABLE 2: PRE-TEST EXPOSURE TRIALS

Trial N°	Compressed/Mixing Air Pressure (psi)	Compressed Air Volume (Lpm)	Compressed Mixing Air (Lpm)	Total Air Volume (Lpm)	Dust Generator Motor Setting	Packing Pressure (lbs/in2)	Chamber Conc. (mg/L)	Particle Size Sampled
1	30/30	30.0	6.0	36.0	15.0	2,000	11.60	No
2	30/30	30.0	6.0	36.0	10.0	2,000	6.88	No
3	30/30	30.0	6.0	36.0	8.0	2,000	5.13	Yes

TABLE 3: SUMMARY OF PRE-TEST EXPOSURE TRIAL

Trial No.	Chamber Concentration (mg/L)	Mass Median Aerodynamic Diameter2 (μm)
3	5.13	2.88

TABLE 4: GRAVIMETRIC CHAMBER CONCENTRATIONS

Sample Number Chamber	Time of Sample (hour)	Mass Collected (mg)	Airflow Sampled (Lpm)	Collection Time (min)	Concentration (mg/L)
1	0.5	20.4	4	1	5.10
2	1	20.3	4	1	5.08
3	2	21.2	4	1	5.30
4	2.5	20.3	4	1	5.08
5	3.5	19.5	4	1	4.88
6	3.75	20.4	4	1	5.10

Average + standrad deviation: 5.09 + 0.13

Table 4: SUMMARY OF PARTICULE SIZE DISTRIBUTION:

Sample No.	Time of Sample (hours)	Collection Time (minutes)	Mass Median Aerodynamic Diameter (μm)	Geometric Standard Deviation
1	1.5	1	3.07	2.17
2	3	1	2.86	2.14

These two samples show a medium MMAD of 2.97 µm

TABLE 7: INDIVIDUAL BODY WEIGHTS

Animal No.	Sex	Body Weight (g)	Body Weight (g)	Body Weight (g)	Body Weight (g)	Body Weight (g)
		Initial	Day 1	Day 3	Day 7	day 14
3301	M	309	296	304	322	340
3302	M	288	280	285	300	315
3303	M	305	294	300	318	330
3304	F	196	194	195	207	211
3305	F	209	206	209	219	230
3306	F	200	194	199	209	217

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of this study, the single exposure acute inhalation LC50 of the test substance is greater than 5.09 mg/L (limit test, OECD) in male and female rats.

In accordance with the provisions of Regulation (EC) No. 1272/2008 on the Classification, Labeling, and Packaging of Substances and Mixtures, classification is not required based on the results of this study.

Executive summary:

The gravimetric and nominal chamber concentrations were 5.09 mg/L and 9.31 mg/L, respectively. Based on graphic analysis of the particle size distribution as measured with an ACFM Andersen Ambient Particle Sizing Sampler, the mass median aerodynamic diameter was estimated to be 2.97 μm. The total amount of test substance used was 81.0 grams.

All animals survived exposure to the test atmosphere. Following exposure, all animals exhibited irregular respiration. However, all animals recovered from this symptom by Day 2 and appeared active and healthy for the remainder of the 14-day observation period. Although all animals lost body weight by Day 1, all animals showed a continued weight gain thereafter through Day 14. No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period. Therefore, it was concluded that the LC 50 for male and female rats was > 5.09 mg/L.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

5.09 mg/m³ air

Quality of whole database:

Test was performed according to the GLP and international guideline

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Oral:

In the key study scored as reliability 1 according to Klimisch (Guillot & Lheritier, 1986) conducted an acute oral toxicity study according to the EU Method B.1. Groups of fasted, 6-7 week old Sprague Dawley rats (5/sex) were given a single oral dose of yttrium oxide (> 99.9 % a.i.) in aqueous dispersion of 10% arabic gum at dose of 5000 mg/kg bw (limit test) and were observed for 14 days.

In the supporting study, scored as reliability 2 according to Klimisch, an acute oral toxicity study (Lambert CE et al, 1993), groups of fasted, Sprague-Dawley rats (5/sex) were given a single oral dose of yttrium oxide (purity unknown) in distilled water at dose of 5000 mg/kg bw and observed for 14 days.
 

As no clinical signs and no mortality were observed during the studies both studies concluded to an oral LD50 Combined (males and females) > 5000 mg/kg bw.

Inhalation

In the only available study, conducted in accordance with the standardised guideline OECD 436 and in compliance with GLP, and thus scored as reliability 1 according to Klimisch, male and female rats (3 per sex) were exposed (nose only) for 4 hours to a dust atmosphere containing the test material at a mean concentration of 5.09 mg/L and a 2.97 µm particles size (Carolyn Lowe; 2013) and were observed for 14 days for mortality and clinical signs.

All animals survived exposure to the test atmosphere. Following exposure, all animals exhibited irregular respiration. However, all animals recovered from this symptom by Day 2 and appeared active and healthy for the remainder of the 14-day observation period. Although all animals lost body weight by Day 1, all animals showed a continued weight gain thereafter through Day 14. No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period. The study conducted to a LC50 > 5.09mg/L.

Dermal

In accordance with the column 2 adaptation of REACH Annex VIII, the acute dermal toxicity study (required in section 8.5.3) is not considered scientifically justified as the oral and inhalation exposure routes are the most appropriate to assess the acute toxicity hazard presented by the substance based on its physico-chemical characteristics and use pattern, as the substance is a powder form.

Justification for selection of acute toxicity – oral endpoint
Test was performed according to the GLP and international guideline. A publication performed by Lambert is considered as supporting study as both studies had the same conclusions.

Justification for selection of acute toxicity – inhalation endpoint
Only one study is available, the test was performed according to the GLP and international guideline.

Justification for selection of acute toxicity – dermal endpoint
A data waiver has been submitted to address this endpoint.

Justification for classification or non-classification

Oral

In accordance with the criteria for classification as defined in the Regulation 1272/2008/EC, the test material does not need to be classified for acute oral toxicity.

Inhalation

In accordance with the criteria for classification as defined in the Regulation 1272/2008/EC, the test material does not need to be classified for acute inhalation toxicity.