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Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
no data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Well documented, scientifically sound study that is similar to OECD 413 "Subchronic Inhalation Toxicity: 90-day study" guideline with the following deviations: (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.

Data source

Reference
Reference Type:
publication
Title:
Inhalation Toxicity of Zirconium Compounds: Short-Term Studies
Author:
Spiegl CJ, Calkins MC, DeVoldre JJ, Scott JK
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 413 (Subchronic Inhalation Toxicity: 90-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 dichloride oxide
EC Number:
231-717-9
EC Name:
Zirconium dichloride oxide
Cas Number:
7699-43-6
Molecular formula:
Cl2OZr
IUPAC Name:
Dichloro(oxo)zirconium
Details on test material:
- Name of test material (as cited in study report): ZrCl4 but as dissolved in water converted to ZrOCl2
- Physical state: Mist
- Impurities (identity and concentrations): Al (0.005%), Ba (Trace), Ca (0.008%), Cu (Trace), Fe (0.004%), Mg (0.006%), Si (0.01%), Ti (0.001%),

Test animals

Species:
other: cat, dog, guinea pig, rabbit, rat
Strain:
not specified
Sex:
not specified

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: no data
Remarks on MMAD:
MMAD / GSD: Mass median particle diameter: 0.56 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
Doses / concentrations
Dose / conc.:
11.3 mg/m³ air (analytical)
No. of animals per sex per dose:
Cat- 4
Dog - 4
Guinea Pig - 20
Rabbit - 20
Rat - 72
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: 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.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Description (incidence):
3 guinea pig & 8 rats died during exposure to the test substances.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Throughout the exposure periods the weekly weight responses were identical with those of normal animals.
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:
effects observed, treatment-related
Description (incidence and severity):
Decrease on hemoglobin in the blood for the 3 dogs. Minimum reached after 4 weeks. Depression in the red blood cells count was also observed but in a lower proportion. The lower depression occurred between week 5 & 7.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
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 findings:
no effects observed
Description (incidence and severity):
No significant urine changes were found among the criteria studied.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
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.
Histopathological findings: neoplastic:
not examined
Other effects:
not specified

Effect levels

Dose descriptor:
NOAEC
Effect level:
>= 11.3 mg/m³ air
Based on:
test mat.
Sex:
not specified
Basis for effect level:
body weight and weight gain
clinical biochemistry
clinical signs
haematology
histopathology: non-neoplastic
mortality
urinalysis

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
Inhalation of 11.3 mg/m3 zirconium dichloride oxide for 60 days produced no significant changes in animals in mortality rate, growth, biochemistry, hematology values or histopathology. In two animals (cats) among 124 testicular athrophy was observed.