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EC number: 222-102-6 | CAS number: 3349-08-4
- 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
Repeated dose toxicity: inhalation
Administrative data
- Endpoint:
- chronic toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- May 1988 to May 1990
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- carcinogenicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- May 1988 to May 1990
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- other: reference to same study, different species (mouse)
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
- GLP compliance:
- yes
- Species:
- rat
- Strain:
- other: F344/N
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Taconic Farms, Germantown, NY, USA.
- Age at study initiation: 6-week old
- Weight at study initiation: ~108-133 g
- Fasting period before study: not reported
- Housing: individually housed
- Diet: ad libitum, except during exposure
- Water: ad libitum, except during exposure
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.2-29.6°C
- Humidity (%): 8-99%
- Air changes (per hr): 9-21/hour
- Photoperiod (hrs dark / hrs light): 12-h light/dark photo cycle
IN-LIFE DATES: June 1988 to June 1990 - Route of administration:
- inhalation: aerosol
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- other: distilled and deionized water
- Remarks on MMAD:
- MMAD / GSD: MMAD =2.08-2.52 µm
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Stainless steel multitiered whole exposure chambers (Hazleton, Aberdeen, MD, USA)
- Source and rate of air: High-efficiency particulate air filter (Flanders, Washington, DC)
- System of generating particulates/aerosols: Aerosols were generated by nebulization of test substance solutions (62.1 g/L in distilled and deionized water)
- Temperature, humidity, pressure in air chamber: Temp. 17.2-29.6 deg. C; humidity 8-99%
- Air flow rate: The aerosol was mixed with additional dilution air to achieve the proper concentration and flow rate.
- Method of particle size determination: Aerosol concentration was determined by taking three 2-h filter samples throughout the exposure day.
Real-time determination of aerosol concentration was made using real time aerosol monitor - model S units. Aerosol size was determined using cascade impactors. (The range of mass median aerodynamic diameters and GSD obtained throughout the study were 2.2-2.5 um and GSD=2.2)
TEST ATMOSPHERE
- Brief description of analytical method used: aerosol concentrations determined gravimetrically
- Samples taken from breathing zone: yes
VEHICLE: water - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Aerosol concentration was determined by taking three 2-h filter samples throughout the exposure day. Real-time determination of aerosol concentration was made using real time aerosol monitor - model S units. Aerosol size was determined using cascade impactors.
- Duration of treatment / exposure:
- 6 h / d
- Frequency of treatment:
- 5 days per week for a period of 2 years
- Dose / conc.:
- 0 mg/m³ air (nominal)
- Dose / conc.:
- 0.125 mg/m³ air (nominal)
- Dose / conc.:
- 0.25 mg/m³ air (nominal)
- Dose / conc.:
- 0.5 mg/m³ air (nominal)
- No. of animals per sex per dose:
- Groups of 63 to 65 male and 63 to 64 female rats
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: based on previous 13-week study
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were observed twice daily.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: conducted at the start of the study, weekly for 13 weeks, monthly during the remainder of the study, and at the end of the study period.
BODY WEIGHT: Yes
- Time schedule: conducted at the start of the study, weekly for 13 weeks, monthly during the remainder of the study, and at the end of the study period.
HAEMATOLOGY: Yes
- Blood was collected from the retroorbital sinus of as many as five male and five female mice at the 15-month interim evaluation.
- Hematology: hematocrit, hemoglobin, erythrocytes, mean erythrocyte volume, mean erythrocyte hemoglobin, mean erythrocyte hemoglobin concentration, reticulocytes, total leukocytes and differential, and nucleated erythrocytes. - Sacrifice and pathology:
- GROSS PATHOLOGY/HISTOPATHOLOGY: Yes
Necropsy was performed on all animals.
The following organs were weighed at 7- and 15-months: brain, right kidney, liver, lung, spleen, and thymus.
Complete histopathology was performed on all mice. Gross lesions and tissues examined included: adrenal gland, bone, brain, clitoral gland, epididymis or oviduct, esophagus, heart, gallbladder, large intestine (including cecum, colon, rectum), small intestine (including duodenum, jejunum, ileum), kidneys, larynx, liver, lung, lymph nodes, mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate, salivary gland, seminal vesicle, skin, spleen, stomach, testis, thymus, thyroid gland, trachea, urinary bladder, and uterus. - Other examinations:
- Ni levels in lung tissues were analyzed
- Statistics:
- The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958). Dose-related effects were analyzed using Cox's (1972) method for testing two groups for equality, and Tarone's (1975) life table test to identify dose-related trends. Organ and body weight data were analyzed using the parametric multiple comparison procedures of Dunnett (1955) and Williams (1971, 1972).
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The final mean body weights compared to the control group per 0.125 mg/m3, 0.25 mg/m3 and 0.5 mg/m3 exposure groups were 99 %, 101 % and 98 %, respectively for the male rats and 97 %, 97 % and 94 % for the females, respectively.
- 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
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Lung weights in exposed animals were greater than controls, this was considered to be related to inflammatory lung reactions that occurred in response to test substance exposure. At 15 months, the lung weights of in the high exposure group was 33-41 % more compared to the control.
- Gross pathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- A spectrum of exposure-related nonneoplastic respiratory tract lesions seen after exposure included focal alveolar/bronchiolar hyperplasia, inflammation, and/or fibrosis of the lung and lymphoid hyperplasia of the lung-associated lymph nodes. Atrophy of the olfactory epithelium was also seen after exposure.
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- ORGAN WEIGHTS:
Significant organ weight changes reported:
-increased relative lung weights of 0.25 and 0.5 mg/m3 males at 7-month evaluation.
-increased relative and absolute lung weights of 0.5 mg/m3 females at 7-month evaluation.
-increased relative and absolute lung weights of 0.5 mg/m3 males and females at 15-month evaluation.
HAEMATOLOGY:
There were no substance-related hematology differences or clinical findings reported. Lung Ni levels were significantly higher in Ni-exposed rats relative to the control animals. Lung Ni levels increased with increasing Ni exposure levels.
HISTOPATHOLOGY: NON-NEOPLASTIC
Significantly-increased incidences of non-neoplastic lung lesions reported for 2-year study:
-chronic active lung inflammation of 0.25 and 0.5 mg/m3 rats.
-macrophage hyperplasia of 0.25 and 0.5 mg/m3 rats.
-alveolar proteinosis of 0.25 and 0.5 mg/m3 rats.
-fibrosis of 0.25 and 0.5 mg/mg3 rats.
Result (carcinogenicity): negative - Dose descriptor:
- LOAEL
- Effect level:
- 0.25 mg/m³ air
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: chronic active lung inflammation
- Remarks on result:
- other: equivalent to 0.056 mg Ni/m3
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 0.125 mg/m³ air
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: overall effects
- Remarks on result:
- other: equivalent to 0.027 mg Ni/m3
- Key result
- Critical effects observed:
- no
- Conclusions:
- No evidence of carcinogenic activity of the test substance nickel sulfate hexahydrate as aerosol has been revealed in rats in this 2-years inhalation study. The NOAEL was determined to be ca. 0.125 mg/m3 air, equivalent to 0.027 mg Ni/m3 air.
Data source
Reference
- Reference Type:
- publication
- Title:
- Comparative Carcinogenic Effects of Nickel Subsulfide, Nickel Oxide, or Nickel Sulfate Hexahydrate Chronic Exposures in the Lung
- Author:
- Dunnick JK, Elwell MR, Radovsky AE, Benson JM, Hahn FF, Nikula KJ, Barr EB, Hobbs CH
- Year:
- 1 995
- Bibliographic source:
- Cancer Research 55: 5251-5256.
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- nickel(2+);sulfate;hexahydrate
- EC Number:
- 600-152-3
- Cas Number:
- 10101-97-0
- Molecular formula:
- H12NiO10S
- IUPAC Name:
- nickel(2+);sulfate;hexahydrate
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: F344/N
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Taconic Farms, Germantown, NY
- Housing: Hazleton 2000 whole-body chambers
- Diet: ad libitum during non-exposure periods
- Water: ad libitum
ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 hr dark, 12 hr light
Administration / exposure
- Route of administration:
- inhalation: aerosol
- Type of inhalation exposure:
- whole body
- Vehicle:
- water
- Remarks on MMAD:
- MMAD / GSD: MMAD =2.08-2.52 µm
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Stainless steel multitiered whole exposure chambers (Hazleton, Aberdeen, MD, USA)
- Source and rate of air: High-efficiency particulate air filter (Flanders, Washington, DC)
- System of generating aerosols: Aerosols were generated by nebulization of test substance solutions (62.1 g/L in distilled and deionized water)
- Method of particle size determination: Aerosol concentration was determined by taking three 2-h filter samples throughout the exposure day.
Real-time determination of aerosol concentration was made using real time aerosol monitor - model S units. Aerosol size was determined using cascade impactors. (The range of mass median aerodynamic diameters and GSD obtained throughout the study were 2.2-2.5 um and GSD=2.2) - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Aerosol concentration was determined by taking three 2-h filter samples throughout the exposure day. Real-time determination of aerosol concentration was made using real time aerosol monitor - model S units. Aerosol size was determined using cascade impactors.
- Duration of treatment / exposure:
- 6h /d
- Frequency of treatment:
- 5 d/wk, 2 yr
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1 mg/m³ air (nominal)
- Dose / conc.:
- 0.5 mg/m³ air (nominal)
- Dose / conc.:
- 0.25 mg/m³ air (nominal)
- Dose / conc.:
- 0.125 mg/m³ air (nominal)
- Dose / conc.:
- 0 mg/m³ air (nominal)
- No. of animals per sex per dose:
- Groups of 63 to 65 male and 63 to 64 female rats
- Control animals:
- yes
- Details on study design:
- - Dose selection rationale: based on previous 13-week study
Examinations
- Observations and examinations performed and frequency:
- DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: every 4 weeks
BODY WEIGHT: Yes
- Time schedule for examinations: every 4 weeks - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, complete necropsies were done on all animals. At necropsy, all organs and tissues were examined for grossly visible lesions, and all major tissues and lesions were preserved in 10 % neutral-buffered formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin for microscopic examination.
HISTOPATHOLOGY: Yes. Complete histopathology was performed on high-exposure and control groups and to a no-effect level in target tissues. - Other examinations:
- Ni concentration in the lungs
- Statistics:
- Tests of significance included pairwise comparisons of each exposed group with controls and a test for overall exposure-related trends. Organ and body weight data were analyzed using parametric multiple comparison procedures, and lung burden data were analyzed using nonparametric multiple comparison methods. The reported values were considered significant at the P < 0.05 level.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The final mean body weights compared to the control group per 0.125 mg/m3, 0.25 mg/m3 and 0.5 mg/m3 exposure groups were 99 %, 101 % and 98 %, respectively for the male rats and 97 %, 97 % and 94 % for the females, respectively.
- 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
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Lung weights in exposed animals were greater than controls, this was considered to be related to inflammatory lung reactions that occurred in response to test substance exposure. At 15 months, the lung weights of in the high exposure group was 33-41 % more compared to the control.
- Gross pathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- A spectrum of exposure-related nonneoplastic respiratory tract lesions seen after exposure included focal alveolar/bronchiolar hyperplasia, inflammation, and/or fibrosis of the lung and lymphoid hyperplasia of the lung-associated lymph nodes. Atrophy of the olfactory epithelium was also seen after exposure.
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- GROSS & HISTOPATHOLOGY:
A spectrum of exposure-related nonneoplastic respiratory tract lesions included: focal alveolar/bronchiolar hyperplasia, inflammation, and/or fibrosis of the lung and lymph oid hyperplasia of the lung-associated lymph nodes, and atrophy of the olfactory epithelium.
There were no increases in lung neoplasms in rats or mice exposed to nickel sulfate. The A/B neoplasms that were observed in the exposed groups were similar in incidence and morphology to those observed in controls.
OTHER FINDINGS:
The lung burden at 7 or 15 months in rats and mice was 1-2 µg Ni/g lung.
Effect levels
open allclose all
- Dose descriptor:
- LOAEC
- Effect level:
- 0.25 mg/m³ air
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: chronic active lung inflammation
- Remarks on result:
- other: equivalent to 0.056 mg Ni/m3
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 0.125 mg/m³ air
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: overall effects
- Remarks on result:
- other: equivalent to 0.027 mg Ni/m3
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 0.25 mg/m³ air
- System:
- respiratory system: lower respiratory tract
- Organ:
- lungs
- Treatment related:
- yes
Applicant's summary and conclusion
- Conclusions:
- The NOAEL of the test substance as aerosol was found to be 0.125 mg/m3 air.
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