Nickel bis(2-ethylhexanoate)

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

chronic toxicity: inhalation

Remarks:

combined repeated dose and carcinogenicity

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 453)

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Comparative Carcinogenic Effects of Nickel Subsulfide, Nickel Oxide, or Nickel Sulfate Hexahydrate Chronic Exposures in the Lung

Author:

Dunnick JK, Elwell MR, Radovsky AE, Benson JM, Hahn FF, Nikula KJ, Barr EB, Hobbs CH

Year:

1995

Bibliographic source:

CANCER RESEARCH. 55: 5251-5256

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

1996

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

Deviations:

not specified

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:

Nickel sulphate

EC Number:

232-104-9

EC Name:

Nickel sulphate

Cas Number:

7786-81-4

Molecular formula:

H2O4S.Ni

IUPAC Name:

Nickel sulfate

Test animals

Species:

rat

Strain:

other: F344/N

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Taconic Farms, Germantown, NY
- Housing: Hazleton 2000 whole-body chambers
- Diet (e.g. ad libitum): ad libitum during non-exposure periods
- Water (e.g. ad libitum): ad libitum


ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 hr dark, 12 hr light

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

other: no data

Remarks on MMAD:

MMAD / GSD: MMAD =2.08-2.52 um

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Hazieton 1000 (mice) and Hazleton 2000 (rats) whole-body chambers (Lab Products, Inc., Maywood, NJ)
- Method of holding animals in test chamber: not reported
- Source and rate of air: not reported
- Method of conditioning air: not reported
- System of generating particulates/aerosols: Nickel sulfate aerosols were generated by nebulization of nickel sulfate solutions
- Temperature, humidity, pressure in air chamber: not reported
- Air flow rate: not reported
- Air change rate: not reported
- Method of particle size determination: Aerosol concentration was determined by taking three 2-h filter samples throughout the exposure day.
Real-time determination of aerosol concentration was made using real time aerosol monitor - model S units. Aerosol size was determined using cascade impactors. (The range of mass median aerodynamic diameters and GSD obtained throughout the study were 2.2-2.5 um and GSD=2.2)
- Treatment of exhaust air: not reported

TEST ATMOSPHERE
- Brief description of analytical method used: Aerosol concentration was determined by taking three 2-h filter samples throughout the exposure day.
Real-time determination of aerosol concentration was made using real time aerosol monitor - model S units. Aerosol size was determined using cascade impactors. (The range of mass median aerodynamic diameters and GSD obtained throughout the study were 2.2-2.5 um and GSD=2.2)
- Samples taken from breathing zone:not reported

VEHICLE (if applicable)
- water

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Aerosol concentration was determined by taking three 2-h filter samples throughout the exposure day.
Real-time determination of aerosol concentration was made using real time aerosol monitor-model S units.

Duration of treatment / exposure:

6 hr/day

Frequency of treatment:

5 d/wk, 2 yr

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 0.125, 0.25, 0.5, 1.0 mg/m3
Basis:
nominal conc.

No. of animals per sex per dose:

Groups of 63 to 65 male and 63 to 64 female rats

Control animals:

yes

Details on study design:

- Dose selection rationale: based on previous 13-week study

Positive control:

Not applicable

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: every 4 weeks

BODY WEIGHT: Yes
- Time schedule for examinations: every 4 weeks

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

OTHER: Lung Ni burden

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:

Tests of significance included pairwise comparisons of each exposed group with controls and a test for overall exposure-related trends. Organ and body weight data were analyzed using parametric multiple comparison procedures, and lung burden data were analyzed using nonparametric multiple comparison methods. The reported values were considered significant at the P < 0.05 level.

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 specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

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:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

GROSS PATHOLOGY/HISTOPATHOLOGY:
Complete necropsies were done on all animals. At necropsy, all organs and tissues were examined for grossly visible lesions, and all major
tissues and lesions were preserved in 10% neutral-buffered formalin, embed ded in paraffin, sectioned, and stained with hematoxylin and
eosin for microscopic examination.

Additional animals were added for lung burden determinations at 7 or 15 months, Ni analyzed by atomic absorption spectroscopy.

MORTALITY & BODY WEIGHT:
Survival and body weights were similar to in exposed mice and rats to controls.

ORGAN WEIGHTS:
At 15-months, the lung weight in the high-exposure nickel sulfate mice was 30-37% more than control lung weight, and in the rats, 33-41% more than controls.

GROSS & HISTOPATHOLOGY:
A spectrum of exposure-related nonneoplastic respiratory tract lesions included: focal alveolar/bronchiolar hyperplasia, inflammation, and/or
fibrosis of the lung and lymph oid hyperplasia of the lung-associated lymph nodes, and atrophy of the olfactory epithelium.

There were no increases in lung neoplasms in rats or mice exposed to nickel sulfate. The A/B neoplasms that were observed in the exposed
groups were similar in incidence and morphology to those observed in controls.

OTHER FINDINGS:
The lung burden at 7 or 15 months in rats and mice was 1-2 ug Ni/g lung for nickel sulfate.

Effect levels

1

Dose descriptor:

NOAEC

Effect level:

ca. 0.027 other: mg Ni/m3 (as Ni sulfate hexahydrate)

Sex:

male/female

Basis for effect level:

other: chronic active lung inflammation

2

Dose descriptor:

LOAEC

Effect level:

0.056 other: mg Ni/m3 (as Ni sulfate hexahydrate)

Sex:

male/female

Basis for effect level:

other: Chronic active lung inflammation

Target system / organ toxicity

Critical effects observed:

not specified