Registration Dossier

Diss Factsheets

Administrative data

Description of key information

1. Information on zirconium dioxide
Acute toxicity: oral
The LD50-value for acute oral toxicity was determined via the acute toxic class method in female Sprague-Dawley rats and was > 5000 mg/kg bw.
Acute toxicity: inhalation
The LC50 was determined in an acute inhalation toxicity study according to the acute toxic class method and was determined to be higher than 4.3 mg/L in male and female Crl:CD(SD) albino rats via nose-only inhalation exposure to dust aerosol of zirconium dioxide.
Acute toxicity: dermal
No available data
2. Information on magnesium oxide
Acute toxicity: oral
A test performed with magnesium hydroxide was considered as representative for magnesium oxide. The LD50-value for acute oral toxicity determined via the up-and-down procedure in rats was > 2000 mg/kg bw.
Acute toxicity: inhalation
No available data
Acute toxicity: dermal
No available data
3. Conclusion on magnesium zirconium oxide
Acute toxicity: oral
It is expected that the substance will have a similar hazard profile as the individual substances zirconium dioxide and magnesium oxide. Based on reliable data available for these individual substances, magnesium zirconium oxide is not expected to cause any adverse acute toxic effects after oral intake up to a dose of 2000 mg/kg bw. Based on this information, magnesium zirconium oxide does not need to be classified for acute oral toxicity.
Acute toxicity: inhalation
Because for acute oral toxicity, the individual components magnesium oxide and zirconium dioxide were found to be equally non-hazardous, read across from the most abundant component in the crystal lattice, i.e. zirconium dioxide, is performed to cover the endpoint of acute inhalation toxicity, with the LC50 being > 4.3 mg/L air (no adverse effects observed).
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:
2010-04-13 to 2010-04-29
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: 8 weeks approx.
- Weight at study initiation: Body weight variation of selected animals did not exceed +/- 20% of the sex mean.
- Fasting period before study: Animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test substance. Water was available ad libitum.
- Housing: Group housing of 3 animals per cage in labeled Macrolon cages containing sterilised sawdust as bedding material.
- Diet: Pelleted rodent diet was available ad libitum.
- Water: Ad libitum
- Acclimation period: Not stated

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.8-21.5°C
- Humidity (%): 34-60%
- Photoperiod (hrs dark / hrs light): 12 hours dark and 12 hours light

IN-LIFE DATES: From: 13th April 2010 To: 29th April 2010
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: Standard vehicle for use in testing

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Limit test
Doses:
2000 mg/kg
No. of animals per sex per dose:
3 female animals per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed for mortaility/viability twice daily. Body weights were measured on day 1 (pre-administration), day 8 and day 15.
- Necropsy of survivors performed: Yes.
- Other examinations performed: Clinical signs were observed at periodic intervals on the day of dosing (day 1) and once daily thereafter, until day 15. The symptoms were graded according to fixed scales and the time of onset, degree and duration were recorded.

Statistics:
Not required
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No mortality occurred (see Table 1).
Clinical signs:
other: Hunched posture and/or piloerection was noted among all animals on Day 1 (see Table 2).
Other findings:
Macroscopic findings:
No abnormalities were found at macroscopic post mortem examination of the animals ( see Table 4).

Table 1: Mortality Rate

 

Test day

1

1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

Hours after treatment

 

 

0

 

 

2

 

 

4

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Females 2000 MG/KG

 

X

 

X

 

X

 

X

 

X

 

X

 

 

X

 

X

 

X

 

X

 

X

 

 

X

 

X

 

X

 

X

 

X

 

X

Females 2000 MG/KG

 

X

 

 

X

 

 

X

 

 

X

 

 

X

 

 

X

 

X

 

 

X

 

X

 

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 Key: X = no signs observed

 Table 2: Clinical Signs

Test day

 

1

1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

Hours after treatment

Max grade

 

0

 

2

 

4

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Females 2000 MG/KG

Animal 1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Posture

Hunched posture

 

(1)

 

 

 

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

Skin/fur

Piloerection

 

(1)

 

X

 

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

Animal 2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Posture

Hunched posture

 

(1)

 

 

 

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

Animal 3

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Posture

Hunched posture

 

 

(1)

 

 

 

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

Females 2000 MG/KG 

Animal 4

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Posture

Hunched posture

 

(1)

 

 

 

 

 

X

 

X

 

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

Skin/fur

piloerection

 

(1)

 

X

 

 

X

 

X

 

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

 

X

Animal 5

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Posture

Hunched posture

 

(1)

 

 

 

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

Skin/fur

piloerection

 

 

(1)

 

X

 

 

X

 

X

 

X

 

X

 

X

 

X

 

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

Animal 6

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Posture

Hunched posture

 

(1)

 

 

 

 

X

 

X

 

X

 

X

 

X

 

X

 

 

X

 

X

 

 

X

 

X

 

X

 

X

 

X

 

X

Skin/fur

piloerection

 

(1)

 

X

 

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

Key: X = no signs observed

√ = signs observed

Table 3: Body Weights (Gram)

 

Sex/Dose

Animal

Day 1

Day 8

Day 15

Females 2000 MG/KG

 

 

 

 

 

1

149

175

189

 

2

151

180

192

 

3

 

146

174

189

 

Mean

149

176

190

 

St. Dev

3

3

2

 

N

 

3

3

3

 

4

155

179

196

 

5

153

174

188

 

6

 

161

185

194

 

Mean

156

179

193

 

St.Dev

4

6

4

 

N

3

3

3

 

Table 4: Macroscopic Findings

 

Animal Organ

Finding

Day of Death

Females 2000 Mg/Kg

1

No Findings Noted

Scheduled necropsy

Day 15 after treatment

2

No Findings Noted

Scheduled necropsy

Day 15 after treatment

3

No Findings Noted

Scheduled necropsy

Day 15 after treatment

Females 2000 Mg/Kg

4

No Findings Noted

Scheduled necropsy

Day 15 after treatment

5

No Findings Noted

Scheduled necropsy

Day 15 after treatment

6

No Findings Noted

Scheduled necropsy

Day 15 after treatment

 

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: OECD GHS
Conclusions:
The oral LD50 value of magnesium hydroxide in Wistar rats was established to exceed 2000 mg/kg body weight.
According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.
Based on these results, magnesium hydroxide does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to the:
- Globally Harmonised System of Classification and Labelling of Chemicals (GHS) of the United Nations (2007).
- Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures.
Executive summary:

First set of females - dose level = 2000 mg/kg

Second set of females - dose level = 2000 mg/kg

No mortality occurred. Hunched posture and/or piloerection was noted among all animals on Day 1. The mean body weight gain shown by the animals over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain. No abnormalities were found at macroscopic post mortem examination of the animals.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2008-01-16 to 2008-04-10
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
Certificate provided by Groupe Interministeriel Des Produits Chimiques
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Elevage JANVIER (53940 Le Genest St Isle, France)
- Age at study initiation: 8 weeks old
- Weight at study initiation: between 188 g and 207 g
- Fasting period before study: 1 day
- Housing: Three healthy female rats were kept in solid-bottomed clear polycarbonate cages with a stainless steel mesh lid.
- Diet: foodstuff provided ad libitum; food was removed at D-1 and then redistributed 4 hours after the test item administration.
- Water: tap-water from public distribution system provided ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 22 degree C
- Humidity (%): 39 and 55%
- Air changes (per hr): not applicable
- Photoperiod (hrs dark / hrs light): 12 hours daily

IN-LIFE DATES: From: 2008-02-05 To: 2008-02-20
Route of administration:
oral: gavage
Vehicle:
other: distilled water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: no data
- Amount of vehicle (if gavage): no data
- Justification for choice of vehicle: no data

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg body weight

DOSAGE PREPARATION (if unusual): The animals of the treated group received an effective dose of 2000 mg/kg body weight of the test item, diluted in distilled water and administered by gavage under a volume of 10 mL/kg body weight using a suitable syringe graduated fitted with an oesophageal metal canula.

Doses:
2000 mg/kg bw
No. of animals per sex per dose:
6 female rats
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were weighed on D0 (just before administering the test item), then on D2, D7, and D14.
Weight changes were calculated and recorded.
- Necropsy of survivors performed: yes; Only those organs likely to be modified in cases of acute toxicity were examined. Those presenting macroscopic anomalies can be removed and preserved in view of microscopic examinations.
- Other examinations performed: Systematic examinations were carried out to identify any behavioural or toxic effects on the major physiological functions 14 days after administration of the test item.
Observations and a mortality report were then carried out every day for 14 days.
Statistics:
no data
Sex:
female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Mortality:
No mortality occurred during the study.
Clinical signs:
other: No clinical signs related to the administration of the test substance were observed.
Gross pathology:
The macroscopic examination of the animals at the end of the study did not reveal treatment-related changes.
Other findings:
no data
Interpretation of results:
GHS criteria not met
Conclusions:
The LD50 of CC10 Zirconium Oxide is higher than 5000 mg/kg body weight by oral route in the rat.
Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
Read across based on a study from Phycher (2008) with zirconium dioxide and a study from van Otterdijk (2010a) with magnesium dihydroxide. The read across justification document is attached in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Key result
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Based on the results of the study from Phycher (2008) with zirconium dioxide and the study from van Otterdijk (2010a) with magnesium dihydroxide it could be concluded that the LD50 for magnesium zirconium oxide would be > 2000 mg/kg bw.
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 deionized 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:
Read across based on a study performed with zirconium dioxide. The read across justification document is attached in 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 magnesium 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 physicochemical and toxicological properties suggest no potential for a significant rate of absorption through the skin
other:
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
No reliable data were available for acute toxicity via the dermal route of exposure. However, according to Annex VIII of the REACH Regulation, in addition to the oral route, for substances other than gases, the information mentioned under section 8.5 shall be provided for at least one other route. As information is provided for the inhalation and the oral route of exposure, an acute dermal toxicity study should not be performed.

Additional information

1. Information on zirconium dioxide

Acute toxicity: oral

One reliable study was identified. Acute toxicity was determined via the acute toxic class method (OECD Guideline 423 and EU Method B1 tris) in female Sprague-Dawley rats. The LD50-value was > 5000 mg/kg bw.

Acute toxicity: inhalation

One reliable study was performed by WIL Research Laboratories on request of the MOZO Consortium in 2010. Acute inhalation toxicity was tested according to OPPTS Guideline 870.1300 and OECD Guideline 436. Zirconium dioxide was administered to 1 group of 3 male and 3 female Crl:CD(SD) albino rats via nose-only inhalation exposure as a dust aerosol at a concentration of 4.3 mg/L, which was the maximum obtainable mean concentration, for 4 hours. The exposure atmosphere was characterized by a mean mass median aerodynamic diameter (± geometric standard deviation) of 2.0 µm ± 1.75 µm. As no mortality occurred during the study, the LC50 of zirconium dioxide was greater than 4.3 mg/L.

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 harmful classification (DSD) or category 4 classification (CLP), further testing was considered not feasible as the maximum obtainable mean concentration for exposure was 4.3 mg/L and no mortality occurred at that concentration. Therefore classification for acute inhalation toxicity was deemed unnecessary.

Acute toxicity: dermal

No data available.

2. Information on magnesium oxide

Acute toxicity: oral

For magnesium oxide a study performed with magnesium hydroxide was added to the dossier. The results are considered representative for magnesium oxide because in the presence of moisture magnesium oxide will form magnesium hydroxide according to the following reaction:

MgO + H2O <--> Mg(OH)2

A GLP study with Mg(OH)2 was added to the weight of evidence approach. The study was performed according to OECD Guideline 423 in rats. The LD50-value was > 2000 mg/kg bw (van Otterdijk, 2010a).

Acute toxicity: inhalation

No data available.

Acute toxicity: dermal

No data available.

3. Conclusion on magnesium zirconium oxide

Acute toxicity: oral

The acute oral LD50 for zirconium dioxide has been determined to be > 5000 mg/kg bw and that for magnesium hydroxide (relevant for magnesium oxide) has been demonstrated to be > 2000 mg/kg bw. No experimental information is available for magnesium zirconium oxide. However, it is expected that the substance will have a similar hazard profile as the individual components in its crystal lattice, i.e. zirconium dioxide and magnesium oxide. Based on abovementioned information, magnesium zirconium oxide is not expected to cause any adverse acute toxic effects after oral intake up to a dose of 2000 mg/kg bw. Therefore, the substance does not need to be classified for acute oral toxicity.

Acute toxicity: inhalation

Because it was already demonstrated for acute oral toxicity that magnesium oxide and zirconium dioxide have a similar non-hazardous toxicological profile, it was considered acceptable to cover the acute inhalation toxicity endpoint by key data for zirconium dioxide alone. Here also, no adverse effects have been observed during the study, the LC50 being > 4.3 mg/L, which was the highest technically feasible concentration. Magnesium zirconium oxide is expected to be non-hazardous via inhalation too. Consequently, as for zirconium dioxide, no classification would be needed for acute inhalation toxicity either.

Acute toxicity: dermal

No reliable data are available for acute toxicity via the dermal route of exposure. However, according to Annex VIII of the REACH Regulation, in addition to the oral route, for substances other than gases, the information mentioned under section 8.5 shall be provided for at least one other route. As information is provided for the inhalation and the oral route, an acute dermal toxicity study should not be performed.

Justification for classification or non-classification

1. Information on zirconium dioxide

- Based on the available data and according to the DSD/CLP criteria, zirconium dioxide should not be classified for acute toxicity via the oral route of exposure.

- No reliable data are available on acute toxicity via the dermal route of exposure. Based on the oral LD50 > 2000 mg/kg bw, no testing or classification for dermal toxicity is required though.

- Based on the available data and according to the DSD/CLP criteria, zirconium dioxide should not be classified for acute toxicity via the inhalation route of exposure.

2. Information on magnesium oxide

- Based on the available data for magnesium hydroxide and according to the DSD/CLP criteria, classification of magnesium oxide for acute oral toxicity is not considered necessary.

- No reliable data are available for the other routes of exposure. Based on the oral LD50 > 2000 mg/kg bw obtained for magnesium dihydroxide, no testing or classification for dermal toxicity is required though.

3. Conclusion on magnesium zirconium oxide

Magnesium zirconium oxide is a stabilised zirconia, whereby zirconium dioxide and magnesium oxide are incorporated in a single crystal lattice. Based on acute toxicity data for the individual components zirconium dioxide and magnesium oxide, neither of which are classified for acute toxicity, magnesium zirconium oxide can be concluded to be not classified for acute toxicity either according to DSD/CLP Regulations.