Ytterbium (III) oxide

Endpoint summary

Description of key information

Acute oral toxicity

One reliable acute toxicity study via the oral route of administration is available. After single dosing of 2000 mg/kg to rats, the LD50 was established as greater than 2000 mg/kg bw (Di Manno, 2014; Klimisch 1). Based on these results, the test substance is considered not classified as acute oral toxicant.

Acute toxicity via inhalation

In a reliable acute inhalation toxicity study performed according to OECD guideline 403, no deaths occurred in a group of animals exposed to the concentration of 1.31 mg/L (maximum achievable concentration) for 4 hours (Tóth, 2017; Klimisch 1). The 4-h LC50 was therefore considered to be greater than 1.31 mg/L and the substance is thus not classified as acute toxicant via inhalation.

Acute dermal toxicity

The acute oral LD50 is greater than 2000 mg/kg bw and no systemic effects or macroscopic abnormalities were observed in the reliable study available for this endpoint. According to Annex VIII, column 2 of the REACH Regulation (revision May 2016), acute dermal toxicity can be waived if the substance under consideration is not classified as acute oral toxicant or as STOT SE, and no systemic effects have been observed in in vivo studies with dermal exposure. The latter criterion (in vivo skin sensitisation study) is also fulfilled. Moreover, in addition to the oral route of exposure, for substances other than gases, the information mentioned under REACH section 8.5.2 to 8.5.3 shall be provided for at least one other exposure route (REACH Regulation, column 2 adaptation of Annex VIII). For ytterbium oxide, a key study is available for the inhalatory route of exposure. Therefore, an acute dermal toxicity study should not be performed.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

3 March 2014 - 10 December 2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Specific details on test material used for the study:

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: On the day of administration, the test item was freshly formulated at a concentration of 200 mg/mL (anhydrous form) with the vehicle.
- No correction factor was used in this study.

FORM AS APPLIED IN THE TEST (if different from that of starting material): formulation with a 0.5% aqueous solution of carboxymethylcellullose at a concentration of 200 mg/mL

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Italy s.r.l., San Pietro al Natisone (UD), Italy
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 7 weeks old
- Weight at study initiation: 236.10 g (average) at the start of the study (Day 1) (SD = 14.628)
- Fasting period before study: Yes. Food was removed from the cages overnight prior to dosing (Day -1) and was made available approximately 4 h after dosing.
- Housing: Up to 5 animals per cage. Polisulphone solid bottomed cages of 59.5x38x20 cm with nesting material provided into suitable bedding bags.
- Diet (e.g. ad libitum): Ad libitum (except for the dosing procedure). 4 RF 18 (Mucedola S.r.l., Via G. Galilei 4, 20019, Settimo Milanese (MI), Italy.
- Water (e.g. ad libitum): Ad libitum. Drinking water supplied to each cage via a water bottle.
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2°C
- Humidity (%): 55 +/- 15%
- Air changes (per hr): ca. 15-20
- Photoperiod (hrs dark / hrs light): 12 L:12 D - artificial (fluorescent tubes)

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

0.5% aqueous solution

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: not reported

Doses:

2000 mg/kg

No. of animals per sex per dose:

1 during preliminary test, 4 during main test

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations:
*Mortality and morbidity: twice daily
*Clinical signs: on dosing, approximately 0.5 h after dosing, approximately 2 h after dosing, approximately 4 h after dosing, and daily thereafter for a total of 14 days
*Body weight: at allocation (Day -1), on the day of dosing (Day 1), and on Days 2, 8 and 15
- Necropsy of survivors performed: Yes, on all animals (gross necropsy examination for both external and internal abnormalities, with particular attention to the gastro-intestinal tract). Animals were sacrificed by carbon dioxide narcosis.

Preliminary study:

During the observation period, no mortality occurred and no clinical signs were noted in the single female animal dosed at 2000 mg/kg. Therefore, the dose for the main study was also 2000 mg/kg.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

No mortality was observed in the 4 animals treated at 2000 mg/kg.

Clinical signs:

other: No clinical signs were observed in the 4 animals treated at 2000 mg/kg.

Gross pathology:

No abnormalities were observed at the necropsy examinations.

Other findings:

No other findings reported.

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of the study, the acute oral LD50 value of ytterbium oxide was found to be above 2000 mg/kg bw in female Sprague Dawley rats. No mortality and no clinical signs were observed in the treated animals. According to these results, ytterbium oxide needs not to be classified according to CLP criteria.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Published data with limited level of detail. Only one dose tested, lower than the limit test dose.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

not specified

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

Yb2O3 was obtained from the St. Eloi Corporation, Cincinnati, Ohio, USA.
Purity: > 98%

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: No data
- Females (if applicable) nulliparous and non-pregnant: No data
- Age at study initiation: Adult
- Weight at study initiation: 190-250 g
- Fasting period before study: No data
- Housing: air-conditioned quarters
- Diet (e.g. ad libitum): ad libitum, Rockland Rat diet
- Water (e.g. ad libitum): ad libitum
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): air conditioned
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

IN-LIFE DATES: From: No data To: No data

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

aqueous 0.2% solution of CMC

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 50% suspension
- Amount of vehicle (if gavage): No data

Doses:

1000 mg/kg (only dose tested)

No. of animals per sex per dose:

20 females

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 30 days
- Other examinations performed: clinical signs

Statistics:

LD50 and 95% confidence limits were calculated by the method of Litchfield and Wilcoxon (1949).

Sex:

female

Dose descriptor:

LD50

Effect level:

> 1 000 mg/kg bw

Based on:

test mat.

Mortality:

No data

Clinical signs:

other: No data

Gross pathology:

No data

Other findings:

No data

Interpretation of results:

study cannot be used for classification

Conclusions:

The LD50 of the test item for female rats was found to be > 1000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

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:

23 September 2016 - 21 February 2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

7 September 2009

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

31 May 2008

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Version / remarks:

August 1998

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Specific details on test material used for the study:

- Treatment of test material prior to testing: The test item was used as supplied.
- No correction factor was applied in this study.

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633 Sulzfeld
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: Group 0.1: 12 weeks. Group 1: 8-9 weeks.
- Weight at study initiation: Group 0.1: 439 g (male) and 243 g (female). Group 1: 370-424 g (males) and 215-237 g (females).
- Fasting period before study: no data
- Housing: Group caging (5 animals, by sex, per cage), individual caging during the sighting study. Type III polypropylene solid floor cages with stainless steel mesh lids. Lignocel Bedding for Laboratory Animals and Arbocel nesting material were available to animals during the study. Rodents were housed with deep wood sawdust bedding to allow digging and other normal rodent activities.
- Diet (e.g. ad libitum): ssniff SM R/M “Autoclavable Complete Feed for Rats and Mice – Breeding and Maintenance” (ssniff Spezialdiäten GmbH, D-59494 Soest, Germany; batch: 278 5652, expiry: November 2016; batch: 141 8884, expiry: January 2017), ad libitum.
- Water (e.g. ad libitum): Tap water fit for human consumption, ad libitum.
- Acclimation period: 41 days (Sighting), 14 days (Main study)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.5 - 25.7°C
- Humidity (%): 31 - 56%
- Air changes (per hr): 15-20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12 dark/12 light

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

clean air

Mass median aerodynamic diameter (MMAD):

3.24 µm

Geometric standard deviation (GSD):

1.97

Remark on MMAD/GSD:

For Group 0.1: MMAD = 3.03, GSD = 2.05

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 and test material input rates were varied to achieve the required atmospheric characteristics.

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 of 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 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 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 about 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) located at the top of the exposure chamber and a glass separator. The rate of formulation use was controlled by the rotation speed.
- 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 0.55, 0.96, 1.55, 2.11, 3.56, 6.66 and 10.55 µm was calculated. From these data, using software supplied with the impactor, 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 breathing zone, used aerosol entered the outer cylinder from where it was exhausted through a suitable filter system. Atmosphere generation was therefore dynamic.
- Temperature, humidity (main study): 21.2°C (19.6 - 22.1°C), 3.6% (3.0 - 5.4%) relative humidity

TEST ATMOSPHERE
- The test atmosphere was sampled at regular intervals during each exposure period. Samples were taken from an unoccupied exposure port (representing the animal’s breathing zone) by pulling a suitable, known volume of test atmosphere through weighed GF10 glass fibre filters (Whatman GmbH, Hahnestraße 3 – D-37586 Dassel, Germany).
- 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 went through the chamber during the same period.

CLASS METHOD
- Rationale for the selection of the starting concentration: no data

Analytical verification of test atmosphere concentrations:

yes

Remarks:

gravimetrical determination

Duration of exposure:

4 h

Concentrations:

Group 0.1: 1.50 mg/L (actual), 35.94 mg/L (nominal)
Group 1: 1.31 mg/L (actual), 37.78 mg/L (nominal)

No. of animals per sex per dose:

Group 0.1: 1 male, 1 female
Group 1: 5 males, 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations:
*Morbidity/mortality: hourly during exposure, one hour after exposure, and twice daily during the 14-day observation period
*Clinical signs: at hourly intervals during exposure, as soon as practically possible following removal from restraint at the end of exposure, one hour after exposure and subsequently once daily for fourteen days
* Body weight: prior to treatment on the day of exposure (Day 0) and on Days 1, 3, 7 and 14
- Necropsy of survivors performed: Yes. At the end of the 14-day observation period, the animals were euthanised by exsanguination under anaesthesia (intra-peritoneal injection of pentobarbital solution – Euthanimal 40%) and gross macroscopic examination was performed. All animals 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 data

Preliminary study:

During the sighting study, no mortalities were observed in the single exposed male and the single exposed female. Therefore the main study was performed under similar exposure conditions.

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 1.31 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

1.31 mg/L was the maximum achievable test concentration

Mortality:

No mortality was observed in either group.

Clinical signs:

other: Wet fur, fur staining was recorded mostly on the day of exposure. These observations were considered to be related to the restraint and exposure procedures and, in isolation, were considered not to be biologically significant. In the Group 0.1, laboured r

Body weight:

In both groups, the exposure procedure caused minimal or no body weight loss in the animals (0.0%-3.9%). After Day 3, normal body weight gain was observed.

Gross pathology:

No macroscopic findings.

Other findings:

No other findings reported.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute inhalation median lethal concentration (4-h LC50) of the test item ytterbium oxide in CRL: (WI) Wistar strain rats, was considered to be greater than 1.31 mg/L (the maximum achievable concentration), since no mortalities were observed in the exposed groups. Based on these results, ytterbium oxide is considered not classified as acute toxicant via inhalation according to the CLP Regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

1 310 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because the substance does not meet the criteria for classification as acute toxicity or STOT SE by the oral route and no systemic effects have been observed in in vivo studies with dermal exposure (e.g. skin irritation, skin sensitisation)

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute oral toxicity

Two acute toxicity studies via oral administration are available. The study of Di Manno (2014) is considered reliable without restrictions (Klimisch 1) and is the key study for endpoint coverage. This GLP-compliant study was performed according to OECD guideline 420 and EC test method B.1.bis (fixed dose procedure). During the sighting study, one female animal was dosed at 2000 mg/kg. No mortality or clinical signs were seen during the 14-day observation period. The main study was then performed using the same single dose of 2000 mg/kg in 4 female rats. Here too, no mortality or clinical signs were noted during the observation period. Body weight changes were within the expected range for this strain and age of animals. During necropsy, no abnormalities were observed. In conclusion, ytterbium oxide has no toxic effect on the rat following oral administration of a single dose of 2000 mg/kg and therefore the LD50 is considered to be higher than 2000 mg/kg. Based on these results, the test substance is considered not classified as acute oral toxicant.

The second study (Bruce et al., 1963; Klimisch 3) is considered as a supporting study. The authors reported the LD50 to be > 1000 mg/kg for female rats. A single dose was tested, which was lower than the limit dose for acute oral toxicity testing (2000 mg/kg) and could therefore not be used for classification. Because of this, and because of the limited details reported on methodology as well as results, the study was scored Klimisch 3.

Acute toxicity via inhalation

One reliable study is available. In this study, the acute inhalation toxicity of the test item was assessed following a 4-hour exposure period (according to OECD 403, Tóth, 2017; Klimisch 1). In the sighting exposure, 1 male and 1 female rat were exposed to the maximum feasible concentration of 1.50 mg/L. As no death occurred during sighting, 5 male and 5 female rats were exposed for 4 hours to the maximum achievable concentration of 1.31 mg/L during the main study. As no death occurred at this concentration, the study was terminated according to the OECD 403 guideline. The MMAD was 3.03 µm (GSD 2.05 µm) during the sighting study and 3.24 µm (GSD 1.97 µm) during the main study. Wet fur and fur staining were recorded mostly on the day of exposure. These observations were considered to be related to the restraint and exposure procedures and, in isolation, were considered not to be biologically significant. The animals in Group 0.1 (sighting study) showed laboured respiration (slight to moderate) and noisy respiration (slight) on the day of exposure. Animals were symptom free from Day 1. In Group 1 (main study), laboured respiration (slight to extreme) and decreased activity (slight) was observed. The animals were symptom free from Day 2. Body weight loss was between 0.0 and 3.9%. After Day 3, normal body weight gain was observed. During necropsy, no macroscopic observations related to treatment with the test item were observed. The 4-h LC50 was considered to be > 1.31 mg/L (maximum achievable concentration).

Acute dermal toxicity

The acute oral LD50 is greater than 2000 mg/kg bw and no systemic effects or macroscopic abnormalities were observed in the reliable study available for this endpoint (Di Manno, 2014). According to Annex VIII, column 2 of the REACH Regulation (revision May 2016), acute dermal toxicity can be waived if the substance under consideration is not classified as acute oral toxicant or STOT SE, and no systemic effects have been observed in in vivo studies with dermal exposure. The latter criterion is also fulfilled (in vivo skin sensitisation study). Moreover, in addition to the oral route of exposure, for substances other than gases, the information mentioned under REACH section 8.5.2 to 8.5.3 shall be provided for at least one other exposure route (REACH Regulation, column 2 adaptation of Annex VIII). For ytterbium oxide, a key study is available for the inhalatory route of exposure. Therefore, an acute dermal toxicity study should not be performed.

Justification for classification or non-classification

Acute oral toxicity

The LD50 is greater than 2000 mg/kg bw and therefore the test substance is considered not classified as acute oral toxicant according to the CLP Regulation.

Acute inhalation toxicity

The 4-h LC50 is considered greater than 1.31 mg/L, which was the maximum technically achievable exposure concentration, and therefore the test substance is considered not classified as acute toxicant via inhalation according to the CLP Regulation.

Acute dermal toxicity

No acute dermal toxicity study is available. However, based on the acute oral LD50 being > 2000 mg/kg bw and based on the fact that no adverse effects have been observed in other studies involving dermal exposure (in vivo skin sensitisation study), the substance can be safely concluded not to be classified as acute dermal toxicant according to the CLP Regulation.