Nickel sulphide

Basic toxicokinetics

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-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

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:

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 NiS in 5% saline was administered to rats by gavage and sacrificed 24 hr after exposure.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Nickel sulphide

EC Number:

240-841-2

EC Name:

Nickel sulphide

Cas Number:

16812-54-7

Molecular formula:

NiS

IUPAC Name:

nickel(2+) sulfanediide

Details on test material:

- Name of test material (as cited in study report): NiS

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system 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 as NiS

No. of animals per sex per dose / concentration:

8 males

Control animals:

yes, concurrent vehicle

Positive control reference chemical:

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:

Student's t-test.

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, 2.12% of adminstered dose was absorbed (based on Ni levels in organs, blood, and urine) at 24 hr.

Details on distribution in tissues:

Exposure to NiS resulted in a significant increase in Ni levels in the kidney, lung, liver, heart, pancreas, and brain.

Transfer into organs

Transfer into organs 1

Test no.:

#1

Transfer type:

other: oral to lung

Observation:

distinct transfer

Remarks:

0.34 +/- 0.27 ug Ni/g (treated) vs. 0.04 +/- 0.01 (control), p < 0.05

Transfer into organs 2

Test no.:

#2

Transfer type:

other: oral to liver

Observation:

distinct transfer

Remarks:

0.11 +/- 0.07 ug Ni/g (treated) vs. 0.03 +/- 0.01 (control), p < 0.05

Transfer into organs 3

Test no.:

#3

Transfer type:

other: oral to kidney

Observation:

distinct transfer

Remarks:

6.4 +/- 2.7 ug Ni/g (treated) vs. 0.03 +/- 0.01 (control), p < 0.01

Transfer into organs 4

Test no.:

#4

Transfer type:

other: oral to spleen

Observation:

not determined

Remarks:

0.14 (treated) vs. 0.03 +/- 0.01 (control); no standard deviation reported for treated group

Transfer into organs 5

Test no.:

#5

Transfer type:

other: oral to pancreas

Observation:

distinct transfer

Remarks:

0.25 +/- 0.22 ug Ni/g (treated) vs. 0.03 +/- 0.01 (control), p < 0.05

Transfer into organs 6

Test no.:

#6

Transfer type:

other: oral to heart

Observation:

distinct transfer

Remarks:

0.60 +/- 0.31 ug Ni/g (treated) vs. 0.03 +/- 0.01 (control), p < 0.01

Transfer into organs 7

Test no.:

#7

Transfer type:

other: oral to brain

Observation:

distinct transfer

Remarks:

0.04 +/- 0.02 ug Ni/g (treated) vs. 0.02 +/- 0.01 (control), p < 0.05

Details on excretion:

A small fraction of ingested dose was absorbed and excreted via urine after 24 hours (1.97% of ingested dose)

Toxicokinetic parameters

Test no.:

#1

Toxicokinetic parameters:

other: absorbed fraction (2.12% of total dose after 24 hrs)

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
	ug of Ni
	Organs	Blood	Urine	Total	AbsorbedFraction, %
NiS	11.9 (4.8)	2.7 (2.2)	197 (65)	212 (70)	2.12

Date are Mean +/- (SD)

Nickel Concentrations in Organs Significantly Elevated at 24 Hours After Exposure

	Lung	Liver	Kidney	Pancreas	Heart	Brain	Blood
NiS	0.34 (0.27)	0.11 (0.07)	6.4 (2.7)	0.25 (0.22)	0.60 (0.31)	0.04 (0.02)	0.21 (0.11)
Control	0.04 (0.01)	0.03 (0.01)	0.03 (0.01)	0.03 (0.01)	0.03 (0.01)	0.02 (0.01)	0.03 (0.01)

P values ranged from < 0.001 to < 0.05 by Student's t-test; organs are ug/g tissue; blood is ug/mL

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
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 in vitro solubility and in vivo distribution of eight nickel compounds (including NiS) in male Wistar rats following a single oral exposure. The solubility of 300 mg of each compound was measured in 50 mL of distilled water or saline. Of the 8 compounds examined, NiS exhibited relatively high solubility – 1850 to 2176 μg/mL (in distilled water or saline, respectively) versus 1 to 4 μg/mL for NiO. Rats were administered a nickel compound by gavage (10 mg in 5% saline) and sacrificed 24 hr after exposure. No significant changes in body weight or organ weights (lung, liver, kidney, spleen, pancreas, heart, and brain) following NiS exposure were observed. Nickel concentrations were measured in lung, liver, kidney, spleen, pancreas, heart, blood, and brain were measured via atomic absorption spectrophotometry. Relative to levels of nickel in control tissues, nickel levels were significantly elevated in the lung (0.34 vs.0.04 μg/g), liver (0.11 vs. 0.03 μg/g), kidney (6.4 vs. 0.03 μg/g), pancreas (0.25 vs. 0.03 μg/g), heart (0.6 vs. 0.03 μg/g), brain (0.04 vs. 0.02 μg/g) and blood (0.21 vs. 0.03 μg/mL) of NiS-treated animals. In all, only 2.1% of the administered NiS was measurable (i.e. recovered) in organs, blood or urine 24 hr after exposure. The authors concluded that these results suggested that the kinetic behavior of Ni compounds administered orally was closely related with the solubility of Ni compounds, and that the solubility of nickel compounds is one of the important factors for determining the health effect of nickel compounds (however heath effects were not evaluated in this study). STUDY RATED BY AN INDEPENDENT REVIEWER