Hafnium

Endpoint summary

Description of key information

As Hf powder is pyrophoric, it is technically not possible to generate an inhalable test atmosphere even for long term studies. The evaluation of repeated dose toxicity inhalation of Hf powder may not be technically possible.
Based on the same behaviour and toxicological effects, a read across with ZrO2 is performed. No effect was observed following repeated inhalation of ZrO2.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

no data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

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.

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

Remarks:

Doses / Concentrations:
11 mg Zr/m3
Basis:
analytical conc.

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 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 with those of normal animals.


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


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 cirteria 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.

Dose descriptor:

NOAEC

Effect level:

> 11

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:

not specified

Conclusions:

Inhalation of 11 mg/m3 zirconium for 60 days produced no significant changes in animals in mortality rate, growth, biochemistry, hematology values or histopathology. The NOAEC was deemed to be greater than 11 mg Zr/m3.

Executive summary:

In this 60 day repeated dose inhalation test, cat, dog, guinea pig, rabbit and rat were exposed to 11 mg Zr/m3 as dust in whole body. No significant changes in animals were observed in mortality rate, growth, biochemistry, hematology values or histopathology. The NOAEC was deemed to be greater than 11 mg Zr/m3.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

no data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

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.

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

Remarks:

Doses / Concentrations:
11 mg Zr/m3
Basis:
analytical conc.

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 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 with those of normal animals.


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


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 cirteria 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.

Dose descriptor:

NOAEC

Effect level:

> 11

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:

not specified

Conclusions:

Inhalation of 11 mg/m3 zirconium for 60 days produced no significant changes in animals in mortality rate, growth, biochemistry, hematology values or histopathology. The NOAEC was deemed to be greater than 11 mg Zr/m3.

Executive summary:

In this 60 day repeated dose inhalation test, cat, dog, guinea pig, rabbit and rat were exposed to 11 mg Zr/m3 as dust in whole body. No significant changes in animals were observed in mortality rate, growth, biochemistry, hematology values or histopathology. The NOAEC was deemed to be greater than 11 mg Zr/m3.

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

The justification for the use of Zr/ ZrO2 data as a read across approach was developped in the toxicological summary.

In addition, particle size influences the deposition behaviour in the respiratory tract and potential toxic effects.

The Hf powder particle size was found to be generally between 44 µm and 0.8 mm.(see section 4.5 of the dossier)

In the Spiegl et al. study (1956), the D50 or mass median aerodynamic diameter was set to 1.5 µm for ZrO2. Thus, ZrO2 particles will be able to reach lower parts of the respiratory system. The use of data from ZrO2 particles ("alveolar particles") is toxicologically protective or toxicologically equivalent (for some Zr powder during the manufacturing process) for Hf powder.

One reliable study (Spiegl et al., 1956 - K2) described a 30 day and 60 day repeated dose inhalation test in several animal species. Exposition to 75 mg Zr/m3 (100.8 mg/m3 ZrO2) for 30 days or 11 mg Zr/m3 (15.4 mg/m3 ZrO2) for 60 days produced no significant effect on animal mortality, rate, growth, haematology values or histopathology. The NOAEC were deemed to be greater than the concentration tested.

Another study scored K3 (Delongeas et al., 1983) confirmed the absence of effects on mortality, behaviour and growth, following daily instillation of 800 mg/kg zirconium oxychloride (230 mg Zr/ kg/day) via gastric tube, for 16 days.

As 30 day and 60 day studies are available, no longer studies were necessary, taking into account the low toxicity of this substance.

Justification for classification or non-classification

Substances should be classified in category 2 for specific target organ toxicity (repeated exposure) on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations. Based on the available data and the absence of toxicity effects observed, the substance was not classified under the CLP Regulation 1272/2008 and the directive Classification and Labelling 67/548/EC.