Trinickel disulphide

Repeated dose toxicity: other routes

Administrative data

Endpoint:

short-term repeated dose toxicity: other route

Type of information:

experimental study

Adequacy of study:

supporting 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:

other: book chapter

Title:

Mechanistic Evaluations Of The Pulmonary Toxicology Of Nickel Subsulfide

Author:

Fisher GL, Chrisp CE, McNeill KL, McNeill DA, Democko C, Finch GL

Year:

1984

Bibliographic source:

MacFarland, HN et al. (Ed.). Advances In Modern Environmental Toxicology, Vol. 6. Applied Toxicology Of Petroleum Hydrocarbons; Symposium, Washington, D.C., USA May 11-13, 1982. Princeton Scientific Publishers: Princeton, N.J., USA.

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

A/J mice were exposed to Ni3S2 particles of different sizes via intratracheal instillation either once or once per week for 4 weeks. Lethality was compared between exposure duration and particle size.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Trinickel disulphide

EC Number:

234-829-6

EC Name:

Trinickel disulphide

Cas Number:

12035-72-2

Molecular formula:

Ni3S2

IUPAC Name:

(trinickel-1-ylidene)-1λ⁴-disulfene

Details on test material:

- Name of test material (as cited in study report): Ni3S2
- Other:
Fine: MMD = 1.8 um, GSD = 1.55
Coarse: MMD = 13.3 um, GSD = 2.17

Test animals

Species:

mouse

Strain:

other: Strain A/J

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 8-10 weeks

Administration / exposure

Route of administration:

other: intratracheal

Vehicle:

other: PBS

Details on exposure:

Mice were anesthetized with 60 mg/kg sodium pentobarbitol and placed on specially made holders. A fiber optic system was used to illuminate the oropharynx and a dissecting microscope gave sufficient magnification to allow insertion of a sterile one inch by 23 gauge cannula into the trachea. The tip of the cannula was inserted just anterior to the first bifurcation and the dose material slowly delivered. A 20 uL sample was well tolerated and was large enough to minimize sample to sample variation. Survivals of vehicle control and experimental animals were excellent.

Suspensions of nickel subsulfide were prepared by addition of sterile phosphate-buffered saline (PBS) to the test material in a carcinogen glove box. These suspensions were then sealed and sonicated for 10 min to deagglomerate and assure a uniform distribution of particles in the suspension. Prior gravimetric studies with hematite indicated that accurate and repeatable dosing required vortex mixing of the suspension vial immediately before each dose sample was withdrawn.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

acute

Frequency of treatment:

once per week for 1 or 4 weeks

Doses / concentrations

Remarks:

Doses / Concentrations:
4-100 mg Ni3S2/kg for single exposure
0.5-64 mg Ni3S2/kg for once per week for 4 weeks

No. of animals per sex per dose:

10-20 males

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: not stated

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION:
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, on animals that dies shortly after exposure
HISTOPATHOLOGY: No

Other examinations:

Not applicable.

Statistics:

Not applicable.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not examined

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
The lethality of fine particles was much greater than course particles in animals receiving a single dose; the LD50 values were 4 and 50 mg/kg, respectively. In contrast, the LD50 values were nearly identical for animals exposed to fine and course particles for 4 weeks; 1 and 2 mg/kg, respectively. Toxicity was first clinically manifested as rough hair coats, weight loss, and anorexia.

BODY WEIGHT AND WEIGHT GAIN
Toxicity was first clinically manifested as rough hair coats, weight loss, and anorexia.

GROSS PATHOLOGY
Gross examination of the nickel subsulfide treated mice that died shortly after exposure showed that the lungs were dark red and did not deflate upon opening of the thoracic cavity – indicating that lethality was associated with pulmonary hemorrhage and possible congestion and edema. No other grossly visible signs of toxicity were noted.

Effect levels

1

Dose descriptor:

other: LD50

Effect level:

1 mg/kg bw/day (actual dose received)

Sex:

male

Basis for effect level:

other: Lethality from Fine Ni3S2

2

Dose descriptor:

other: LD50

Effect level:

2 mg/kg bw/day (actual dose received)

Sex:

male

Basis for effect level:

other: Lethality from Coarse Ni3S2

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

LD50 After Intratracheal Exposure to Ni3S2

		LD50 (mg/kg)
Strain	Size: MMD, GSD	Single	Multiple*
A/J	Fine, 1.8 um, 1.55	4	1
A/J	Coarse, 13.3 um, 2.17	50	2
B6C3F1**	Fine, 1.8 um, 1.55	4	1

*, exposed once per week for 4 weeks

**, B6C3F1 data are considered K3 because less data was provided, but are shown for comparison

Applicant's summary and conclusion

Conclusions:

The authors concluded that repeated exposure to course Ni3S2 resulted in cumulative lethality; these findings demonstrate the importance of physical form in the evaluation of pulmonary toxicity.

Executive summary:

Fisher et al. (1984) examined the lethality and toxicity of Ni3S2 particles of different size on A/J mice lungs following intratracheal instillation. The MMAD and GSD for the fine particles were 1.8 μm and 1.55, whereas the MMAD and GSD for coarse particles were 13.3 μm and 2.17. Groups of animals were exposed to 0-100 mg/kg for a single dose, or 0-64 mg/kg once per week for 4 consecutive weeks. The lethality of fine particles was much greater than that of course particles in animals receiving a single dose; the LD50 values were 4 and 50 mg/kg, respectively. In contrast, the LD50 values were nearly identical for animals exposed to fine and course particles for 4 weeks; 1 and 2 mg/kg, respectively. Toxicity was first clinically manifested as rough hair coats, weight loss, and anorexia. Mortality as a result of exposure occurred from one to four days following exposure; animals that survived this period generally recovered. Gross examination of the nickel subsulfide treated mice that died shortly after exposure showed that the lungs were dark red and did not deflate upon opening of the thoracic cavity – indicating that lethality was associated with pulmonary hemorrhage and possible congestion and edema. No other grossly visible signs of toxicity were noted. This study also contained a more limited analysis in B6C3F1 mice. These animals were only exposed to fine Ni3S2 for 1 or 4 weeks. The LD50 values for the fine particles were identical to those in A/J mice (i.e. 4 and 1 mg/kg for single and multiple exposures). The authors concluded that repeated exposure to course Ni3S2 resulted in cumulative lethality; these findings demonstrate the importance of physical form in the evaluation of pulmonary toxicity. STUDY RATED BY AN INDEPENDENT REVIEWER