Trinickel disulphide

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study (OECD 413)

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 1

Reference Type:

publication

Title:

Lung Toxicity after 13-Week Inhalation Exposure to Nickel Oxide, Nickel Subsulfide, or Nickel Sulfate Hexahydrate in F344/N Rats and B6C3F1 Mice

Author:

Dunnick JK, Elwell MR, Benson JM, Hobbs CH, Hahn FF, Haly PJ, Cheng YS, Eidson AF

Year:

1989

Bibliographic source:

FUNDAMENTAL AND APPLIED TOXICOLOGY. 12: 584-594

Reference 2

Reference Type:

publication

Title:

SUBCHRONIC INHALATION TOXICITY OF NICKEL SUBSULFIDE TO RATS AND MICE

Author:

Benson JM, Burt DG, Cheng YS, Eidson AF, Gulati DK, Hahn FF, Hobbs CH, Pickrell JA

Year:

1990

Bibliographic source:

Inhalation Toxicology. 2:1-19

Reference 3

Reference Type:

study report

Title:

Unnamed

Year:

1996

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Deviations:

not applicable

Principles of method if other than guideline:

not applicable

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
- Substance type: low temperature form
- Analytical purity: > 97%

Test animals

Species:

rat

Strain:

other: F344/N

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Frederick Cancer Research Facility, Frederick, MD
- Age at study initiation: 7-8 wk
- Housing: individual cages in multitiered inhalation chambers throughout the course of the studies
- Diet (e.g. ad libitum): ad libitum during non-exposure periods
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +/- 2 C
- Humidity (%): 17-45%
- Photoperiod (hrs dark / hrs light): 12 hr dark, 12 hr light

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

not specified

Vehicle:

other: no data

Remarks on MMAD:

MMAD / GSD: MMAD = 2.4 um
GSD = 2.2

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Multitiered inhalation chambers, H-2000, Hazleton Systems, Aberdeen, MD
- System of generating particulates/aerosols: Nebulizer. The aerosol was passed through a K-85 discharger to neutralize electrical charge and mixed with diluting air to achieve the desired concentration in the chambers.
- Air change rate: flow through the chamber was 12 ± 2 air changes/h.
- Method of particle size determination: Aerosol size distribution was determined using cascade impactors.


TEST ATMOSPHERE
- Brief description of analytical method used: monitored by taking three 2-h filter samples during the 6-h exposure day and found to be
within ± 10% of target levels.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The aerosol concentration in the exposure chambers was monitored by taking three 2-hr filter samples during the 6-hr exposure day that were found to be within ± 10% of target levels. The mean daily concentration in the exposure chambers was calculated from the filter samples.

Duration of treatment / exposure:

6 hr/day

Frequency of treatment:

5 d/wk, 13wk

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0.11 mg Ni/m3
Basis:
nominal conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0.2 mg Ni/m3
Basis:
nominal conc.

Doses / concentrations 3

Remarks:

Doses / Concentrations:
0.4 mg Ni/m3
Basis:
nominal conc.

Doses / concentrations 4

Remarks:

Doses / Concentrations:
0.9 mg Ni/m3
Basis:
nominal conc.

Doses / concentrations 5

Remarks:

Doses / Concentrations:
1.8 mg Ni/m3
Basis:
nominal conc.

No. of animals per sex per dose:

10 males, 10 females

Control animals:

other: yes: filtered air

Details on study design:

- Dose selection rationale: based on previous 12-day study

Positive control:

Not applicable

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data


DETAILED CLINICAL OBSERVATIONS: No data
- Time schedule:


BODY WEIGHT: Yes
- Time schedule for examinations: Final


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: 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, organ weights
HISTOPATHOLOGY: Yes. Complete histopathology was performed on high-exposure and control groups and to a no-effect level in target tissues.

Other examinations:

lung Ni concentration

Statistics:

The significance of differences between dosed and control group means was assessed using multiple comparison procedures with two-tailed tests.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not examined

Details on results:

BODY WEIGHT AND WEIGHT GAIN:
bodyweight was significantly reduced (4-7%) in three of the four highest dose groups (but not in second highest group) in males only
ORGAN WEIGHTS
lung weight increased in all animals at all doses

HISTOPATHOLOGY: NON-NEOPLASTIC
Inflammatory changes were seen in the lung, nasal cavity, and bronchial lymph node after exposure to Ni compounds.
The lung lesions included alveolar macrophage hyperplasia, inflammation, and fibrosis. Alveolar macrophage hyperplasia consisted of an increase in the number of macrophages within alveolar spaces.
The change in the bronchial lymph nodes consisted of minimal to mild lymphoid hyperplasia.

Effect levels

1

Dose descriptor:

LOEC

Effect level:

0.2 other: mg Ni/m3

Sex:

male

Basis for effect level:

other: significant decrease in bodyweight at this and higher concentrations (except at 0.9 mg Ni/m3)

2

Dose descriptor:

LOEC

Effect level:

0.1 other: mg Ni/m3

Sex:

male/female

Basis for effect level:

other: significant increase in lung weight at 13 weeks

3

Dose descriptor:

LOEC

Effect level:

0.1 other: mg Ni/m3

Sex:

male/female

Basis for effect level:

other: 10/10 animals with alveolar macrophage hyperplasia

4

Dose descriptor:

LOEC

Effect level:

0.1 other: mg Ni/m3

Sex:

male/female

Basis for effect level:

other: 2-3 animals per sex with chronic active inflammation in lung (out of 8-10 animals per sex)

5

Dose descriptor:

NOEC

Effect level:

0.1 other: mg Ni/m3

Sex:

male

Basis for effect level:

other: 0 animals with olfactory epithelial atrophy (8-10 animals)

6

Dose descriptor:

NOEC

Effect level:

0.2 other: mg Ni/m3

Sex:

female

Basis for effect level:

other: 0 animals with olfactory epithelial atrophy (8-10 animals)

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Not applicable.

Applicant's summary and conclusion

Conclusions:

Toxicity to the lung correlated with solubility of the nickel compound rather than amount of nickel in the lung. Nickel sulfate and nickel subsulfide were more toxic to the lung of rats and mice than was nickel oxide. Rats were more sensitive than mice to the effects of inhaled nickel.

The 3 nickel compounds had similar effects in the respiratory tract in that all produced atrophy of the olfactory epithelium and a chronic inflammation in the lung.

Executive summary:

As part of a study on the toxicity of NiSO4, Ni3S2 and NiO, Dunnick et al. (1989) examined the toxicity of inhaled Ni3S2 in F344/N rats exposed 6 hr/d, 5 d/wk, for 13 weeks (0.15, 0.3, 0.6, 1.2, and 2.5 mg Ni3S2 /m3; 0.11, 0.2, 0.4, 0.9, and 1.8 mg Ni/m3). This dose range was based on results from an earlier 12-day study where 5 mg Ni3S2 /m3 caused lung lesions. Chamber concentrations and aerosol size were determined analytically (MMAD: 2.4 μm; GSD 2.2). Following exposure, mortality, clinical signs of toxicity, body and organ weights, tissue histopathology, reproductive markers, and Ni lung burden were evaluated (see Basic Toxicokinetics section for lung burden data).

No exposure-related mortality was observed; bodyweight was significantly reduced (4-7%) in three of the four highest dose groups (but not in second highest group) in males only. Lung weights were significantly increased in all exposure groups, and roughly 2-fold in both sexes starting at 0.4 mg Ni/m3. No exposure-related changes in thymus, liver, kidney, brain or testis weights were observed. Inflammation was observed in the nasal cavity, bronchial lymph nodes and the lung. Alveolar macrophage hyperplasia was elevated in all animals at all doses, and there was a dose-dependent increase in the incidence of chronic active inflammation and olfactory epithelial atrophy. No reproductive effects were observed (e.g. sperm morphology, estrous cycle). The authors concluded that toxicity to the lung correlated with solubility of the nickel compound rather than amount of nickel in the lung (lung burden is described in Basic Toxicokinetics sections). Nickel sulfate and Ni3S2 were more toxic to the lung of rats and mice than was NiO. Rats were more sensitive than mice to the effects of inhaled nickel. This investigation was part of a comprehensive bioassay conducted by the National Toxicology Program (1996). STUDY RATED BY AN INDEPENDENT REVIEWER