Registration Dossier

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

Referenceopen allclose all

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 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

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 / concentrationsopen allclose all
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
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

open allclose all
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
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
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
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.

Applicant's summary and conclusion