Registration Dossier

Administrative data

Description of key information

No data are available on the repeated dose toxicity of tungsten zirconium oxide.

As the comparison of basic toxicological data (Annex VII endpoints) for tungsten zirconium (hydroxide) oxide and zirconium dioxide confirmed the validity of the read across assumption, i.e. that the addition of tungsten to the zirconium dioxide crystal lattice does not affect the unhazardous character of zirconium dioxide, higher toxicological endpoints such as the repeated dose toxicity endpoints were covered using the approach followed in the zirconium dioxide dossier.


Repeated dose toxicity: oral
Two studies were used in a weight of evidence approach to cover this endpoint:
- Rossiello (2013) performed a combined repeated dose toxicity study with reproduction/developmental toxicity screening test via oral route in rats with the read across substance zirconium acetate according to OECD guideline 422 (GLP). A NOAEL of >=1000 mg/kg bw/day (expressed as zirconium acetate anhydrous) was derived. No adverse effects were reported in this study.

- No effects were reported after oral administration to rats during 17 weeks of zirconium basic carbonate (hydrated form) in the form of a moist paste containing 20.9% zirconium dioxide equivalent. The total intake of zirconium dioxide during the test period was 0, 0.9, 9 and 103.5 g. The equivalent NOAEL for zirconium dioxide was >= 3150-7080 mg/kg bw/day (Harrison et al., 1951).


Repeated dose toxicity: inhalation
No effects were reported in the study of Spiegl et al. (1956) for any of the species studied (cat, dog, guinea pig, rabbit and rat) after inhalation of zirconium dioxide dust during 30 or 60 days. The 30-day NOAEC was >= 100.8 mg ZrO2/m3 and the 60-day NOAEC was >= 15.4 mg ZrO2/m3.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2012-12-06 to 2013-02-07
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Italia S.p.A., Calco (Lecco), Italy
- Age at study initiation: 6 to 7 weeks
- Weight at study initiation: 204.5 to 212.8 g (males); 164.8 to 180.2 g (females)
- Fasting period before study: none
- Housing: From arrival to pairing, animals were housed up to 5 of one sex to a cage, in polisulphone solid bottomed cages measuring 59.5 x 38 x 20 cm. Nesting material was provided inside suitable bedding bags and changed at least twice a week. During mating, animals were housed one male to one female in clear polycarbonate cages measuring approximately 43 x 27 x 18 cm with a stainless steel mesh lid and floor. Each cage tray held absorbent material which was inspected and changed daily. After mating, the males were re-caged as they were before mating while females were transferred to individual solid bottomed cages for the gestation period, birth and lactation.
- Diet: ad libitum, except prior to drawing of blood for clinical chemistry examinations
- Water: ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 55 +/- 15%
- Air changes (per hour): 15 to 20
- Photoperiod (hours dark / hours light): 12/12

Route of administration:
oral: gavage
Vehicle:
other: purified water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS
The required amount of zirconium acetate solution (containing 40.7% of zirconium acetate anhydrous) was dissolved in the vehicle (purified water) to obtain final concentrations of 10, 30 and 100 mg/mL. The formulations were prepared daily or up to 7 days before dosing according to stability data. The concentrations were calculated and expressed in terms of zirconium acetate content (40.7%).

VEHICLE
- Concentration in vehicle: 10, 30, 100 mg/L (expressed as active compound content)
- Amount of vehicle (if gavage): 10 mL/kg body weight (for males, dose volumes were adjusted once per week for each animal according to the last recorded body weight; for females, dose volumes were calculated according to individual body weight on days 0, 7, 14 and 20 post coitum and on day 1 post partum, thereafter individual dose volumes remained constant)
- Purity: not requiered
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Prior to commencement of treatment, analysis was performed to confirm that the proposed formulation procedure was acceptable (check of concentration). Samples of dosing formulations prepared on Weeks 1 and 5 [when 10 females per group were present] were also analysed to verify the concentrations. Samples of the formulations were collected and sent at ambient temperature to the analytical laboratory. Chemical analyses were carried out according to an Inductively Coupled Plasma-Optical Emission Spectroscopy (ICP-OES) method.
Duration of treatment / exposure:
- Males were treated two weeks prior to pairing, throughout pairing and thereafter through the day before scheduled sacrifice (32 days of dosing).
- Females were treated two weeks prior to pairing, throughout pairing until day 3 post partum or the day before scheduled sacrifice (up to 50 days of dosing).
Frequency of treatment:
Once daily
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Dose / conc.:
53 other: mg/kg bw/day (actual dose received, based on Zr)
Dose / conc.:
159 other: mg/kg bw/day (actual dose received, based on Zr)
Dose / conc.:
530 other: mg/kg bw/day (actual dose received, based on Zr)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose levels were selected in consultation with the Sponsor based on information from a non-GLP 2 week preliminary toxicity study (RTC Study no. 94150EXT).
- Rationale for animal assignment: Rats were allocated to groups by computerised stratified randomisation to give approximately equal initial group mean body weights.
- Rationale for selecting satellite groups: not applicable (satellite group not included)
- Post-exposure recovery period in satellite groups: not applicable (satellite group not included)
Positive control:
None
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were checked each morning and afternoon for mortality.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before commencement of treatment and at least once daily during the study, each animal was observed and any clinical sign was recorded. Observations were performed at the same time interval each day, the interval was selected taking into consideration the presence of post-dose reactions.

BODY WEIGHT: Yes
- Time schedule for examinations: Males were weighed weekly from allocation to termination. Females were weighed weekly from allocation to positive identification of mating and on Days 0, 7, 14 and 20 post coitum. Dams were also weighed on Days 1 and 4 post partum.

FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly during the pre-mating period starting from allocation. Individual food consumption for the females was measured on Days 7, 14 and 20 post coitum starting from Day 0 post coitum and on Day 4 post partum starting from Day 1 post partum.
- Parameters checked: the weight of food consumed by each cage of males and females

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: as part of the sarificial procedure
- Anaesthetic used for blood collection: Yes (isofluorane)
- Animals fasted: Yes
- How many animals: 5 per sex (females with viable litters i possible)
- Parameters checked: haematocrit; haemoglobin; red blood cell count; reticulocyte count; mean red blood cell volume; mean corpuscular haemoglobin; mean corpuscular haemoglobin concentration; white blood cell count; differential leucocyte count (neutrophils, lymphocytes, eosinophils, basophils, monocytes, large unstained cells); platelets

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: as part of the sarificial procedure
- Anaesthetic used for blood collection: Yes (isofluorane)
- Animals fasted: Yes
- How many animals: 5 per sex (females with viable litters i possible)
- Parameters checked: alkaline phosphatase; alanine aminotransferase; aspartate aminotransferase; gamma-glutamyltransferase; urea; creatinine; glucose; triglycerides; bile acids; phosphorus; total bilirubin; total cholesterol; total protein; albumin; globulin; A/G Ratio; sodium; potassium; calcium; chloride

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: for males 5 days before necropsy and for females on Day 3 post partum.
- Dose groups that were examined: from each group, 5 males and 5 females were randomly selected.
- Battery of functions tested: grip strength; sensory reactivity to stimuli; motor activity assessment

FUNCTIONAL OBSERVATION BATTERY TESTS
- Time schedule for examinations: once before commencement of treatment and at least once a week thereafter, each animal was given a detailed clinical examination.
- Battery of functions tested: removal (from cage); handling reactivity; lachrymation; palpebral closure; salivation; piloerection; rearing; spasms; myoclonia; mobility impairment; arousal (animal activity); vocalisation; stereotypies; unusual respiratory pattern; bizarre behaviour; urination; defecation; tremors; gait.
Sacrifice and pathology:
SACRIFICE: Yes
- Males were killed after the mating of all females (after 32 days of treatment period).
- Females with live pups were killed on Day 4 post partum while females which did not give birth 25 days after positive identification of mating were killed shortly (Day 27 post coitum).
- All parental animals were killed by exsanguination under isofluorane anaesthesia.
- Pups were euthanised by intraperitoneal injection of thiopenthal.

TISSUE PRESERVATION: Yes
- Procedure: Samples of tissues were fixed and preserved in 10% neutral buffered formalin (except eyes, testes and epididymides which were fixed in modified Davidson's fluid and preserved in 70% ethyl alcohol).
- Organs / tissues preserved: all abnormalities; adrenal glands; bone marrow (from sternum); brain; caecum; colon; duodenum; heart; ileum; jejunum (including Peyer’s patches); kidneys; liver; lungs (including mainstem bronchi); lymph nodes - cervical ; lymph nodes - mesenteric; nasal cavity; oesophagus; pituitary gland; prostate gland; rectum; sciatic nerve; spinal column; spinal cord (cervical, thoracic, lumbar); spleen; stomach; thymus (where present); thyroid ; trachea; urinary bladder
- Reproductive organs / tissues preserved: epididymides; ovaries with oviducts; seminal vesicles with coagulating glands; testes; uterus - cervix; vagina.

GROSS PATHOLOGY: Yes
- Time schedule for examinations: Terminal sacrifice. All animals.
- Organs / tissues examined: All parent animals and pups wee examined macroscopically for any structural changes.
- Reproductive organs / tissues examined: Sexual organs were specifically examined. The number of implantation sites and corpora lutea was recorded for all dams with litters. The uteri of non-pregnant females were placed in a solution of ammonium sulfide to visualize possible hemorrhagic areas of implantation sites.

HISTOPATHOLOGY: Yes
- Time schedule for examinations: Tissues were collected from 5 males and 5 females (randomly selected) in the control and high dose group killed at terminal sacrifice and from all animals with abnormalities in all dose groups.
- Procedure: Tissues were dehydrated and embedded in paraffin wax, sections of the tissues were cut at 5 micrometer thickness and stained with haematoxylin and eosin. Testes and epididymides were cut at 2-3 micrometer thickness and stained with Periodic Acid Schiff (PAS) and morphological evaluation of the seminiferous epithelium (staging of spermatogenic cycle) was performed.
- Organs / tissues examined: all abnormalities; adrenal glands; bone marrow (from sternum); brain; caecum; colon; duodenum; heart; ileum; jejunum (including Peyer’s patches); kidneys; liver; lungs (including mainstem bronchi); lymph nodes - cervical ; lymph nodes - mesenteric; pituitary gland; prostate gland; rectum; sciatic nerve; spinal cord (cervical, thoracic, lumbar); spleen; stomach; thymus (where present); thyroid ; trachea; urinary bladder
- Reproductive organs / tissues examined: epididymides; ovaries with oviducts; seminal vesicles with coagulating glands; testes; uterus - cervix; vagina

ORGAN WEIGHT: Yes
- Time schedule for examinations: Organs were collected from all animals surviving the scheduled test period.
- Procedure: Organs were dissected free of fat and weighed. The ratios of organ weight to body weight were calculated for each animal.
- Organs / tissues examined: adrenal glands; brain; heart; kidneys; liver; prostate gland; spleen; thymus
- Reproductive organs / tissues examined: epididymides; ovaries with oviducts; testes
Other examinations:
VAGINAL SMEARS: Yes
Vaginal smears were taken daily in the morning starting two weeks before pairing until a positive identification of copulation was made. The vaginal smear data were examined to determine anomalies of the oestrous cycle and pre-coital interval (i.e., the number of nights paired prior to the detection of mating).

REPRODUCTIVE INDICES: Yes
- The following reproductive indices were calculated: copulatory index; fertility index; pre-coital interval (mean number of days between pairing and mating); pre-implantation loss; pre-birth loss; pup loss at birth; cumulative pup loss on Day 4 post partum; sex ratios on Day 4 psot partum.

SPERMATOGENIC CYCLE: Yes
- A detailed qualitative examination of the testes was performed in control and high dose groups. The evaluation, taking into account the tubular stages of the spermatogenic cycle, was conducted in order to identify treatment-related effects, such as missing germ cell layers or types, retained spermatids, multinucleated or apoptotic germ cells and sloughing of spermatogenic cells into the lumen.
- Seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and to the integrity of the various cell types within the different stages.
Statistics:
- Standard deviations were calculated as appropriate. For continuous variables the significance of the differences amongst group means was assessed by Dunnett’s test or a modified t test, depending on the homogeneity of data.
- Statistical analysis of histopathological findings was carried out by means of the non-parametric Kolmogorov-Smirnov test if n was more than 5.
- The non-parametric Kruskal-Wallis analysis of variance was used for the other parameters. Intergroup differences between the control and treated groups were assessed by the non-parametric version of the Williams test.
- The criterion for statistical significance was p<0.05
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
(effects cannot conclusively be attributed to treatment)
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
(toxicologically irrelevant)
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
- No mortality occurred in the study.
- No clinical findings of toxicological significance were observed. Hair loss was occasionally recorded throughout the study including control animals. One female of the mid-dose group had salivation on Day 20 post coitum. One high dose female, that did not give birth, showed prolapse of the uterus on Day 27 post coitum. Another high dose female had rales during pairing.

BODY WEIGHT AND WEIGHT GAIN
- Body weight and body weight gain did not show relevant differences between groups. In particular, body weight gain was in some occasions higher in treated groups compared to the control group.

HAEMATOLOGY
- No changes of toxicological relevance were recorded.
- A statistically significant decrease of lymphocytes recorded in some females dosed with 300 mg/kg bw/day (up to 42% below controls) was not dose-related and, therefore, considered incidental.
- No changes were observed in the coagulation test.

CLINICAL CHEMISTRY
- A number of males dosed with 1000 mg/kg bw/day showed a slight decrease of protein and globulin (approximately 10%). Due to the low severity, these changes were considered of no toxicological importance.
- In addition, one animal showed high triglycerides (6.2 fold compared with controls). Due to the low incidence, this finding cannot be conclusively attributed to treatment; however, it also cannot be ruled out that it was related to treatment.

NEUROBEHAVIOUR
- Motor activity recorded at the end of treatment did not show significant differences between control and treated groups.

ORGAN WEIGHTS
- A slight significant reduction of epididymides weight occurred in the high-dose group; however, this reduction was found to be related to the higher terminal body weight in the high-dose group compared to controls. In addition, this change was minimal and no histological associated-findings were found. Therefore, it was considered of no toxicological relevance.

TERMINAL BODY WEIGHT AND ORGAN WEIGHTS
Body weight at term and organ weights did not show differences of toxicological relevance.

HISTOPATHOLOGY: NON-NEOPLASTIC
- Minimal, focal vacuolation of squamous epithelium (limiting ridge) of the non-glandular region of the stomach was observed in the high and mid-dose males with an increased incidence in the high dose males and similar severity levels across treatment groups. However, such gastric change was noted only in males, in a specific zone of the forestomach (limiting ridge) with focal and minimal severity and since humans do not have forestomach (squamous epithelium), such change could be considered toxicologically as a minor change.
- The remaining lesions reported in control and treated animals were considered to be an expression of spontaneous and/or incidental pathology, commonly seen in this species and age under the experimental conditions.

OTHER FINDINGS:
Spermatogenic cycle:
- A detailed qualitative examination of the testes was performed in control and high dose groups. The evaluation, taking into account the tubular stages of the spermatogenic cycle, was conducted in order to identify treatment-related effects, such as missing germ cell layers or types, retained spermatids, multinucleated or apoptotic germ cells and sloughing of spermatogenic cells into the lumen.
Seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and to the integrity of the various cell types within the different stages; regular layering in the germinal epithelium was noted.
Dose descriptor:
NOAEL
Remarks:
(systemic effects)
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Remarks:
anhydrous zirconium acetate
Sex:
male/female
Basis for effect level:
other: Based on a lack of toxicologically relevant systemic effects in male or female parental animals in any dose group.
Critical effects observed:
no

The overall results of the test formulation analyses were within the limits of acceptance for concentration (15% of the theoretical concentration).

Conclusions:
On the basis of the results obtained in this study, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity was considered to be >=1000 mg/kg bw/day (expressed as zirconium acetate anhydrous) for males and females.
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non GLP study. The study was conducted according to a method equivalent to the OECD 408 guideline without major deviations.
Remarks:
However, no data on test conditions and preparation of animals were reported. Follow-up of body weight was done weekly, however no individual animal data were reported. No histopathology observations were done. No individual reporting was done.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
no histopathology was done, detailed data on study set-up and results are lacking
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
other: Albino
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: recently weaned
- Weight at study initiation: 50 g
- Fasting period before study: no data
- Housing: no data
- Diet (e.g. ad libitum): normal diet
- Water (e.g. ad libitum): normal diet
- Acclimation period: no data
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Three groups of 20 rats each were distributed as litter mates and fed during 17 weeks with a mixture of standard rat diet and hydrated zirconium carbonate (HZC) at 0.2%, 2.0% and 20% (w/w).
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
17 weeks
Frequency of treatment:
continuously in the diet
Dose / conc.:
0.2 other: % (w/w)
Remarks:
Equivalent of 300 to 130 mg/kg bw/day calculated in week 1 and week 15 respectively
Basis: nominal in diet
Dose / conc.:
2 other: % (w/w)
Remarks:
Equivalent of 3300 to 1300 mg/kg bw/day calculated week 1 and week 15 respectively
Basis: nominal in diet
Dose / conc.:
20 other: % (w/w)
Remarks:
Equivalent of 33900 to 15100 mg/kg bw/day calculated week 1 and week 15 respectively
Basis: nominal in diet
No. of animals per sex per dose:
10 males and 10 females
Control animals:
yes, plain diet
Details on study design:
Three groups of 20 rats each were distributed as litter mates.
Positive control:
No positive control
Observations and examinations performed and frequency:
Animals observed daily and weighed weekly. Records were kept of the quantities of food and water consumed.
Sacrifice and pathology:
Gross pathology of the organs.
Other examinations:
- Samples of blood were obtained from 8 animals in each group (4 males/4 females) at the weeks 8 & 16 of the test
- Hemoglobin was determined, erythrocytes and leucocytes were counted, and differential counts were made
- Urine was also examined
Statistics:
No data
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
- No mortality during the test
- Growth curves were normal and identical to control rats
- No significant differences in the hematologic findings were noted among the various groups examined
- The urine did not differ significantly among the groups in color, reaction, odor, albumin content or microscopic appearance
- For all animals, their fur was smooth, their eyes and noses were clear and their mucous membranes were healthy in appearance
- The heart, lungs, thyroid, thymus, liver, spleen, kidneys, adrenals, stomach, intestines, bladder and genital organs were grossly normal in all animals
Dose descriptor:
NOAEL
Effect level:
>= 3 150 - 7 080 mg/kg bw/day (actual dose received)
Based on:
other: 20.9% ZrO2 in the test material (HZC)
Sex:
male/female
Basis for effect level:
other: The NOAEL is based on the daily consumption calculated from equivalent intake levels of ZrO2 and body weights of rats.
Critical effects observed:
no

Level of HZC in diet: 0%, 0.2%, 2.0% and 20%

Total intake food: 2182 g, 2176 g, 2149 g and 2475 g

Total intake ZrO2: 0 g, 0.9 g, 9.0 g and 103.5 g

Total intake water: 4193 g, 4774 g, 4097 g and 4021 g

Initial weight males: 52-54 g; females: 50-51 g

Weight after 17 weeks males: 340-349 g; females 210-230 g

Weight gain (average) males: 285-295 g; females 160-179 g

Daily consumption of HZC: 0, 0.13-0.30 g/kg, 1.3-3.3 g/kg and 15.1-33.9 g/kg

Conclusions:
Ingestion of equivalent cumulative doses of 0.9 g, 9 g and 103.5 g of ZrO2 in the form of hydrated zirconium carbonate for a period of 17 weeks did not cause any deaths in the 60 rats exposed during the test. This indicates the absence of cumulative toxic effects. After autopsy, no abnormality was observed on heart, lungs, thyroids, thymus, liver, spleen, kidneys, adrenals, stomach, intestines, bladder and genital organs, consequently, it can be concluded that ingestion of HZC (containing 20.9% ZrO2) does not induce harmful effects.
Endpoint:
sub-chronic 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 performed with zirconium acetate and a study performed with zirconium basic carbonate. The read across justification document is attached to IUCLID section 13.
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Dose descriptor:
other: read across conclusion
Remarks on result:
other: Tungsten zirconium oxide is concluded not to present any hazard after repeated oral exposure.
Remarks:
Conclusion based on the results of the read across studies of Rossiello (2013) performed with the water soluble zirconium acetate and Harrison et al. (1951) performed with the insoluble zirconium basic carbonate.
Critical effects observed:
no
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
no data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented, scientifically sound study that is similar to the OECD 412 "Repeated Dose Inhalation Toxicity: 28-day or 14-day study" guideline with some deviations.
Remarks:
(1) only one dose was used rather than 3; (2) 2 dogs, 6 rabbits, and 20 rats (sex not provided) were exposed rather than 5 animals/sex/dose; (3) complete list of tissues examined for gross and histopathology were not provided; (4) no urinalysis or clinical chemistry parameters were examined.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Remarks:
see rationale for reliability
GLP compliance:
no
Limit test:
no
Species:
other: dog, rabbit, rat
Strain:
not specified
Sex:
not specified
Route of administration:
inhalation: dust
Type of inhalation exposure:
whole body
Vehicle:
other: no data
Remarks on MMAD:
MMAD / GSD: Mass median particle diameter: 1.5 microns
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: copper-lined chamber constructed of wood with observation windows on three sides, 6 x 8 x 6 ft high and volume of 288 cubic feet.
- Method of conditioning air: A centrally located duct in the ceiling of the chamber served as the inlet for the test substance. Baffles below the inlet and two fans near the ceiling dispersed the test substance and distributed the test substance uniformly throughout the chamber. In the four bottom corners were outlets connected to an exhaust system. Air turnover during exposure was approximately 140 cfm or one change every two minutes with no recycling.
- System of generating particulates/aerosols: Wright dust feed.
- Temperature, humidity, pressure in air chamber: 74 +/- 3 degrees F; 47% +/- 6%; few hundredths of an inch of water less than atmospheric pressure.
- Air flow rate: 140 cfm or one change every two minutes.
- Method of particle size determination: test substance was twice ground in a Mikropulverizer to a mean bulk particle size.
- Treatment of exhaust air: not recycled

TEST ATMOSPHERE
- Brief description of analytical method used: Hourly samples were taken with a filter paper sampler and weighed on an analytical balance, spectrographic analysis of each day's accumulation of filter paper samples was used to verify the weight-samples and to make such slight adjustments in concentration results as might occasionally arise from varying amounts of nuisance dust.
- Samples taken from breathing zone: yes, hourly
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Hourly samples were taken with a filter paper sampler and weighed on an analytical balance, spectrographic analysis of each day's accumulation of filter paper samples was used to verify the weight-samples and to make such slight adjustments in concentration results as might occasionally arise from varying amounts of nuisance dust.
Duration of treatment / exposure:
30 days
Frequency of treatment:
6 hours/day 5 days/week
Dose / conc.:
100.8 mg/m³ air
Remarks:
Basis: analytical conc. (ZrO2)
No. of animals per sex per dose:
Dog 2 (sex not known)
Rabbit 6 (sex not known)
Rat 20 (sex not known)
Control animals:
other: yes, only control rabbits and rats were used
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: No data

BODY WEIGHT: Yes
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: weekly
- Animals fasted: No data
- How many animals: 2 dogs
- Parameters: Red blood cell and differential white cell counts, as well as determinations of hemoglobin, mean corpuscular cell volume and clotting time

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
HISTOPATHOLOGY: Yes, lung, kidney, liver. Other tissues were examined, but the specific list of other tissues was not provided
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: One rabbit died during exposure to the test substances, however this matched the control group.

BODY WEIGHT AND WEIGHT GAIN: Throughout the exposure periods the weekly weight responses were identical to those of normal animals.

HAEMATOLOGY: There were no reported hematological changes in the two dogs that were selected for this parameter during the exposure period.

HISTOPATHOLOGY: NON-NEOPLASTIC: There are no reported histological changes that could be attributed to the test substance. The abnormalities that were reported were similar for all species regardless of dose, duration of exposure or test substance inhaled. In all exposed animals, an apparently granular material, brownish-black and doubly refracting, was found in alveolar walls and in phagocytes. Occasionally, this dust was also seen in bronchi and lymph nodes.
Dose descriptor:
NOAEC
Effect level:
>= 100.8 mg/m³ air
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: no effects were reported in any species tested
Critical effects observed:
no
Conclusions:
Inhalation of 100.8 mg/m3 zirconium dioxide for 30 days produced no significant changes in animals in mortality rate, growth, hematology values or histopathology. The NOAEC was deemed to be greater than (or equal to) 100.8 mg/m3.
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
no data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented, scientifically sound study that is similar to the OECD 413 "Subchronic Inhalation Toxicity: 90-day study" guideline with some deviations.
Remarks:
1) only 1 dose tested rather than 3; (2) exposure was for 60 days rather than 90 days; (3) complete list of tissues examined for histopathology was not provided; (4) limited clinical chemistry and urinalysis; (5) 4 cats, 4 dogs, 20 guinea pigs, 19 rabbits and 72 rats (sex not provided) were exposed rather than 10 rodents per sex per dose.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
yes
Remarks:
see rationale for reliability
GLP compliance:
no
Limit test:
no
Species:
other: cat, dog, guinea pig, rabbit, rat
Strain:
not specified
Sex:
not specified
Route of administration:
inhalation: dust
Type of inhalation exposure:
whole body
Vehicle:
other: no data
Remarks on MMAD:
MMAD / GSD: Mass median particle diameter: 1.6 microns
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: copper-lined chamber constructed of wood with observation windows on three sides, 6 x 8 x 6 ft high and volume of 288 cubic feet.
- Method of conditioning air: A centrally located duct in the ceiling of the chamber served as the inlet for the test substance. Baffles below the inlet and two fans near the ceiling dispersed the test substance and distributed the test substance uniformly throughout the chamber. In the four bottom corners were outlets connected to an exhaust system. Air turnover during exposure was approximately 140 cfm or one change every two minutes with no recycling.
- System of generating particulates/aerosols: Wright dust feed.
- Temperature, humidity, pressure in air chamber: 74 +/- 3 degrees F; 47% +/- 6%; few hundredths of an inch of water less than atmospheric pressure.
- Air flow rate: 140 cfm or one change every two minutes.
- Method of particle size determination: test substance was twice ground in a Mikropulverizer to a mean bulk particle size.
- Treatment of exhaust air: not recycled

TEST ATMOSPHERE
- Brief description of analytical method used: Hourly samples were taken with a filter paper sampler and weighed on an analytical balance, spectrographic analysis of each day's accumulation of filter paper samples was used to verify the weight-samples and to make such slight adjustments in concentration results as might occasionally arise from varying amounts of nuisance dust.
- Samples taken from breathing zone: yes, hourly
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Hourly samples were taken with a filter paper sampler and weighed on an analytical balance, spectrographic analysis of each day's accumulation of filter paper samples was used to verify the weight-samples and to make such slight adjustments in concentration results as might occasionally arise from varying amounts of nuisance dust.
Duration of treatment / exposure:
60 days
Frequency of treatment:
6 hours/day, 5 days/week
Dose / conc.:
15.4 mg/m³ air
Remarks:
Basis: analytical conc. (ZrO2)
No. of animals per sex per dose:
Cat- 4
Dog - 4
Guinea Pig - 20
Rabbit - 19
Rat - 72
Control animals:
other: yes, only control rabbits and rats were used
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: No data

BODY WEIGHT: Yes
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: weekly
- Animals fasted: No data
- How many animals: 4 dogs
- Parameters: Red blood cell and differential white cell counts, as well as determinations of hemoglobin, mean corpuscular cell volume and clotting time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: semi-monthly
- Animals fasted: No data
- How many animals: 4 dogs and 4 rabbits
- Parameters: Blood nonprotein nitrogen

URINALYSIS: Yes
- Time schedule for collection of blood: semi-monthly
- Animals fasted: No data
- How many animals: 4 dogs and 4 rabbits
- Parameters: urinary protein

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
HISTOPATHOLOGY: Yes, lung, kidney, liver. Other tissues were evaluated, but a complete list of other tissues was not provided
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: One rabbit and one guinea pig in the 15.4 mg ZrO2/m3 dose group died during exposure to the test substances; however, this matched the deaths observed in the the control group.

BODY WEIGHT AND WEIGHT GAIN: Throughout the exposure periods the weekly weight responses were identical to those of normal animals. Adult cats, dogs, guinea pigs, and rabbits maintained their weights with only slight random fluctuations; both male and female rats showed small gains consistent with their ages.

HAEMATOLOGY: Four dogs exposed to 15.4 mg ZrO2/m3 showed no hematologic changes during semi-monthly intervals of analysis.

CLINICAL CHEMISTRY: No significant blood changes were found among the criteria studied. Blood fibrinogen levels also remained constant during exposure of animals to the test substance.

URINALYSIS: No significant urine changes were found among the criteria studied.

HISTOPATHOLOGY: NON-NEOPLASTIC: There are no reported histological changes that could be attributed to the test substance. The abnormalities that were reported were similar for all species regardless of dose, duration of exposure or test substance inhaled. The lungs showed varying, but small, amounts of congestion, edema and hemorrhage, approximately half of all animals having histological lesions. Control animals, however, exhibited a similar rate of incidence. In all exposed animals, an apparently granular material, brownish-black and doubly refracting, was found in alveolar walls and in phagocytes. Occasionally, this dust was also seen in bronchi and lymph nodes. Among the other tissues, only the kidney consistently showed damage. These renal lesions were a low-grade interstitial nephritis of parasitic origin. Occasionally, parasitic granulomata were found, and two instances of testicular atrophy were noted among 160 animals.
Dose descriptor:
NOAEC
Effect level:
>= 15.4 mg/m³ air
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: no effects were reported in any of the animals studied
Critical effects observed:
no

Concentrations in tissues:

The pattern of deposition of zirconium in tissues was quite similar in all animals exposed to ZrO2. By far the largest amounts were found in the lung and in the pulmonary lymph nodes, but with large variations among species.

Histology following exposure to 15.4 mg ZrO2/m3:

 Species Lung (1) Kidney (2)  Liver  Other
 Cat  3/4  0/4  0/4  0/4
 Dog * *  0/4  *
 Guinea pig  9/18  0/18  0/18  0/18
 Rabbit  2/10  1/10  0/10  0/10
 Rat  8/10  0/10 0/10   0/10

(1) Congestion, edema, hemorrhage; occasional consolidation

(2) Interstitial nephritis

* Parasitic granulomata in lung, liver, kidney, and pulmonary lymph nodes of 3 of 4 animals.

Mean Zirconium Concentration in Tissues (µg Zr/g):

 Species  Number of animals  Lung (µg/g)  Pulmonary Lymph Node (µg/g)
 Rat  10  158  17
 Dog  4  74  731
 Rabbit  10  16  
 Cat  4  20  
 Guinea pig  18  71  
Conclusions:
Inhalation of 15.4 mg/m3 zirconium dioxide for 60 days produced no significant changes in mortality rate, growth, biochemistry, hematology values or histopathology. The NOAEC was deemed to be greater than (or equal to) 15.4 mg/m3.
Endpoint:
sub-chronic toxicity: inhalation
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 performed with zirconium dioxide. The read across justification document is attached to IUCLID section 13.
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Dose descriptor:
other: read across conclusion
Remarks on result:
other: Tungsten zirconium oxide is concluded not to present any hazard after repeated inhalation exposure.
Remarks:
Conclusion based on the results of the read across study of Spiegl et al. (1956) performed with zirconium dioxide.
Critical effects observed:
no
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
no data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented, scientifically sound study that is similar to the OECD 412 "Repeated Dose Inhalation Toxicity: 28-day or 14-day study" guideline with some deviations.
Remarks:
(1) only one dose was used rather than 3; (2) 2 dogs, 6 rabbits, and 20 rats (sex not provided) were exposed rather than 5 animals/sex/dose; (3) complete list of tissues examined for gross and histopathology were not provided; (4) no urinalysis or clinical chemistry parameters were examined.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Remarks:
see rationale for reliability
GLP compliance:
no
Limit test:
no
Species:
other: dog, rabbit, rat
Strain:
not specified
Sex:
not specified
Route of administration:
inhalation: dust
Type of inhalation exposure:
whole body
Vehicle:
other: no data
Remarks on MMAD:
MMAD / GSD: Mass median particle diameter: 1.5 microns
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: copper-lined chamber constructed of wood with observation windows on three sides, 6 x 8 x 6 ft high and volume of 288 cubic feet.
- Method of conditioning air: A centrally located duct in the ceiling of the chamber served as the inlet for the test substance. Baffles below the inlet and two fans near the ceiling dispersed the test substance and distributed the test substance uniformly throughout the chamber. In the four bottom corners were outlets connected to an exhaust system. Air turnover during exposure was approximately 140 cfm or one change every two minutes with no recycling.
- System of generating particulates/aerosols: Wright dust feed.
- Temperature, humidity, pressure in air chamber: 74 +/- 3 degrees F; 47% +/- 6%; few hundredths of an inch of water less than atmospheric pressure.
- Air flow rate: 140 cfm or one change every two minutes.
- Method of particle size determination: test substance was twice ground in a Mikropulverizer to a mean bulk particle size.
- Treatment of exhaust air: not recycled

TEST ATMOSPHERE
- Brief description of analytical method used: Hourly samples were taken with a filter paper sampler and weighed on an analytical balance, spectrographic analysis of each day's accumulation of filter paper samples was used to verify the weight-samples and to make such slight adjustments in concentration results as might occasionally arise from varying amounts of nuisance dust.
- Samples taken from breathing zone: yes, hourly
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Hourly samples were taken with a filter paper sampler and weighed on an analytical balance, spectrographic analysis of each day's accumulation of filter paper samples was used to verify the weight-samples and to make such slight adjustments in concentration results as might occasionally arise from varying amounts of nuisance dust.
Duration of treatment / exposure:
30 days
Frequency of treatment:
6 hours/day 5 days/week
Dose / conc.:
100.8 mg/m³ air
Remarks:
Basis: analytical conc. (ZrO2)
No. of animals per sex per dose:
Dog 2 (sex not known)
Rabbit 6 (sex not known)
Rat 20 (sex not known)
Control animals:
other: yes, only control rabbits and rats were used
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: No data

BODY WEIGHT: Yes
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: weekly
- Animals fasted: No data
- How many animals: 2 dogs
- Parameters: Red blood cell and differential white cell counts, as well as determinations of hemoglobin, mean corpuscular cell volume and clotting time

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
HISTOPATHOLOGY: Yes, lung, kidney, liver. Other tissues were examined, but the specific list of other tissues was not provided
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: One rabbit died during exposure to the test substances, however this matched the control group.

BODY WEIGHT AND WEIGHT GAIN: Throughout the exposure periods the weekly weight responses were identical to those of normal animals.

HAEMATOLOGY: There were no reported hematological changes in the two dogs that were selected for this parameter during the exposure period.

HISTOPATHOLOGY: NON-NEOPLASTIC: There are no reported histological changes that could be attributed to the test substance. The abnormalities that were reported were similar for all species regardless of dose, duration of exposure or test substance inhaled. In all exposed animals, an apparently granular material, brownish-black and doubly refracting, was found in alveolar walls and in phagocytes. Occasionally, this dust was also seen in bronchi and lymph nodes.
Dose descriptor:
NOAEC
Effect level:
>= 100.8 mg/m³ air
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: no effects were reported in any species tested
Critical effects observed:
no
Conclusions:
Inhalation of 100.8 mg/m3 zirconium dioxide for 30 days produced no significant changes in animals in mortality rate, growth, hematology values or histopathology. The NOAEC was deemed to be greater than (or equal to) 100.8 mg/m3.
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
no data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented, scientifically sound study that is similar to the OECD 413 "Subchronic Inhalation Toxicity: 90-day study" guideline with some deviations.
Remarks:
1) only 1 dose tested rather than 3; (2) exposure was for 60 days rather than 90 days; (3) complete list of tissues examined for histopathology was not provided; (4) limited clinical chemistry and urinalysis; (5) 4 cats, 4 dogs, 20 guinea pigs, 19 rabbits and 72 rats (sex not provided) were exposed rather than 10 rodents per sex per dose.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
yes
Remarks:
see rationale for reliability
GLP compliance:
no
Limit test:
no
Species:
other: cat, dog, guinea pig, rabbit, rat
Strain:
not specified
Sex:
not specified
Route of administration:
inhalation: dust
Type of inhalation exposure:
whole body
Vehicle:
other: no data
Remarks on MMAD:
MMAD / GSD: Mass median particle diameter: 1.6 microns
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: copper-lined chamber constructed of wood with observation windows on three sides, 6 x 8 x 6 ft high and volume of 288 cubic feet.
- Method of conditioning air: A centrally located duct in the ceiling of the chamber served as the inlet for the test substance. Baffles below the inlet and two fans near the ceiling dispersed the test substance and distributed the test substance uniformly throughout the chamber. In the four bottom corners were outlets connected to an exhaust system. Air turnover during exposure was approximately 140 cfm or one change every two minutes with no recycling.
- System of generating particulates/aerosols: Wright dust feed.
- Temperature, humidity, pressure in air chamber: 74 +/- 3 degrees F; 47% +/- 6%; few hundredths of an inch of water less than atmospheric pressure.
- Air flow rate: 140 cfm or one change every two minutes.
- Method of particle size determination: test substance was twice ground in a Mikropulverizer to a mean bulk particle size.
- Treatment of exhaust air: not recycled

TEST ATMOSPHERE
- Brief description of analytical method used: Hourly samples were taken with a filter paper sampler and weighed on an analytical balance, spectrographic analysis of each day's accumulation of filter paper samples was used to verify the weight-samples and to make such slight adjustments in concentration results as might occasionally arise from varying amounts of nuisance dust.
- Samples taken from breathing zone: yes, hourly
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Hourly samples were taken with a filter paper sampler and weighed on an analytical balance, spectrographic analysis of each day's accumulation of filter paper samples was used to verify the weight-samples and to make such slight adjustments in concentration results as might occasionally arise from varying amounts of nuisance dust.
Duration of treatment / exposure:
60 days
Frequency of treatment:
6 hours/day, 5 days/week
Dose / conc.:
15.4 mg/m³ air
Remarks:
Basis: analytical conc. (ZrO2)
No. of animals per sex per dose:
Cat- 4
Dog - 4
Guinea Pig - 20
Rabbit - 19
Rat - 72
Control animals:
other: yes, only control rabbits and rats were used
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: No data

BODY WEIGHT: Yes
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: weekly
- Animals fasted: No data
- How many animals: 4 dogs
- Parameters: Red blood cell and differential white cell counts, as well as determinations of hemoglobin, mean corpuscular cell volume and clotting time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: semi-monthly
- Animals fasted: No data
- How many animals: 4 dogs and 4 rabbits
- Parameters: Blood nonprotein nitrogen

URINALYSIS: Yes
- Time schedule for collection of blood: semi-monthly
- Animals fasted: No data
- How many animals: 4 dogs and 4 rabbits
- Parameters: urinary protein

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
HISTOPATHOLOGY: Yes, lung, kidney, liver. Other tissues were evaluated, but a complete list of other tissues was not provided
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: One rabbit and one guinea pig in the 15.4 mg ZrO2/m3 dose group died during exposure to the test substances; however, this matched the deaths observed in the the control group.

BODY WEIGHT AND WEIGHT GAIN: Throughout the exposure periods the weekly weight responses were identical to those of normal animals. Adult cats, dogs, guinea pigs, and rabbits maintained their weights with only slight random fluctuations; both male and female rats showed small gains consistent with their ages.

HAEMATOLOGY: Four dogs exposed to 15.4 mg ZrO2/m3 showed no hematologic changes during semi-monthly intervals of analysis.

CLINICAL CHEMISTRY: No significant blood changes were found among the criteria studied. Blood fibrinogen levels also remained constant during exposure of animals to the test substance.

URINALYSIS: No significant urine changes were found among the criteria studied.

HISTOPATHOLOGY: NON-NEOPLASTIC: There are no reported histological changes that could be attributed to the test substance. The abnormalities that were reported were similar for all species regardless of dose, duration of exposure or test substance inhaled. The lungs showed varying, but small, amounts of congestion, edema and hemorrhage, approximately half of all animals having histological lesions. Control animals, however, exhibited a similar rate of incidence. In all exposed animals, an apparently granular material, brownish-black and doubly refracting, was found in alveolar walls and in phagocytes. Occasionally, this dust was also seen in bronchi and lymph nodes. Among the other tissues, only the kidney consistently showed damage. These renal lesions were a low-grade interstitial nephritis of parasitic origin. Occasionally, parasitic granulomata were found, and two instances of testicular atrophy were noted among 160 animals.
Dose descriptor:
NOAEC
Effect level:
>= 15.4 mg/m³ air
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: no effects were reported in any of the animals studied
Critical effects observed:
no

Concentrations in tissues:

The pattern of deposition of zirconium in tissues was quite similar in all animals exposed to ZrO2. By far the largest amounts were found in the lung and in the pulmonary lymph nodes, but with large variations among species.

Histology following exposure to 15.4 mg ZrO2/m3:

 Species Lung (1) Kidney (2)  Liver  Other
 Cat  3/4  0/4  0/4  0/4
 Dog * *  0/4  *
 Guinea pig  9/18  0/18  0/18  0/18
 Rabbit  2/10  1/10  0/10  0/10
 Rat  8/10  0/10 0/10   0/10

(1) Congestion, edema, hemorrhage; occasional consolidation

(2) Interstitial nephritis

* Parasitic granulomata in lung, liver, kidney, and pulmonary lymph nodes of 3 of 4 animals.

Mean Zirconium Concentration in Tissues (µg Zr/g):

 Species  Number of animals  Lung (µg/g)  Pulmonary Lymph Node (µg/g)
 Rat  10  158  17
 Dog  4  74  731
 Rabbit  10  16  
 Cat  4  20  
 Guinea pig  18  71  
Conclusions:
Inhalation of 15.4 mg/m3 zirconium dioxide for 60 days produced no significant changes in mortality rate, growth, biochemistry, hematology values or histopathology. The NOAEC was deemed to be greater than (or equal to) 15.4 mg/m3.
Endpoint:
sub-chronic toxicity: inhalation
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 performed with zirconium dioxide. The read across justification document is attached to IUCLID section 13.
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Dose descriptor:
other: read across conclusion
Remarks on result:
other: Tungsten zirconium oxide is concluded not to present any hazard after repeated inhalation exposure.
Remarks:
Conclusion based on the results of the read across study of Spiegl et al. (1956) performed with zirconium dioxide.
Critical effects observed:
no
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

As the comparison of basic toxicological data (Annex VII endpoints) for zirconium dioxide and tungsten zirconium (hydroxide) oxide confirmed the validity of the read across assumption, i.e. that the addition of tungsten to the crystal lattice of zirconium dioxide does not affect the unhazardous character of zirconium dioxide, higher endpoints such as repeated dose toxicity endpoints were covered using the approach followed in the zirconium dioxide dossier. The read across justification is attached to IUCLID Section 13.

Repeated dose toxicity: oral

No reliable information is available for zirconium dioxide. Read across is performed using oral repeated dose toxicity studies with zirconium acetate (a 'water soluble' zirconium compound) and zirconium basic carbonate (an insoluble zirconium compound such as zirconium dioxide). These two studies are used in a weight of evidence approach to conclude that no adverse systemic effects are expected after repeated oral exposure to zirconium dioxide either.

No effects were reported after oral administration to rats during 17 weeks of zirconium hydrated basic carbonate in the form of a moist paste containing 20.9% zirconium dioxide in a reliable study (Klimisch 2) (Harrison et al., 1951). The total intake of zirconium dioxide during the test period was 0, 0.9, 9 and 103.5 g. The equivalent NOAEL for zirconium dioxide was >= 3150-7080 mg/kg bw/day.

The systemic toxic effects of zirconium acetate solution (containing 40.7% of the active ingredient zirconium acetate) after oral repeated exposure, as well as any toxic effects on reproduction and development were investigated in Sprague Dawley rats up to early lactation (day 4 post partum). The study (Rossiello, 2013) was performed according to OECD guideline 422 (GLP).

Three groups of 10 males and 10 females each received the test item, by oral gavage, at 100, 300 and 1000 mg/kg bw/day, expressed as zirconium acetate (anhydrous form). A similar constituted control group received the vehicle alone during the treatment period. The test item was diluted in purified water (vehicle) at concentrations of 10, 30 and 100 mg of zirconium acetate/mL. Chemical analyses of the formulated test item were performed during the study and the overall results were within the limits of acceptance. The overall dosing period was 32 days for males, which included 2 weeks before pairing and continuously thereafter up to the day before necropsy and up to 50 days for females including 2 weeks before pairing and thereafter during pairing, gestation and lactation periods until day 3 post partum.

The animals were followed for daily clinical signs, weekly body weight, food consumption, neurotoxicity assessment, oestrous cycle, mating performance, clinical pathology evaluation including haematology and clinical chemistry and offspring delivery. A detailed macroscopic examination, organ weights and histopathology including the spermatogenic cycle were performed.

 

No treatment-related findings were observed either during the in vivo phase or at post mortem examination. Microscopically, a treatment-related finding was seen in males receiving 300 and 1000 mg/kg bw/day consisting of minimal focal vacuolation of squamous epithelium (limiting ridge) of non-glandular region of the stomach. This change may be attributed to a local irritant effect of the compound administered by oral gavage and since humans do not have a forestomach or structure analogous to the forestomach, it is not considered of toxicological relevance.

No systemic adverse effects were therefore reported. On the basis of these results, the NOAEL (No Observed Adverse Effect Level) for systemic toxicity after repeated oral exposure was considered to be >= 1000 mg of zirconium acetate/kg bw/day for both males and females.

Taking into account the concept of the more water soluble is the substance the higher is its potential for systemic bioavailability, it could be concluded that systemic toxicity after repeated oral exposure to zirconium dioxide (an insoluble zirconium compound) may be even lower than after repeated oral exposure to zirconium acetate (a 'water soluble' zirconium compound).

Repeated dose toxicity: inhalation

For zirconium dioxide, one reliable study is available for this endpoint, reporting on two experiments: a 30-day repeated dose inhalation study in dog, rabbit and rat and a 60-day repeated dose toxicity study in cat, dog, guinea pig, rabbit and rat. No effects were reported in any of the species studied after inhalation of zirconium dioxide dust (NOAEC >= 100.8 mg ZrO2/m3 in the 30-day study and NOAEC >= 15.4 mg ZrO2/m3 in the 60-day study).

Justification for classification or non-classification

Based on the available data for repeated dose toxicity via the oral and inhalation route and according to the CLP criteria, zirconium dioxide should not be classified for STOT - repeated exposure. Since comparison of basic toxicological data (Annex VII endpoints) for zirconium dioxide and tungsten zirconium (hydroxide) oxide indicated that the read across assumption is valid, i.e. that the addition of tungsten to the crystal lattice of zirconium dioxide does not alter the unhazardous character of zirconium dioxide, it is considered acceptable to assume non-classification for tungsten zirconium oxide too.