Registration Dossier

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards, well documented and acceptable for publication.
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:
ISHlMATSU S, KAWAMOTO T, MATSUNO K, KODAMA Y
Year:
1995
Bibliographic source:
Biological Trace Element Research. 49: 43-52.

Materials and methods

Objective of study:
distribution
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
10 mg NiO in 5% saline was administered to rats by gavage. The rats were sacrificed 24 hr after exposure.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): NiO
- Substance type: green and black
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
- Weight at study initiation: 200 g
- Acclimation period: 2 days

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 5% saline
Details on exposure:


VEHICLE
- Justification for use and choice of vehicle (if other than water): increased solubility


Duration and frequency of treatment / exposure:
single exposure
Doses / concentrations
Remarks:
Doses / Concentrations:
10 mg Ni in NiO
No. of animals per sex per dose:
8 males
Control animals:
yes, concurrent vehicle
Positive control:
Not applicable.
Details on study design:
Not applicable.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): urine, blood, lung, liver, kidney, spleen, pacreas, heart, brain
- Time and frequency of sampling: 24 hr


METABOLITE CHARACTERISATION STUDIES
After weighing each organ, it was treated with a mixture of nitric acid and sulfuric acid until completely digested, and the solution was brought to a certain volume with 0.1N nitric acid. Blood samples were used for analysis after being diluted 10 times with 0.1N nitric acid. In addition, 24-h urine was collected by metabolic cage, and each 5 mL of urine was completely digested with nitric acid and brought to a certain volume with 0.1N nitric acid in the same way as the organs. The Ni concentration in the sample solution was determined by a flameless atomic absorption spectrophotometry; the detection limit was 1 ppb.

Statistics:
Not reported.

Results and discussion

Preliminary studies:
Preliminary data indicated that the soluble Ni compounds were excreted for the most part within 72 h after the oral administration
and the retained amount of Ni in the organ was small. Therefore, the animals were sacrificed 24 h after the administration.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
In all, 0.01% of green NiO and 0.04% of black NiO was absorbed (based on Ni levels in organs, blood, and urine) at 24 hr.
Details on distribution in tissues:
Following exposure to green NiO, the concentration of Ni in organs and blood was not significantly different from control animals. Exposure to black NiO resulted in a significant increase in Ni levels in the lung and kidney.
Details on excretion:
Not reported.

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
only Ni content was measured.

Any other information on results incl. tables

                Amount of Nickel 24 hr After Oral Exposure

 

          Amount of Ni (ug)

 
   Organs  Blood Urine   Total  AbsorbedFraction, %
 Green NiO  0.4 (0.1) 0.4 (0.1)  0.2 (0.1)  0.9 (0.2)  0.01
 Black NiO  1.1 (0.7) 0.3 (0.1)   2.6 (1.7) 4.1 (2.0)  0.04 

Date are Mean +/- (SD)

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results (oral route of exposure)
The authors concluded that these results suggest that the kinetic behavior of Ni compounds administered orally is closely related with the solubility of Ni compounds, and that the solubility of Ni compounds is one of the important factors for determining the health effect of Ni compounds.
Executive summary:

Ishimatsu et al. (1995) examined the solubility and oral distribution of eight Ni compounds (including green and black NiO) in rats following oral exposure. Solubility of 300 mg of each compound was measured in 50 mL of distilled water or saline. Of the 8 compounds examined, green NiO was the least soluble (~ 1 μg/mL), followed by Ni metal and then black NiO (~ 3.9 - 4.5 μg/mL). For oral exposure, each nickel compound was administered by gavage (10 mg in 5% saline); rats were sacrificed 24 hr after exposure. Following exposure to green NiO, the concentration of Ni in these organs as well as blood was not significantly different from control animals. Exposure to black NiO resulted in a significant increase in Ni levels in the lung and kidney. In all, 0.01 and 0.04% of green and black NiO, respectively, were measurable (absorbed) based on Ni levels in organs, blood, and 24 hr urine. The authors concluded that these results suggest that the kinetic behavior of Ni compounds administered orally is closely related with the solubility of Ni compounds, and that the solubility of Ni compounds is one of the important factors for determining the health effect of Ni compounds (however health effects were not evaluated in this study). Though only one dose was utilized, the findings of this study are useful in demonstrating the potential kinetic differences between green and black NiO. STUDY RATED BY AN INDEPENDENT REVIEWER