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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: Meets generally accepted scientific standards, well documented and acceptable for assessment
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

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:
Principles of method not described. Details of test methods described throughout the following sections.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Nickel dinitrate
- 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: 22.3% Nickel
- All other details on the test material was not reported 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:
Following administration of a single dose of 10 mg nickel (nickel nitrate in 5% starch saline solution) by gavage to male Wistar rats, the absorption was 34%

Following administration of a single dose of 10 mg nickel (nickel sulphate in 5% starch saline solution) by gavage to male Wistar rats, the absorbed fraction 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 NiS04, NiCl2, and Ni(N03)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 NiS04. The ratio in the kidneys for the Ni(N03)2 and Ni-M 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(G) group, showing similar results as the control
group. The ratio of Ni in the kidneys depended on the solubility of the administered Ni compound.
Transfer into organs
Test no.:
#1
Transfer type:
other: all organs
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 NiCl2 was measured in the urine at 914 ug.
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 nitrate in 5% starch saline solution) by gavage to male Wistar rats, the absorption was 34%.
Executive summary:

STUDY RATED BY AN INDEPENDENT REVIEWER.