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Diss Factsheets

Toxicological information

Genetic toxicity: in vivo

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Administrative data

Endpoint:
in vivo mammalian germ cell study: cytogenicity / chromosome aberration
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Referenceopen allclose all

Reference Type:
other: ECHA disseminated Dossier
Title:
ECHA disseminated Dossier of Nickel sulfate (CAS 7786-81-4)
Year:
2007
Bibliographic source:
ECHA disseminated Dossier of Nickel sulfate (CAS 7786-81-4), query date 2020-11-25
Reference Type:
study report
Title:
Unnamed
Year:
2007

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
GLP compliance:
yes
Type of assay:
mammalian erythrocyte micronucleus test

Test material

Constituent 1
Chemical structure
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
Specific details on test material used for the study:
nickel sulfate hexahydrate

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, NC, USA.
- Age at study initiation: 8 weeks
- Weight at study initiation: 239-267 g
- Fasting period before study: not reported
- Housing: 2 per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 64 - 79 deg F
- Humidity: humidity 30-70%
- Air changes (per hr): 10 per hr
- Photoperiod (hrs dark / hrs light): 12 hr light/dark cycle.

IN-LIFE DATES: From: April 21, 2003 To: Aug. 2003

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
- Vehicle/solvent used: Cell culture control water
- Lot No: 017156 and 01100526
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: each day the test article was prepared freshly by adding to the vehicle. Formulations were held at room temperature.
Animals were dosed by oral gavage once daily for three consecutive days, six males per dose level. The dose levels were 125, 250, or 500 mg/kg bw/day.
Duration of treatment / exposure:
3 days
Frequency of treatment:
Once daily
Post exposure period:
24 hours after 3rd dose
Doses / concentrationsopen allclose all
Dose / conc.:
500 mg/kg bw/day (nominal)
Dose / conc.:
250 mg/kg bw/day (nominal)
Dose / conc.:
125 mg/kg bw/day (nominal)
No. of animals per sex per dose:
6 males
Control animals:
yes, concurrent vehicle
Positive control(s):
Cyclophosphamide was used as the positive control administered by oral gavage dissolved in deionized water at a dose of 60 mg/kg bw.

Examinations

Tissues and cell types examined:
Animals were euthanized approximately 24 hours after the third dose for extraction of bone marrow.
Blood was also collected prior to euthanization.
Nickel in bone marrow and blood was analyzed by AAS.
Details of tissue and slide preparation:
Following centrifugation to pellet the marrow, the supernatant was spread on slides, fixed with methanol and stained in acridine orange, dried, and analyzed under fluorescent microscopy.
Evaluation criteria:
Slides were scored for micronuclei and to determine the PCE to NCE cell ratio. The percent micronucleated cells was determined by analyzing micronuclei from at least 2000 PCEs per animal. The criteria were those of Schmid 1976.
Statistics:
Data analysis was conducted using ANOVA

Results and discussion

Test results
Key result
Sex:
male
Genotoxicity:
negative
Toxicity:
no effects
Remarks:
no cytotoxicity effects on bone marrow even at maximum tolerated dose established based on mortality and clinical observations
Vehicle controls validity:
valid
Negative controls validity:
not examined
Positive controls validity:
valid
Additional information on results:
RESULTS OF RANGE-FINDING STUDY
- Dose range: 125-1750 mg/kg bw/day
- No cytotoxicity observed at 750 or 1000 mg/kg bw/day. Mean PCE:NCE ratios were 0.32 and 0.64 compared to 0.81 (control)
The maximum tolerated dose was estimated at 500 mg/kg bw/day

RESULTS OF DEFINITIVE STUDY
Clinical signs of toxicity were noted in all treatment animals including hypoactivity, salivation, black feces, irregular respiration, squinted/closed eyes.
No mortality occurred.
Nickel did not significantly increase micronucleated PCEs at any dose level. Nickel was not significantly cytotoxic to bone marrow at any dose level.
Dose-dependent nickel concentrations were detected in plasma and bone marrow samples.
The author's suggest the results support the non-genotoxic mode of action for soluble nickel.

Applicant's summary and conclusion

Conclusions:
The test substance nickel sulfate hexahydrate was evaluated as negative in the rat bone marrow micronucleaus assay under the conditions of this assay.