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Repeated dose toxicity: inhalation

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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-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Referenceopen allclose all

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 Type:
study report
Title:
Unnamed
Year:
1996

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
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

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): NiO
- Substance type: green; formed at 1350 C (Cas NO. 1313-99-1)
- Analytical purity: > 99%

Test animals

Species:
rat
Strain:
other: F344/N
Sex:
male/female
Details on test animals 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 = 2.2-2.5 um
GSD = 1.8
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Multitiered inhalation chambers, H-2000
- System of generating particulates/aerosols: NiO aerosols were generated 4' fluid bed generators
- Air change rate: flow through the chamber was 12 ± 2 air changes/h
- Method of particle size determination: Aerosol size was determined using cascade impactors


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.

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 / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0.62 mg NiO/m3
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
1.25 mg NiO/m3
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
2.5 mg NiO/m3
Basis:
nominal conc.
No. of animals per sex per dose:
50 males, 50 females
Control animals:
yes
Details on study design:
- Dose selection rationale: based on previous 13-week study (Dunnick et al., 1989)
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: lung, thymus, liver, right kidney, brain, right testes or ovary
HISTOPATHOLOGY: Yes. Complete histopathology was performed on high-exposure and control groups and to a no-effect level in target tissues. Including: gross lesions and tissue masses, adrenals, bone (vertebra with spinal cord and femur with bone marrow), brain, epididymus, esophagus, heart, small intestine (duodenum, jejunum, ileum), large intestine (cecum, colon, rectum), islets of pancreas, kidneys, larynx, liver, lung, lymph nodes (bronchial, mandibular, mediastinal, mesenteric), mammary gland, nasal turbinates, pancreas, parathyroid gland, pituitary gland, preputial or clitoral gland (in rats) prostate or uterus, salivary glands, seminal vesicles, skin, spleen, stomach (including forestomach and glandular portions), testes or ovaries, thymus, thyroid gland, trachea, and urinary bladder.
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:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:

ORGAN WEIGHTS
By 7 months, lung weight was significantly increased in females and males at 0.62 mg/m3 and 1.2 mg/m3, respectively.

HISTOPATHOLOGY: NON-NEOPLASTIC
Noncarcinogenic effects included alveolar/bronchiolar (A/B) hyperplasia, inflammation, fibrosis, and lymphoid hyperplasia of the lung-associated lymph nodes.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
See Section 7.7

Effect levels

open allclose all
Dose descriptor:
dose level: 0.62, 1.25, and 2.5 mg NiO/m3 air
Effect level:
2.5 mg/m³ air
Sex:
male/female
Basis for effect level:
other: At the 2.5 mg/m3 dose, 12/52 male rats survived with signigicant increased lung weight and 26/54 female rats survived with significant increased lung weight.
Dose descriptor:
dose level: 0.62, 1.25, and 2.5 mg NiO/m3 air
Effect level:
1.2 mg/m³ air
Sex:
male/female
Basis for effect level:
other: At the 1.2 mg/m3 dose, 15/53 male rats survived with signigicant increased lung weight and 20/53 female rats survived with significant increased lung weight. Adenomas and carcinomas were also observed more often than in controls.
Dose descriptor:
dose level: 0.62, 1.25, and 2.5 mg NiO/m3 air
Effect level:
0.62 mg/m³ air
Sex:
male/female
Basis for effect level:
other: At the 0.62 mg/m3 dose, 15/53 male rats survived t and 26/53 female rats survived with significant increased lung weight. Adenoma and carcinoma occurrence was not different than for control animals.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

 Absolute Lung Weight (grams)            
 NiO mg/m3  0 0.62 1.2  2.5 
 Male - 7 mo  1.72 1.85  2.46*  2.59* 
 Male- 15 mo  2.2 2.15  3.30*  4.09* 
 Female - 7 mo  1.14 1.31*  1.65*  1.78* 
 Female - 15 mo  1.56 1.79  2.41*  3.02* 

* = significantly different from control

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. In addition, lung weight was increased by 7 months.
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 green NiO in F344/N rats exposed for 6 hr/d, 5 d/wk, for 2 years (0.62, 1.25, and 2.5 mg/m3; 0.5, 1.0, 2.0 mg Ni/m3). Chamber concentrations and aerosol size were determined analytically (MMAD: 2.4 μm; GSD 2.2). 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 females and males at 0.62 mg/m3 and 1.2 mg/m3, respectively. At 15 months, significant differences were observed at 1.2 mg/m3 in both sexes. Noncarcinogenic effects included alveolar/bronchiolar (A/B) hyperplasia, inflammation, fibrosis, and lymphoid hyperplasia of the lung-associated lymph nodes. Pigment was observed in the lungs of animals exposed to NiO, and was thought to be deposited Ni. This investigation was part of a comprehensive bioassay conducted by the National Toxicology Program (1996). STUDY RATED BY AN INDEPENDENT REVIEWER