Trinickel dicitrate

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: comparable to guideline study with acceptable restrictions (limited documentation)

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:

Dunnik, J. K. et al.

Year:

1989

Bibliographic source:

Fundamental and Applied Toxicology 12, 584-594

Reference 2

Reference Type:

secondary source

Title:

Nickel Sulphate, CAS-No.: 7786-81-4, EINECS-No.: 232-104-9, RISK ASSESSMENT Final version March 2008, Chapters 0, 1, 2, 4, 5, 6 & 7 – human health only

Author:

Danish Environmental Protection Agency

Year:

2008

Bibliographic source:

European Union Risk Assessment Report

Materials and methods

Principles of method if other than guideline:

Test animals were exposed for 13 weeks to various concentrations of nickel sulfate hexahydrate. Examinations were performed on various organs and tissues but mainly focused on the respiratory tract.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

10101-97-0

EC Number:

600-152-3

Cas Number:

10101-97-0

IUPAC Name:

10101-97-0

Constituent 2

Reference substance name:

nickel sulfate hexahydrate

IUPAC Name:

nickel sulfate hexahydrate

Details on test material:

- Name of test material (as cited in study report): nickel sulfate hexahydrate from Aldrich Chemical Company, Milwaukee
- Molecular formula (if other than submission substance): NiSO4x6H2O
- Molecular weight (if other than submission substance): 262.86
- Analytical purity: > 99%

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: NTP breeding colonies at Frederick Cancer Research Facility, Frederick, Maryland and Simonsen Laboratories, Gilroy, California, USA
- Age at study initiation: 7-8 weeks
- Housing: individually in multitiered inhalation chambers
- Diet (e.g. ad libitum): NIH-07 diet (Zeigler Brothers, Inc., Gardeners, PA); only available druring nonexposure hours


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2
- Humidity (%): 17 - 45
- Air changes (per hr): 12 ± 2
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

not specified

Vehicle:

other: air

Remarks on MMAD:

MMAD / GSD: MMAD = 2.3 µm / GSD = 2.4 µm

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Multitiered inhalation chambers: H-1000 (1.0 m3) and H-2000 (1.7 m3) (Hazleton Systems, Aberdeen, MD)
- System of generating particulates/aerosols: Nebuliser. The resulting aerosol was passed through a K-85 discharger to neutralise electrical charge and mixed with diluting air to achieve the desired concentrations in the chambers.
- Air change rate: 12 ± 2 h
- Method of particle size determination: cascade impactors


TEST ATMOSPHERE
- Brief description of analytical method used: The concentration in the exposure chambers was monitored by taking three 2 h filter samples during the 6 h exposure day. The mean daily concentration was calculated from the filter samples.
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

6 h/day

Frequency of treatment:

5 days/week for 13 weeks

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0.11, 0.24, 0.49, 0.95 and 1.90 mg nickel citrate/m3
Basis:
other: nickel citrate concentration calculated from the concentration of nickel sulfate hexahydrate

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0.12, 0.25, 0.52, 1.0 and 2.01 mg nickel sulfate hexahydrate/m3
Basis:
analytical conc.

No. of animals per sex per dose:

10 + 5 (additional animals)

Control animals:

yes, sham-exposed

Details on study design:

- Dose selection rationale: The exposure levels were selected based on a 12-day study. The top exposure level was set 2.0 mg/m3 because of body weight effects and lung lesions that developed in the 12-day exposures at levels of 3.5 mg/m3.

In addition, 5 male rats for each exposure level were sacrificed after 4, 9 and 13 weeks of exposure as well as 5 female rats for each exposure level were sacrificed after 13 weeks for the quantification of Ni in the lung.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: no data


BODY WEIGHT: Yes
- Time schedule for examinations: no data



OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: No


CLINICAL CHEMISTRY: No


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
Organ weights taken at necropsy were lung, liver, kidneys, testes, brain and thymus. In addition, sperm morphology, sperm number, sperm motility and vaginal cytology were evaluated on selected subgroups of male animals sacrificed at the end of the 13-week exposure period and for females during the last week of exposure.

HISTOPATHOLOGY: Yes
Complete histopathology was performed on high-exposure and control groups and to a no-effect level in target tissues (Lungs were fixed by intratracheal instillation of fixative.).

Other examinations:

Ni content in the lungs of exposed animals.

Statistics:

Multiple comparison procedures with two-tailed tests (Dunn, Shirley and Williams).

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

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:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
No exposure-related mortality was seen.

BODY WEIGHT AND WEIGHT GAIN
Body weight gain was not affected by exposure.

ORGAN WEIGHTS
There was a significant dose-dependent increase in lung weight in animals of both sexes. There were no exposure-related changes in the weights of the other organs examined.

HISTOPATHOLOGY: NON-NEOPLASTIC
Inflammatory changes were seen in the lung, nasal cavity and bronchial lymph node.
Lung lesions included alveolar macrophage hyperplasia, inflammation and fibrosis. These lesions were present in animals at each dose level. The incidence and severity of chronic, active inflammation in the lung increased with dose. The lesions consisted of a mild thickening of the alveolar septae by a mononucleas inflammatory cell infiltrate. Animals exposed to higher substance levels had atrophy of the olfactory epithelium. This minimal change was characterised by a decreased number of sensory cell nuclei, particularly in the olfactory epithelium of the dorsal meatus. There was no evidence of an inflammatory or regenerative response in the olfactory mucosa.
The change in the bronchial lymph nodes consisted of minimal to mild lymphoid hyperplasia in both sexes at higher exposure levels.

OTHER FINDINGS
No exposure-related effects were seen in sperm number, sperm motility or sperm morphology or in length of the estrous cycle.
Concentrations of Ni in the lungs of rats increased with exposure concentration and were significantly different from controls in animals exposed to 0.1 mg Ni/m3 or more. However, equilibrium levels of nickel were reached by 13 weeks in the lung after exposure.

Effect levels

1

Dose descriptor:

NOAEC

Remarks:

local

Effect level:

0.24 mg/m³ air

Sex:

male/female

Basis for effect level:

other: alveolar macrophage hyperplasia (not considered adverse) value for nickel citrate was calculated from nickel sulfate hexahydrate

2

Dose descriptor:

NOAEC

Remarks:

local

Effect level:

0.25 mg/m³ air

Sex:

male/female

Basis for effect level:

other: alveolar macrophage hyperplasia (not considered adverse) nickel sulfate hexahydrate

3

Dose descriptor:

LOAEC

Remarks:

local

Effect level:

0.49 mg/m³ air

Sex:

male/female

Basis for effect level:

other: inflammatory effects in the lung value for nickel citrate was calculated from nickel sulfate hexahydrate

4

Dose descriptor:

LOAEC

Remarks:

local

Effect level:

0.52 mg/m³ air

Sex:

male/female

Basis for effect level:

other: inflammatory effects in the lung nickel sulfate hexahydrate

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Based on the outcome of a simultanously performed stady in mice, the autors stated that rats appeared to be more sensitive than the mouse ((B6C3F1) to the development of chronic active inflammation, with inflammation occuring at lower exposure concentrations for rats than for mice.