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Repeated dose toxicity: inhalation

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Administrative data

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.
Cross-reference
Reason / purpose for cross-reference:
reference to same study
Reference
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.
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
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.

Data source

Reference
Reference Type:
publication
Title:
Inhalation Toxicity of Zirconium Compounds: Short-Term Studies
Author:
Spiegl, C.J., Calkins, M.C., DeVoldre, J.J., Scott, J.K.
Year:
1956
Bibliographic source:
Atomic Energy Commission Project, Rep. No. UR-460, University of Rochester, Rochester, NY, pages 1-26

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Remarks:
see rationale for reliability
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Zirconium dioxide
EC Number:
215-227-2
EC Name:
Zirconium dioxide
Cas Number:
1314-23-4
Molecular formula:
O2Zr
IUPAC Name:
dioxozirconium
Test material form:
solid: particulate/powder
Details on test material:
- Name of test material (as cited in study report): zirconium dioxide
- Physical state: dust, particle size 1.5 µm.
- Analytical purity: > 90%
- Impurities (identity and concentrations):
For the 60-day experiment: Al (.001%), B (.00002%), Ba (.0002%), Ca (.002%), Cr (.0001%), Cu (.0025%), Fe (.0025%), Mg (.0001%), Ni (.0003%), Pb (.0225%), Si (.001%), Ti (.006%), V (.0004%)
For the 30-day experiment: Al (0.026%), B (trace), Ba (0.062%), Ca (0.071%), Cr (trace), Cu (0.008%), Fe (0.049%), Mg (0.16%), Si (< 0.47%), Ti (0.18%)

Test animals

Species:
other: dog, rabbit, rat
Strain:
not specified
Sex:
not specified

Administration / exposure

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
Doses / concentrations
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

Examinations

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

Results and discussion

Results of examinations

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.

Effect levels

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

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

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.

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