Registration Dossier

Administrative data

Description of key information

Acute toxicity: oral
Three reliable studies have been performed according to OECD 401 with three different batches of yttrium doped zirconia (Chemical Evaluation and Research Institute, 2001). The LD50 value derived after oral exposure to yttrium doped zirconia in the three studies is 2000 mg/kg bw.
Acute toxicity: inhalation
The LC50 was higher than 4.3 mg/L (maximal technically achievable mean concentration) in male and female Crl:CD(SD) albino rats via nose-only inhalation exposure (dust aerosol of zirconium dioxide).
Acute toxicity: dermal
No reliable data were available for acute toxicity via the dermal route of exposure.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2001-02-13 to 2001-03-28
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented, scientifically sound study performed according to OECD Guideline 401; however, environmental conditions were not provided.
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Crj: CD (SD) IGS rat (SPF)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc.
- Age at study initiation: 5 weeks
- Weight at study initiation: 103.9-113.6 g for males and 89.0-101.2 g for females
- Fasting period before study: overnight before the administration, and for 3-4 hours after the administration
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data


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


IN-LIFE DATES: From: 2001-02-20 To: 2001-03-06
Route of administration:
oral: gavage
Vehicle:
other: purified water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: no data
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: no data
- Lot/batch no. (if required): A113; Takasugi Pharmaceutical Co., Ltd
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION (if unusual): The animals were put on fasting overnight before the administration, and for 3-4 hours after the administration. The administration was done in the morning by single dose forced oral administration using flexible catheter (Terumo Corporation) and syringes (Terumo Corporation).

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: not applicable
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 male and 5 female
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observed all the samples frequently for up to 6 hours after the administration, then once a day for the next day to 14 days after the administration. All samples were weighed right before the administration, then 1, 3, 7, 14 days after the administration.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight and autopsy
Statistics:
For weight, the average and the standard deviation were calculated for males and females of each group.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
There were no deaths in either male or female animals.
Clinical signs:
Ash gray stools were observed 1 day after the administration, but they disappeared in 2 days. The ash grey stools seen were considered to be a change resulting from the color of the test agent since it was white, and toxicological significance is considered to be low.
Body weight:
No abnormality was seen in either males or females.
Gross pathology:
No abnormality was seen in either males or females.
Other findings:
no data
Conclusions:
The LD50 of the test substance is higher than 2000 mg/kg body weight by the oral route in the rat.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2001-02-13 to 2001-03-28
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented, scientifically sound study performed according to OECD Guideline 401; however, no environmental conditions were provided in the report.
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Crj: CD (SD) IGS rats (SPF)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc.
- Age at study initiation: 5 weeks
- Weight at study initiation: 98.3 - 114.1 g for males and 88.2 - 97.7 g for females
- Fasting period before study: overnight before the administration, and for 3-4 hours after the administration
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data


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


IN-LIFE DATES: From: 2001-02-20 To: 2001-03-06
Route of administration:
oral: gavage
Vehicle:
other: purified water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: no data
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: no data
- Lot/batch no. (if required): A113; Takasugi Pharmaceutical Co., Ltd
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION (if unusual): The animals were put on fasting overnight before the administration, and for 3-4 hours after the administration. The administration was done in the morning by single dose forced oral administration using flexible catheter (Terumo Corporation) and syringes (Terumo Corporation).

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: not applicable
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 male and 5 female
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observed all the samples frequently for up to 6 hours after the administration, then once a day for the next day to 14 days after the administration. All samples were weighed right before the administration, then 1, 3, 7, 14 days after the administration.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, and autopsy
Statistics:
For weight, the average and the standard deviation were calculated for males and females of each group.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
There were no deaths in either male or female.
Clinical signs:
Ash grey stools were observed, but they disappeared in 2 days after the administration. The ash grey stools seen were considered to be a change resulting from the color of the test agent since it was white, and toxicological significance is considered to be low.
Body weight:
No abnormality was seen in either males or females.
Gross pathology:
No abnormality was seen in either males or females.
Other findings:
no data
Conclusions:
The LD50 of the test substance is higher than 2000 mg/kg body weight by the oral route in the rat.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2001-07-09 to 2001-08-28
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented, scientifically sound study performed according to OECD Guideline 401; however, environmental conditions were not provided in the report.
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Crj: CD (SD) IGS rats (SPF)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan, Inc.
- Age at study initiation: 5 weeks
- Weight at study initiation: 115.7 - 127.5 g for males and 101.9 - 111.7 g for females
- Fasting period before study: overnight before the administration, and for 3-4 hours after the administration
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data


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


IN-LIFE DATES: From: 2001-07-19 To: 2001-08-02
Route of administration:
oral: gavage
Vehicle:
other: purified water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: no data
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: no data
- Lot/batch no. (if required): SEJI1860, Wako Pure Chemical Co., Ltd and A116, Takasugi Pharmaceutical Co., Ltd (purified water)
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION (if unusual): The test substance was weighted accurately and ground to a fine powder. The powder was mixed with a suitable amount of arabic gum and purified water. The rest of the arabic gum was added as a solution to obtain a 20.0 w/v % suspension.

The animals were put on fasting overnight before the administration, and for 3-4 hours after the administration. The administration was done in the morning by single dose forced oral administration using Nelaton catheter (Terumo Corporation) and a syringe (Terumo Corporation).

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: not applicable
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 male and 5 female
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observed all the samples frequently for up to 6 hours after the administration, then once a day for the next 14 days. All samples were weighed right before the administration, then 1, 3, 7, 14 days after the administration.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, and macroscopic examination
Statistics:
The mean value and the standard deviation of the body weight were calculated in each group.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No abnormalities were noted in all groups.
Clinical signs:
No abnormalities were noted in all groups.
Body weight:
No abnormalities were noted in all groups.
Gross pathology:
No abnormalities were noted in all groups.
Other findings:
no data
Conclusions:
The LD50 of the test substance is higher than 2000 mg/kg body weight by oral route in the rat.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Acute toxicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
27 April 2010 - 31 May 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Deviations:
no
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:
no
Species:
rat
Strain:
other: Crl:CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, NC; animals were received on 20 April 2010
- Age at study initiation: approximately 11 weeks
- Weight at study initiation: body weight values ranged from 316 g to 357 g for males and from 220 g to 238 g for females. Individual body weights at assignment were within ± 20% of the mean for each sex.
- Fasting period before study: during acclimation to restraint and during the exposure period
- Housing: Upon arrival, all animals were housed in individual suspended wire-mesh cages. The animals were maintained by the WIL Animal Husbandry staff in accordance with WIL standard operating procedures (SOPs). On the day of exposure, the animals were placed in nose-only exposure holding tubes in the animal room, transported to the exposure room, exposed for the requisite duration and then returned to their home cages.
- Diet (e.g. ad libitum): The basal diet used in this study, PMI Nutrition International, LLC, Certified Rodent LabDiet 5002, is a certified feed with appropriate analyses performed by the manufacturer and provided to WIL.
- Water (e.g. ad libitum): Municipal water supplying the facility is analyzed for contaminants according to WIL SOP
- No contaminants were present in animal feed or water at concentrations sufficient to interfere with the objectives of this study. The basal diet and municipal water, delivered by an automatic watering system, were provided ad libitum, except during acclimation to restraint and the exposure period.
- Acclimation period: 5 days, the animals were observed twice daily for mortality and moribundity. The animals were subjected to restraint in the nose-only exposure holding tubes for 1 hour on 27 April 2010 prior to the start of exposure. Animals were held in restraint tubes for 35 minutes prior to initiation of exposure.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): The room temperature control was set to maintain environmental conditions of 71°F ± 5°F (22°C ± 3°C) and 50% ± 20% relative humidity. Room temperature was monitored using the Metasys DDC Electronic Environmental control system and schedule for data collection was on an hourly basis. Actual mean daily temperature ranged from 70.3°F to 72.1°F (21.3°C to 22.3°C).
- Humidity (%): The humidity control was set to maintain environmental conditions of 50% ± 20% relative humidity. Relative humidity was monitored using the Metasys DDC Electronic Environmental control system and as scheduled for data collection on an hourly basis. Mean daily relative humidity ranged from 49.2% to 55.9% during the study.
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark

IN-LIFE DATES: no data
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: air (for compressed air system) and deionised water (for humidified air system)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: the test substance was delivered using an auger-type feeder (Schenck AccuRate, INc., Whitewater, WI) which fed test substance at a constant rate to a jet mill air micronizer (model 00, Jet-O-Mizer, Fluid Energy Aljet, Hatfield, PA) operating as a particle size reduction and dispersion device.
- Exposure chamber volume: 7.9 L convential nose-only exposure system (designed and fabricated by WIL)
- Method of holding animals in test chamber: Animals were restrained in nose-only exposure holding tubes during exposure
- Source and rate of air: Using 2 regulators, dry compressed air was supplied to the micronizing and inlet ports of the jet mill. The resulting aerosol from the jet mill was delivered to the nose-only exposure system through 22-mm respiratory tubing. A glass cyclone was placed in-line after the jet mill to reduce particle size. A tee fitting was placed at the inlet of the exposure system to provide humidified air. Humidified air was added using a Coilhose Pneumatics regulator and controlled using a rotameter-type flowmeter. Dry compressed air passed through a muffler-type bubbler submerged in a 2-L Erlenmeyer flask filled with deionized water to produce humidified air. The airflows used for the animal exposure is as follows: inlet airflow rate = 28.5-29.2 L/minute, micronizing airflow rate is 18.6L/minute, humidified airflow rate is 7.6 L/minute and total airflow rate is 54.7-55.4 L/minute
- Method of conditioning air: see above (source and rate of air)
- System of generating particulates/aerosols: see above (source and rate of air)
- Method of particle size determination: Three aerosol particle size determinations were conducted for this exposure using a 7-stage stainless steel cascade impactor (model 02-140, In-Tox Products, Moriarty, NM). Pre-weighed, 23-mm stainless steel discs were used as the collection substrates. Samples were collected at approximately 1.8 L/minute for 0.25 minutes. The filters were re-weighed and the particle size calculated based on the impactor stage-cut-offs. The aerosol size was expressed as the mass median aerodynamic diameter (MMAD) and the geometric standard deviation (GSD).
- Treatment of exhaust air: Exhaust atmosphere was filtered using a Solberg filter (Solberg Manufacturing, Inc., Itasca, IL) prior to entering the in-house exhaust system with activated charcoal and HEPA-filtration.
- Temperature, humidity, pressure in air chamber: The room temperature and humidity controls were set to maintain environmental conditions of 71°F±5°F (22°C ± 3°C) and 50%±20% relative humidity. Room temperature and relative humidity were monitored using the Metasys DDC Electronic Environmental control system and were scheduled for data collection on an hourly basis. Actual mean daily temperature ranged from 70.3°F to 72.1°F (21.3°C to 22.3°C) and mean daily relative humidity ranged from 49.2% to 55.9% during the study

TEST ATMOSPHERE
- Actual exposure concentrations: Actual exposure concentrations were determined using standard gravimetric methods. Samples were collected on pre-weighed, 25-mm glass-fiber filters (type A/E, PALL Corporation, Ann Arbor, MI) held in an open-faced filter holder positioned in the animal breathing zone within the nose-only exposure system. Following sample collection, the filters were re-weighed and the concentration calculated as the filter weight difference divided by the sample volume. Samples were collected at approximately 2 L/minute for 0.5 mintues.


VEHICLE
- Composition of vehicle (if applicable): not applicable
- Concentration of test material in vehicle (if applicable): not applicable
- Justification of choice of vehicle: not applicable
- Lot/batch no. (if required): not applicable
- Purity: not applicable

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: Effective cut-off diameter: 5.27 µm for stage 1, 4.22 µm for stage 2, 3.20 µm for stage 3, 1.90 µm for stage 4, 1.07 µm for stage 5, 0.41 µm for stage 6 and 0.27 µm for stage 7
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 2.00 µm (mean MMAD) and 1.75 (Mean GSD)

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration: The target exposure concentration was based on toxicity data from similar compounds as outlined in the product MSDS. Under the generation and exposure conditions of this study and requirements for a particle size of 1 to 4 microns and maintenance of a stable concentration for the 4-hour exposure period, it was determined that the maximum obtainable concentration of zirconium dioxide as a dust aerosol was approximately 4.3 mg/L. Since no animals died following exposure to the maximum obtainable concentration of the test substance, additional exposure levels were not required.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
Actual exposure concentration: 4.3 mg/L (SD 1.39 mg/L), this is the maximum obtainable mean concentration for a 4-hour exposure. The nominal exposure concentration was 41.4 mg/L.
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Body weights were obtained immediately prior to exposure on study day 0 and on post-exposure days 1, 3, 7, and 14.
Mortality: each animal was observed for mortality at the approximate midpoint of exposure, immediately following exposure on study day 0, and twice daily thereafter for 14 days.
Clinical observations: each animal was observed immediately following exposure on study day 0 and once daily thereafter for 14 days.
- Necropsy of survivors performed: yes; animals at the scheduled necropsy were euthanized by isoflurane anesthesia followed by exsanguination. The major organ systems of the cranial, thoracic, and abdominal cavities were examined for all animals.
Statistics:
no data
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 4.3 other: mg/L (actual exposure concentration: maximum technically achievable concentration)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
None of the animals died during exposure or during the 14-day post-exposure observation period. Based on the data obtained, the LC50 of zirconium dioxide was found to be greater than 4.3 mg/L, the maximum obtainable mean concentration.
Clinical signs:
other: There were no toxicologically significant clinical signs immediately following exposure. Several animals were noted with clear material on the neck, forelimb(s), trunk, and urogenital area, red material around the nose and mouth, and/or yellow material ar
Body weight:
All animals lost weight (10 g to 39 g) from study day 0 to 1. One male lost weight (9 g) from study day 1 to 3. All animals surpassed their initial (study day 0) body weight by study day 14 and were considered normal.
Gross pathology:
There were no macroscopic findings for any animal at the scheduled necropsy.
Interpretation of results:
GHS criteria not met
Conclusions:
Based on the results of this study, the LC50 of zirconium dioxide was greater than 4.3 mg/L, the maximum obtainable mean concentration, when male and female albino rats were exposed to a dust aerosol of the test substance as a single, 4-hour, nose-only exposure.
Endpoint:
acute toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
The endpoint was covered using an acute inhalation study performed with zirconium dioxide. The read across justification is attached to IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
Key result
Remarks on result:
other: Based on the results of the study from Smith (2010) with zirconium dioxide, it was concluded that yttrium zirconium oxide is not expected to present a hazard for acute inhalation toxicity either.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

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)
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Acute toxicity: oral

Three reliable studies have been identified (Chemical Evaluation and Research Institute, 2001), in which the acute toxicity of three different batches of yttrium zirconium oxide was determined after oral exposure in rats. The LD50 value was defined to be > 2000 mg/kg bw in each of these studies.

Acute toxicity: inhalation

Since no data are available on yttrium zirconium oxide, a key study, performed with the read across substance zirconium dioxide, is included in the dossier (Smith, 2010). The LC50 was found to be higher than 4.3 mg/L (i.e. the maximal technically achievable mean concentration) in male and female rats after nose-only inhalation exposure to a dust aerosol of zirconium dioxide. For justification of read across, see IUCLID Section 13.

Acute toxicity: dermal

Data are available for both the oral and the inhalation route of exposure. According to the REACH Regulation, only one additional route of exposure should be tested other than the oral route of exposure for acute toxicity (column 2, annex VIII, section 8.5). Therefore, it is not necessary to perform an acute toxicity study via the dermal route of exposure with yttrium zirconium oxide.

Justification for classification or non-classification

- Based on the available data on the toxicity of yttrium zirconium oxide after acute oral exposure and according to the CLP criteria, the substance should not be classified for acute toxicity via the oral route of exposure.

- Based on the available data on zirconium dioxide (which can be regarded as the main component of the yttrium zirconium oxide crystal lattice) and according to the CLP criteria, the substance yttrium zirconium oxide should not be classified for acute toxicity via inhalation. Although the LC50 of zirconium dioxide dust aerosol is higher than 4.3 mg/L, which is lower than the classification cut-off value of 5 mg/L for category 4 classification (CLP), further testing would not be considered feasible as the maximum technically obtainable mean concentration for exposure is 4.3 mg/L and no mortality and no overt toxicity occurred at this concentration. Classification for acute inhalation toxicity is therefore deemed unnecessary.

- No data are available on the acute toxicity via the dermal route of exposure. However, since the oral LD50 was consistently > 2000 mg/kg bw in the three available studies, and since no systemic effects have been observed in the available in vivo studies with dermal exposure (i.e. the in vivo skin irritation and skin sensitisation studies), yttrium zirconium oxide can be concluded not to be classified for acute toxicity after dermal exposure either.