Nickel oxalate

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:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

no data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP study performed according to OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test). Reliability score of 2 due to use of the study for read across.

Data source

Reference

Reference Type:

publication

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:

micronucleus assay

Test material

Test material information

Constituent 1

Reference substance name:

Nickel sulfate hexahydrate

IUPAC Name:

Nickel sulfate hexahydrate

Constituent 2

Reference substance name:

10101-97-0

EC Number:

600-152-3

Cas Number:

10101-97-0

IUPAC Name:

10101-97-0

Details on test material:

- Name of test material (as cited in study report): nickel sulfate hexahydrate
- Molecular formula (if other than submission substance): NiO4S.6H2O
- Molecular weight (if other than submission substance): 333.083
- Smiles notation (if other than submission substance): S(=O)(=O)([O-])[O-].[Ni+2]
- InChl (if other than submission substance): InChI=1/Ni.H2O4S/c;1-5(2,3)4/h;(H2,1,2,3,4)/q+2;/p-2
- Physical state: blue-grean appearance
- Impurities: Co 8 ppm, Na 3 ppm, Fe 2 ppm, Mg 0.7 ppm, Ag 0.2 ppm
- Purity: 99.99+%
- Lot No.: 02221PQ
- Source: Sigma Aldrich

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
- Assigned to test groups randomly: no data
- Fasting period before study: no data
- Housing: 2 per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days

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

IN-LIFE DATES: From: 2003-04-21 To: 2003-08-01

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

- Vehicle(s)/solvent(s) used: Cell culture control water
- Lot No: 017156 and 01100526

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
- Each day the test substance was prepared by adding to the vehicle. Formulations held at room temperature. Animals were dosed by oral gavage once daily for three consecutive days to six males per dose level. The dose levels were 125, 250, or 500 mg/kg/day.

DIET PREPARATION
- not applicable

Duration of treatment / exposure:

3 days

Frequency of treatment:

Once daily

Post exposure period:

24 hours after 3rd dose

Doses / concentrations

Remarks:

Doses / Concentrations:
125, 250, 500 mg/kg-d
Basis:
nominal conc.

No. of animals per sex per dose:

6 per dose

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

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 atomic absorption spectroscopy (AAS).

Details of tissue and slide preparation:

The marrow was centrifuged and the supernatant removed. The pellet was then 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 determine 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

Sex:

male

Genotoxicity:

negative

Toxicity:

no effects

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-day
- No cytotoxicity observed at 750 or 1000 mg/kg-day.
- Mean PCE:NCE ratios were 0.32 and 0.64 compared to 0.81 (control)
- Other: the maximum tolerated dose was estimated at 500 mg/kg-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:

Interpretation of results (migrated information): negative
The test substance, nickel sulfate hexahydrate, was evaluated as negative in the rat bone marrow micronucleus assay under the conditions of this assay.