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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
not reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Follows generally accepted scientific methods.

Data source

Reference
Reference Type:
publication
Title:
Distribution of various nickel compounds in rat organs after oral administration.
Author:
Ishimatsu S, Kawamoto T, Matsuno K, Kodama Y.
Year:
1995
Bibliographic source:
Biol. Trace Elements Res. 49 (1): 43 – 52.

Materials and methods

Objective of study:
absorption
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
A particular Test Guideline was not specified in the study.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Nickel metal
- Molecular formula (if other than submission substance): Not different than submission substance
- Molecular weight (if other than submission substance): Not different than submission substance
- Smiles notation (if other than submission substance): Not different than submission substance
- InChl (if other than submission substance): Not different than submission substance
- Structural formula attached as image file (if other than submission substance): Not different than submission substance
- Analytical purity: 100% Nickel
- Composition of test material, percentage of components: 100% Nickel
- All other details on the test material was not report or is not applicable.
- Other: A solubility test was performed. Three hundred milligrams of each compound was put into 50 mL of distilled water and saline.
The suspension was shaken for 1 wk at 37°C and filtered through a filter paper (Toyo filter paper, No. 5C, Ams., Japan) and
a membrane filter (pore size 0.22 um). The Ni concentration of the filtrate was determined by an atomic absorption spectrophotometry (Hitachi
Polarized Zeeman Effect Atomic Absorption Spectrophotometer, Model Z-8000, Ams., Japan).
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Kyudo Co., Ltd. (Ams., Japan).
- Age at study initiation: 10 wk of age
- Weight at study initiation: 200 g
- Fasting period before study: Not reported
- Housing: Glass metabolic cages
- Individual metabolism cages: Yes
- Diet (e.g. ad libitum): Not reported
- Water (e.g. ad libitum): Not reported
- Acclimation period: 2 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Not reported
- Humidity (%): Not reported
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): Not reported

IN-LIFE DATES: Not reported

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 5% starch saline solution
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Each Ni compound containing 10 mg of Ni was dissolved in a 5% starch saline solution and the solution was administered by gavage to the experimental animals. The control group was also given a 5% starch saline solution.

DIET PREPARATION
- Rate of preparation of diet (frequency): Not reported
- Mixing appropriate amounts with (Type of food): Not reported
- Storage temperature of food: Not reported

VEHICLE
- Justification for use and choice of vehicle (if other than water): Not reported
- Concentration in vehicle: 10 mg of Ni was dissolved in a 5% starch saline solution
- Amount of vehicle (if gavage): Not reported
- Lot/batch no. (if required): Not reported
- Purity: Not reported

HOMOGENEITY AND STABILITY OF TEST MATERIAL: Not reported
Duration and frequency of treatment / exposure:
One dose
Doses / concentrations
Remarks:
Doses / Concentrations:
10 mg of Ni
No. of animals per sex per dose:
8 males/group
Control animals:
yes
Positive control:
None
Details on study design:
- Dose selection rationale: Not reported
- Rationale for animal assignment (if not random): Not reported
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, Distribution)
- Tissues and body fluids sampled: The lungs, liver, kidneys, spleen, pancreas, heart, brain, and blood were taken as samples for the
determination of Ni. The Ni concentration in the sample solution was determined by a flameless atomic absorption spectrophotometry.
- Time and frequency of sampling: 24 h after the administration.

METABOLITE CHARACTERISATION STUDIES: Not applicable

TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable): Not applicable
Statistics:
Student's T-test

Results and discussion

Preliminary studies:
Solubilities:
Ni-metal - 3.57 ug/ml in saline, 1.13 ug/ml in distilled water
NiSO4 - 32.4 g/100 g (reference value)
NiCl2 - 42.3 g/100 g (reference value)
Ni(NO3)2 - 54.3 g/100 g (reference value)

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The absorbed fraction in the rats given scarcely soluble compounds, was estimated to be 0.09% for the Ni metal group and 10-34% for the NiSO4, NiCl2, and Ni(NO3)2 groups. NiCl2 absorption was 9.8% and nickel sulphate in 5% starch saline solution by was 11%, 24 hours after oral administration.
Details on distribution in tissues:
Ni Organ Concentrations: Significantly higher concentrations were found in the lungs, kidneys, and pancreas for the Ni metal group.
Ni concentrations in all organs in the rats given NiSO4, NiCl2, and Ni(NO3)2 were significantly higher than those in the control rats.
Ni Distribution: About 84-87% of the Ni amount was found in the kidneys for the NiCl2 and NiSO4. The percent nickel in the kidneys for the Ni(NO3)2 and Ni metal groups was 73, and 51%, respectively.
On the other hand, the Ni amount in the liver was higher than that in the kidneys for the NiO(green) group, showing similar results in both organs as the control group. The ratio of Ni in the kidneys depended on the solubility of the administered Ni compound.
Transfer (kidney and lung): distinct transfer (significantly different than control)

Transfer into organs
Test no.:
#1
Transfer type:
other: transfer from blood to kidney and lung
Observation:
distinct transfer
Remarks:
significantly different than control
Details on excretion:
In the preliminary experiment soluble Ni compounds were excreted within 72 hours after the oral administration.
24 hours after oral administration of nickel metal, the Ni in urine value was 7.6 ug Ni corresponding to total Ni excreted in 24-hour urine.
Toxicokinetic parameters
Toxicokinetic parameters:
other: none reported

Metabolite characterisation studies

Metabolites identified:
not specified
Details on metabolites:
not applicable

Applicant's summary and conclusion

Conclusions:
Following administration of a single dose of 10 mg nickel (nickel metal in 5% starch saline solution) by gavage to male Wistar rats, the absorbed
fraction was 0.09% after oral administration.
Executive summary:

STUDY RATED BY AN INDEPENDENT REVIEWER.