dilithium trimanganese nickel octoxide

Acute Toxicity: other routes

Administrative data

Endpoint:

acute toxicity: other routes

Type of information:

experimental study

Adequacy of study:

weight of evidence

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:

Superoxide radical and toxicity of environmental nickel exposure

Author:

Novelli ELB,Rodrigues NL, Ribas BO

Year:

1995

Bibliographic source:

Human & Experimental Toxicology. 14: 248-251

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Principles of method if other than guideline:

7 mg Ni/kg, in the form of NiO (nickelous oxide, unspecified color), was administered to rats in a single i.m. injection. After 72 hours, serum activity levels of lipoperoxide, amylase, aspartate transaminase, alkaline phosphatase, glutathione peroxidase, and superoxide dismutase (SOD) were measured. Similar studies were repeated where animals were also treated with purified SOD and NiO.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Nickel monoxide

EC Number:

215-215-7

EC Name:

Nickel monoxide

Cas Number:

1313-99-1

Molecular formula:

NiO

IUPAC Name:

Nickel (II) oxide

Details on test material:

- Name of test material (as cited in study report): NiO (nickelous oxide)
- Physical state: unspecified color

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 15 mo
- Weight at study initiation: 180-200 g
- Individual metabolism cages: no
- Diet (e.g. ad libitum): Food (Purina Ltd., 3074 SIF) ad libitum
- Water (e.g. ad libitum): ad libitum

Administration / exposure

Route of administration:

intramuscular

Vehicle:

physiological saline

Details on exposure:

Injections were made into the muscle (i.m.) of the right thigh, approximately parallel with the femur in 0.2 mL of 0.9%NaCl. Another group of animals were administered purified SOD conjugated to polyethylene glycol (SOD-PEG) via i.p. once daily following i.m. injection with NiO or hydroxylamine.

Doses:

7 mg Ni/kg

No. of animals per sex per dose:

Males (numbers not reported).

Control animals:

yes

Details on study design:

- Duration of observation period following administration: single injection, 72 hr post-injection
- Frequency of observations and weighing: once
- Necropsy of survivors performed: no
- Other examinations performed: serum biomarkers (see Table)

Statistics:

Values are presented as means ± s.d. Significance of difference was tested by Student's t-test (P < 0.05).

Results and discussion

Effect levels

Sex:

male

Dose descriptor:

other: dose

Effect level:

7 other: mg Ni/kg

Remarks on result:

other: After 72 hours, NiO treated rats exhibited significant increases in serum lipoperoxide (5.6-fold), amylase, aspartate transaminase, and alkaline phosphatase, as well as a significant decrease in superoxide dismutase (SOD).

Mortality:

Not reported.

Clinical signs:

Not reported.

Body weight:

Not reported.

Gross pathology:

Not reported.

Other findings:

- Other observations: see Table

Any other information on results incl. tables

Effects of NiO on Serum Markers

	Control	NiO	Hydroxylamine
Total protein (g/dL)	5.9 (0.8)	6.7 (0.8)	5.9 (1.2)
Lipoperoxide (ueq/L)	1.8 (0.7)	9.5 (1.2)*	9.8 (0.8)*
Amylase (U/dL)	60.8 (10.7)	98.3 (7.0)*	93.6 (3.1)*
AST (U/mL)	28.9 (9.2)	57.2 (8.3)*	50.7 (0.8)*
ALT (U/mL)	9.5 (0.6)	9.0 (0.6)	9.0 (1.6)
ALP (mU/mL)	63.5 (8.6)	90.1 (10.8)*	109.8 (8.5)*
SOD (U/mL)	0.56 (0.3)	0.30 (0.08)*	0.33 (0.1)*
GSH-PX (U/mg protein)	0.9 (0.1)	0.8 (0.1)	0.8 (0.3)

*, Values are significantly different from those of the control group by Student's t-test (P < 0.05)

AST, aspartate transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase; SOD, superoxide dismutase; GSH-PX, glutathione peroxidase; U, unit of activity

Additional Results:

1, similar findings were reported for NiS as for NiO

2, NiCl2 only increased AST

3, Administration of purified SOD had no significant effect on the parameters in the table in control animals; yet negated all of the significant effects from exposure to NiO, NiS, and hydroxylamine.

Applicant's summary and conclusion

Conclusions:

The authors concluded that the toxicity of nickel compounds involves oxidative reactions such as nickel induced lipid peroxidation, and that the superoxide radical is an important toxic intermediate in the development of insoluble nickel compound damage, since SOD-PEG has a potential therapeutic effect.

Executive summary:

Novelli et al. (1995) examined the ability of several Ni compounds, including NiO, to induce pancreatic, hepatic, and osteogenic lesions. Male Wistar rats were administered a single i.m. injection of NiO (nickelous oxide, unspecified color) at a dose of 7 mg Ni/kg and sacrificed 72 hours later. After 72 hours, NiO treated rats exhibited significant increases in serum lipoperoxide (5.6-fold), amylase, aspartate transaminase, and alkaline phosphatase, as well as a significant decrease in superoxide dismutase (SOD). For comparison, animals were also injected with hydroxylamine as a means of inducing “superoxide flux.” Hydroxylamine increased alkaline phosphatase, amylase, and aspartate transaminase, decreased SOD, and caused no change in glutathione peroxidase. The similar responses between hydroxylamine and NiO were posited to reflect a similar mechanism of action. In this regard, another group of animals were administered purified SOD conjugated to polyethylene glycol (SOD-PEG) via i.p. once daily following i.m. injection with NiO or hydroxylamine. Because SOD catalyses the destruction of superoxide radical and was shown to prevent significant change in the aforementioned parameters, the data suggest the involvement of oxidative mechanisms in the toxicity of NiO. A similar set of studies gave similar results for NiS. In contrast to NiO and NiS, soluble NiCl2 did not induce many changes in these parameters. The authors concluded that the toxicity of nickel compounds involves oxidative reactions such as nickel induced lipid peroxidation, and that the superoxide radical is an important toxic intermediate in the development of insoluble nickel compound-induced damage, since SOD-PEG has a potential therapeutic effect. STUDY RATED BY AN INDEPENDENT REVIEWER