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EC number: 209-156-6 | CAS number: 557-09-5
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Genetic toxicity: in vivo
Administrative data
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
- Remarks:
- Type of genotoxicity: chromosome aberration
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: The study was conducted according to the OECD Guideline and in compliance with GLP.
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 011
- Report date:
- 2011
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Deviations:
- no
- GLP compliance:
- yes
- Type of assay:
- micronucleus assay
Test material
- Reference substance name:
- Zinc oxide
- EC Number:
- 215-222-5
- EC Name:
- Zinc oxide
- Cas Number:
- 1314-13-2
- Molecular formula:
- OZn
- IUPAC Name:
- oxozinc
- Test material form:
- solid: nanoform
- Details on test material:
- TEST ITEM
- Name of test material (as cited in study report): Z-COTE HP1
- Molecular weight (if other than submission substance): 81.38 g/mol
- Physical state: Solid
- Composition of test material, percentage of components: Z-COTE HP1 (98%), coated with triethoxycaprylylsilane (CAS # 2943-75-1; 2%)
- Lot/batch No.: NPL Ref#: ZB250#65
- Expiration date of the lot/batch: June 2014
- Storage condition of test material: Room temperature, dry, exclusion of light
- Particle size: <200nm
- Particle surface area: 12-24 m2/g
- Other: MMAD of the aerosol < 3.0 µm, GSD about 1.5
REFERENCE ITEMS
- Name of test material (as cited in study report): Zinc Oxide 205532, Micron Size Powder
- Molecular weight (if other than submission substance): 81.38 g/mol
- Physical state: Solid
- Composition of test material, percentage of components: Non-coated microscaled ZnO
- Lot/batch No.: NPL Ref#: ZrA250#60
- Expiration date of the lot/batch: May 2014
- Storage condition of test material: Room temperature, dry, exclusion of light
- Other: MMAD of the aerosol < 3.0 µm, GSD about 1.5
- Name of test material (as cited in study report): Z-COTE
- Molecular weight (if other than submission substance): 81.38 g/mol
- Physical state: Solid
- Composition of test material, percentage of components: Non-coated nanoscaled ZnO; purity ZnO: 99%
- Lot/batch No.: NPL Ref#: ZC250#32
- Expiration date of the lot/batch: June 2014
- Particle size: <200nm
- Particle surface area: 12-24 m2/g
- Storage condition of test material: Room temperature, dry, exclusion of light
- Other: MMAD of the aerosol < 3.0 µm, GSD about 1.5
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, Sulzfeld/Germany
- Age at study initiation: Approx. 8 weeks
- Weight at study initiation: Approx. 230g (males), approx. 165g (females)
- Fasting period before study: No
- Housing: 2 rats per cage, absorbing softwood bedding
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 1 d followed by 3 weeks of training in nose-only tubes without exposure
ENVIRONMENTAL CONDITIONS
- Temperature: 22 +/- 2°C
- Humidity: 55 +/- 15°C
- Air changes (per hr): Fully airconditioned
- Photoperiod (hrs dark / hrs light): 12h/12h
Administration / exposure
- Route of administration:
- inhalation: aerosol
- Vehicle:
- clean air
- Details on exposure:
- TYPE OF INHALATION EXPOSURE: nose only
GENERATION OF TEST ATMOSPHERE CHAMBER DESCRIPTION
- Exposure apparatus: Flow-past nose-only exposure system, individually exposure of each rat, exhaled air is immediately exhausted
- Method of holding animals in test chamber: Individual acrylic tubes
- Source and rate of air: Pressurized air, 1L/min
- System of generating particulates/aerosols: Feeding system and high-pressure, high-velocity pressurized air dispersion with computerized control
- Temperature, humidity, pressure in air chamber: 22 +/- 2°C, 55 +/- 15%,
- Air flow rate: 1L/min
- Method of particle size determination: Cascade impactor/ Marple impactor
- Treatment of exhaust air: Disposal in compliance with local, federal and state regulations
TEST ATMOSPHERE
- Brief description of analytical method used: Gravimetrically by filter samples, feed back loop to actual aerosol concentrations measured by an aerosol photometer
- Samples taken from breathing zone: Yes - Duration of treatment / exposure:
- 2 weeks, 5 consecutive days per week, 6 h per day
- Frequency of treatment:
- 5 consecutive days per week, 6 h per day
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
0.5, 2, and 8 mg/m3
Basis:
other: target aerosol concentration of test substance Z-COTE HP1
- Remarks:
- Doses / Concentrations:
8 mg/m3
Basis:
other: target aerosol concentration of reference substance Z-COTE
- Remarks:
- Doses / Concentrations:
8 mg/m3
Basis:
other: target aerosol concentration of reference substance ZnO
- No. of animals per sex per dose:
- 5 males and 5 females per dose
- Control animals:
- yes, concurrent no treatment
- Positive control(s):
- 5 additional rats per sex were dosed once orally with 20 mg/kg cyclophosphamide (CP) monohydrate 24 h pior to sacrifice
Examinations
- Tissues and cell types examined:
- bone marrow tissue- polychromatic erythrocytes (PCE)
- Details of tissue and slide preparation:
- From suspensions of bone marrow tissue, cleaned of nucleated cells by a cellulose column procedure, smears were prepared on slides, fixed for 10 minutes in absolute methanol and stained with May-Grünwald- and Giemsa-solution. Microscopic analysis was conducted on a blind basis. Micronuclei were counted in 2000 polychromatic erythrocytes (PCE) per animal. The ratio of polychromatic to normochromatic erythrocytes (NCE) was determined in 500 red blood cells.
- Evaluation criteria:
- Slide Reading and Measurements
The slides were analyzed microscopically under 630-1000 x magnification. For each animal, the incidence of micronucleated cells per 2.000 PCE of the bone marrow was determined. The ratio of PCE to NCE was calculated by counting the number of PCE per 500 red blood cells (RBC). For both endpoints one of the two existing (A and B) bone marrow smears was used.
Data Evaluation
The micronucleus assay is judged as valid if the clean air controls demonstrate low spontaneous frequencies of micronucleus induction and if the positive controls demonstrate significantly higher frequencies of micronucleus induction as compared to the clean air controls. In addition, in test item treated animals the PCE ratio should not fall below 20% of the clean air control values to avoid unspecific effects due to excessive cytotoxicity in the bone marrow.
In the mammalian erythrocyte micronucleus test a genotoxic effect is claimed if a dose-related increase in the number of polychromatic erythrocytes or a statistically significant increase in the number of micronucleated cells in a single dose group at a single sampling time is observed, but biological relevance of the results is considered first. - Statistics:
- Differences between groups were considered statistically significant at p < 0.05. Data were analyzed using analysis of variance. If the group means differ significantly by the analysis of variance the means of the treated groups were compared with the means of the control groups using Dunnett's test.
The statistical evaluation of the histopathological findings was done with the two-tailed Fisher test by the P.L.A.C.E.S. system.
Results and discussion
Test results
- Sex:
- male/female
- Genotoxicity:
- negative
- Toxicity:
- no effects
- Vehicle controls validity:
- valid
- Negative controls validity:
- valid
- Positive controls validity:
- valid
Any other information on results incl. tables
As assessed by differential cell counting of bone marrow smears, Z‑COTE® HP1 and the particulate reference items Z-COTE®and micron-scaled ZnO in the given doses (0.5, 2.0, and 8.0 mg/m3) didn’t significantly influence red blood cell formation in male Wistar rats (strain: Crl:WU) after 14 days of inhalation exposure. However, there was a high fluctuation rate in PCE numbers, in part, perhaps based on the combination of the micronucleus test with the hOGG1-modified comet assay ex vivo in the male animals. In female Wistars rats (strain: Crl:WU), number of PCE/500 RBC was significantly reduced to 143±23.0 (p ≤0.05) by Z‑COTE®and to 124±23.1 (p ≤0.01) by the positive control CP, as compared to 179±18.0 for the clean air control. In addition, a significant decrease (p ≤0.05, only by using the Student’s t-Test) was observed for the highest Z‑COTE® HP1 dose group (8 mg/m3), indicating some systemic availabilty of, in particular, the nano-scaled particles.
Under the conditions of this assays, Z-COTE® HP1, Z-COTE®, and microscaled ZnO didn’t significantly enhance the number of micronuclei in polychromatic erythrocytes of the bone marrow (after 14 days of inhalation exposure) of both male and female Wistar rats (strain: Crl:WU). In contrast, as expected, the positive control CP significantly induced micronucleus formation in PCE of the bone marrow, with higher rates in male than in female animals.
Table Red blood cell formation and micronucleus induction in bone marrow of rats, after 14 days of exposure to clean air, Z-COTE®HP1, Z-COTE®, or microscaled ZnO
Treatment group |
Concentration, sampling time |
PCE/500 RBC |
PCE:NCE |
MN/2000 PCE |
% MN PCE |
Negative control, |
24 h |
♂ 86 |
♂ 0.22 |
♂ 5.8 |
♂ 0.29 |
Positive control, |
20 mg/kg b.w., |
♂ 67 |
♂ 0.16 |
♂ 55.4** |
♂ 2.77** |
Test item, Z-COTE®HP1 |
0.5 mg/m3, 24 h |
♂ 127 |
♂ 0.36 |
♂ 5.0 |
♂ 0.25 |
Test item, Z-COTE®HP1 |
2.0 mg/m3, 24 h |
♂ 79 |
♂ 0.19 |
♂ 5.4 |
♂ 0.27 |
Test item, Z-COTE®HP1 |
8.0 mg/m3, 24 h |
♂ 84 |
♂ 0.21 |
♂ 2.6 |
♂ 0.13 |
Reference item, Z-COTE® |
8.0 mg/m3, 24 h |
♂ 86 |
♂ 0.21 |
♂ 4.2 |
♂ 0.21 |
Reference item, Microscaled ZnO |
8.0 mg/m3,24 h |
♂ 109 |
♂ 0.29 |
♂ 3.2 |
♂ 0.16 |
PCE: Polychromatic erythrocytes; NCE: Normochromatic erythrocytes; RBC: Red blood cells; MN: Micronuclei; % MN PCE: Percent micronucleated PCE; Significantly different from negative controls:*:P ≤0.05, **:P ≤0.01, Mann-Whitney Rank Sum Test; (*): P ≤0.05, Student’s t-Test.
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): negative
Under the conditions of this assay, no systemic chromosome mutagenic activity was detected in the rat bone marrow micronucleus assay after inhalation exposure to Z-COTE HP1 at dose levels inducing local effects in the lung. Inhaled Z‑COTE® HP1 is considered non-mutagenic in immature bone marrow erythrocytes (PCE) of Wistar rats (strain: Crl:WU). - Executive summary:
A 14-day repeated dose inhalation toxicity study was conducted to establish exposure dose-response relationships of the nanoscaled ZnO (with functionalized surface) in rats after subacute exposure and to compare the effects observed with two reference substances, i.e., nanoscaled ZnO (uncoated) and a microscaled ZnOin rats using nose-only exposure according to the OECD Guideline 412 in compliance with GLP.
In the framework of this study also systemic clastogenic and aneugenic effects were investigated in male and female rats using the bone marrow micronucleus assay according to OECD Guideline 474.
In this study, male rats were exposed (nose only) atconcentration levels of 0, 0.5, 2, or 8 mg/m³ with nanoscaled ZnO (with functionalized surface)and at 8 mg/m3 with reference test substances. Fresh air treated animals served as concurrent control.
There was no treatment-related reduction of body weights in any test group; no clinical signs were detected. In male rats the test item and the reference substances did not mediate significant repression of red blood cell formation. In females the PCE/NCE was significantly reduced in the positive control as well as in females exposed to 8 mg/m³ Z-COTE® HP1 or uncoated Z-COTE®. This effect might indicate that these test itemsreached the bone marrow as target organ.
There was no evidence of a significantly enhanced mean frequency of micronucleated erythrocytes due to Z‑COTE® HP1, Z‑COTE®or microscaled ZnO exposure in males or females, as compared to the vehicle control groups (clean air) at any dose level. The positive and vehicle controls gave valid results.Conclusion: No systemic chromosome mutagenic activity was detected in the rat bone marrow micronucleus assay after inhalation exposure to Z-COTE HP1 at dose levels inducing local effects in the lung.
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