Naphthenic acids, nickel salts

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

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:

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:

NiSO4

IUPAC Name:

nickel(2+) sulfate

Test animals

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Simonsen Laboratories, Gilroy, CA
- Housing: Hazleton 1000 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 = 2.02-2.53 um

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Stainless steel multitiered whole exposure chambers (Hazleton, Aberdeen, MD, USA)
- Method of holding animals in test chamber: not reported
- Source and rate of air: High-efficiency particulate air filter (Flanders, Washington, DC)
- Method of conditioning air: not reported
- System of generating particulates/aerosols: The test compound was generated from aqueous solutions (62.1 g/L in distilled and deionized water) and atomized.
- Temperature, humidity, pressure in air chamber: Temp. 17.2-29.6 deg. C; humidity 8-99%
- Air flow rate: The aerosol was mixed with additional dilution air to achieve the proper concentration and flow rate.
- Air change rate: not reported
- Method of particle size determination: cascade impactor, the mass median aerodynamic diameter (MMAD) ranged from 1.8-3.1 um for all exposure concentrations.
- Treatment of exhaust air: not reported

TEST ATMOSPHERE
- Brief description of analytical method used: aerosol concentrations determined gravimetrically
- Samples taken from breathing zone: yes

VEHICLE: 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, 0.25, 0.5, 1 mg/m3 (equivalent to 0, 0.056, 0.11, 0.22 mg Ni/m3)
Basis:
nominal conc.

No. of animals per sex per dose:

80 males, 80 females

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:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not specified

Details on results:

CLINICAL SIGNS AND MORTALITY:
Survival rates of exposed mice were similar to controls.

BODY WEIGHT AND WEIGHT GAIN:
Mean body weights of 1 mg/m3 males and of all Ni-exposed females were lower than control animals during year 2 of the study.

ORGAN WEIGHTS
Significant organ weight changes reported: -increased absolute lung weights of 1 mg/m3 males and females at 15-month evaluation.
-increased relative lung weight of 1 mg/m3 females at 15-month evaluation.

HAEMATOLOGY:
There were no substance-related hematology differences or clinical findings reported.
Tissue Ni burden levels were below the level of detection at the 7- and 15-month evaluation periods.

HISTOPATHOLOGY: NON-NEOPLASTIC
Significantly increased incidences of non-neoplastic lung lesions reported for 2-year study:
-chronic active lung inflammation of 0.5 and 1 mg/m3 male mice, and 0.25, 0.5, and 1 mg/m3 female mice.
-macrophage hyperplasia of 0.5 and 1 mg/m3 male mice, and 0.25, 0.5, and 1 mg/m3 female mice.
-bronchialization of 0.5 and 1 mg/mg3 male mice, and 0.25, 0.5, and 1 mg/m3 female mice.
-interstitial infiltration of 1 mg/m3 male mice, and 0.5 and 1 mg/m3 female mice.
-alveolar proteinosis of 1 mg/m3 male mice, and 0.5 and 1 mg/m3 female mice.
-bronchial lymphoid hyperplasia of 1 mg/m3 male and female mice.
-bronchial macrophage hyperplasia of 0.5 and 1 mg/m3 male and female mice.
The incidence of atrophy of the olfactory epithelium at the end of the 2-year study was significantly increased in 0.5 and 1 mg/m3 male mice,
and in 1 mg/m3 female mice.

HISTOPATHOLOGY: NEOPLASTIC
No nickel sulfate hexahydrate-related neoplasms (alveolar/bronchiolar adenoma or carcinoma) were found in male or female mice exposed to the
test substance via whole body inhalation for 2 years.

Effect levels

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

Any other information on results incl. tables

On the basis of chronic active lung inflammation, the LOAEL was determined to be 0.056 mg Ni/m3 (0.25 mg nickel sulfate hexahydate/m3).   

No NOAEL could be determined. The authors reported "no evidence of carcinogenic activity of nickel sulfate hexahydrate in male or 

female B6C3F1 mice exposed to 0, 0.25,  0.5, or 1 mg/m3" under the conditions of the 2-year inhalation study.

Applicant's summary and conclusion

Conclusions:

Noncarcinogenic effects included alveolar/bronchiolar (A/B) hyperplasia, inflammation, fibrosis, and lymphoid hyperplasia of the lung-associated lymph nodes.Qualitatively, the effects were similar across the three nickel compounds, but were generally considered by the authors as more severe for NiO and Ni3S2; however, effects in mice were considered less sensitive than rats.

Executive summary:

As part of a study on the toxicity and carcinogenicity of NiSO4, Ni3S2 and NiO, Dunnick et al. (1995) described the toxicity of inhaled Ni3S2 in B6C3F1 mice exposed for 6 hr/d, 5 d/wk, for 2 years (0.15, and 1 mg Ni3S2 /m3; 0.11 and 0.73 mg Ni/m3). Chamber concentrations and aerosol size were determined analytically (MMAD: 2.1 μm; GSD 2.0). Noncarcinogenic effects examined included clinical signs, body and organ weights, tissue histopathology, and lung burden (note: carcinogenic effects and lung burden are described in the Carcinogenicity and Basic Toxicokinetics sections, respectively). No significant differences in mortality were observed between control and treated animals. Bodyweights of exposed animals were said to be within 5-10% of control animals and were not considered characterized as adverse effects. Lung weights in exposed animals were greater than controls and were considered to be due to inflammatory responses. By 7 months, lung weight was significantly increased in males at 1.2 mg/m3 and in females at 0.6 mg/m3. At 15 months, the lung weight was about 0.4 g in male mice treated at either dose versus 0.23 g in control males. In female mice, the lung weights were 0.26, 0.39, and 0.5 g in control mice and the mice treated at low and high doses of Ni3S2 . Noncarcinogenic effects included alveolar/bronchiolar (A/B) hyperplasia, inflammation, fibrosis, and lymphoid hyperplasia of the lung-associated lymph nodes. Qualitatively, the effects were similar across the three nickel compounds, but were generally considered by the authors as more severe for NiO and Ni3S2; however, mice were considered less sensitive than rats. This investigation was part of a comprehensive bioassay conducted by the National Toxicology Program (1996). STUDY RATED BY AN INDEPENDENT REVIEWER