Nickel dihydroxide

Carcinogenicity

Administrative data

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: NTP-study comparable to guideline

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1996

Report date:

1996

Materials and methods

Principles of method if other than guideline:

Standard protocol of the National Toxicology Program

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Trinickel disulphide

EC Number:

234-829-6

EC Name:

Trinickel disulphide

Cas Number:

12035-72-2

Details on test material:

- Name of test material (as cited in study report): Nickel subsulfide
- Physical state: gray or black powder
- Analytical purity: 97-98 %
- Lot/batch No.: three lots (HF-1517,1080786, and 1072588), a blend of the three lots was used.

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Taconic Farms Germantown, NY
- Age at study initiation: 6 weeks
- Weight at study initiation:
- Housing: single in stainless steel wire cages
- Diet: NIH-07 open formula meal diet (Zeigler Brothers, Inc., Gardners, PA), ad libitum
- Water: tap water ad libitum
- Acclimation period: 10 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.6° to 30.5° C
- Humidity (%): 11 % to 93%
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

A continuous aerosol monitor (Model RAM-S, GCA, Co., Bedford, MA)

Duration of treatment / exposure:

104 weeks

Frequency of treatment:

6 hours per day, 5 days per week

Post exposure period:

no post exposure period

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 0.15, or 1 mg nickel subsulfide/m3 (equivalent to 0, 0.11, or 0.73 mg nickel/m3)
Basis:
nominal conc.

No. of animals per sex per dose:

63

Control animals:

yes

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: The animals were observed twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: initially, weekly for the first 13 weeks, monthly thereafter, and at the end of the studies

BODY WEIGHT: Yes
- Time schedule for examinations: initially, weekly for the first 13 weeks, monthly thereafter, and at the end of the studies

OPHTHALMOSCOPIC EXAMINATION: Yes / No / No data
- Time schedule for examinations:
- Dose groups that were examined:

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 15 months of exposure.
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 5 male and 5 female animals
- Parameters examined: eosinophils, erythrocytes, hematocrit, hemoglobin, leukocytes, lymphocytes, mean cell volume, mean cell hemoglobin, mean cell hemoglobin concentration, monocytes, reticulocytes, and segmented neutrophils.

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, all organs and tissues were examined for grossly visible lesion
HISTOPATHOLOGY: Yes, complete histopathology was performed on all rats and mice at the end of the studies and on 5 male and 5 female rats and mice at the 7- and 15-month interim evaluations. At 7 months, only the kidney, lung, lymph nodes (bronchial and mediastinal), and nasal turbinates were examined. For all others, in addition to gross lesions and tissue masses with regional lymph nodes, tissues examined included: adrenal gland, brain (3 sections), clitoral gland, esophagus, eyes (if grossly abnormal), femur, gallbladder (mice), heart and aorta, large intestine (cecum, colon, rectum), small intestine (duodenum, jejunum, ileum), kidney, larynx, liver, lung and mainstem bronchi, lymph nodes(mandibular, mesenteric, bronchial, and mediastinal), mammary gland and adjacent skin, muscle (rats), nasal cavity and turbinates (3 sections), ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, skin, spinal cord and sciatic nerve, spleen, stomach (forestomach and glandular), testis with epididymis and seminal vesicle, thymus, thyroid gland, trachea, urinary bladder, and uterus.

Organs weighed at the 7- and 15-month interim evaluations were brain, right kidney, liver, lung, spleen, and thymus.

Results and discussion

Results of examinations

Details on results:

CLINICAL SIGNS AND MORTALITY
Survival of exposed males and female rats was similar to that of the controls. Chemical-related clinical findings included rapid and shallow breathing following exposure periods.

BODY WEIGHT AND WEIGHT GAIN
Mean body weights of males and females exposed to 0.15 mg/m3 were similar to those of the controls. Mean body weights of rats exposed to 1 mg/m3 were lower than those of the controls throughout the second year of the study.

HAEMATOLOGY
Hematocrit values and hemoglobin concentrations in 1 mg/m3 males and females and the erythrocyte count in 1 mg/m3 males were mildly greater than those in the controls.

ORGAN WEIGHTS
In general, the absolute and relative lung weights of exposed males and females were significantly greater than those of the controls at 7 and 15 months.

HISTOPATHOLOGY: NON-NEOPLASTIC
Nonneoplastic lung lesions generally observed in exposed males and females included fibrosis; chronic active inflammation; focal alveolar epithelial hyperplasia, macrophage hyperplasia, and proteinosis; bronchial lymphoid hyperplasia; and interstitial inflammation.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
There were exposure-related increases in the incidences of alveolar/bronchiolar adenoma in males, alveolar/bronchiolar carcinoma in males and females, and alveolar/bronchiolar adenoma or carcinoma (combined) in males and females at 2 years.

At 2 years, there were significant exposure-related increases in the incidences of benign pheochromocytoma, malignant pheochromocytoma, and benign or malignant pheochromocytoma (combined) in males and of benign pheochromocytoma in females. The incidence of adrenal medulla hyperplasia in 1 mg/m3 females was significantly greater than that of the controls.

At 2 years, the incidences of chronic active inflammation of the nose in 1 mg/m3 females and of olfactory epithelial atrophy in 1 mg/m3 males and females were significantly greater than those of the controls.

The incidences of lymphoid hyperplasia of the bronchial lymph node in exposed males at 7 and 15 months and in exposed males and females at 2 years were significantly greater than those of the controls. Incidences of macrophage hyperplasia in the bronchial lymph node of exposed males at 15 months and exposed males and females at 2 years were greater than those of the controls.

OTHER FINDINGS
Tissue Burden Analyses: Nickel concentrations in the lungs of exposed rats were greater than those of the controls at 7 months (males, 6 to 9 mg nickel/g lung; females, 6 to 9 mg/g lung) and 15 months (males, 4 to 3 mg nickel/g lung; females, 4 to 7 mg/g lung).

Effect levels

Dose descriptor:

NOAEC

Effect level:

<= 150 mg/L air (nominal)

Sex:

male/female

Basis for effect level:

other: histopathology

Remarks on result:

not determinable

Remarks:

no NOAEC identified. Effect type:carcinogenicity (migrated information)

Any other information on results incl. tables

Under the conditions of these 2-year inhalation studies, there was clear evidence of carcinogenic activityof nickel subsulfide in male F344/N ratsbased on increased incidences of alveolar/bronchiolar adenoma, carcinoma, and adenoma or carcinoma (combined) and on increased incidences of benign, malignant, and benign or malignant (combined) pheochromocytoma of the adrenal medulla. There was clear evidence of carcinogenic activity of nickel subsulfide in female F344/N rats based on increased of alveolar/bronchiolar carcinoma and bronchiolar adenoma or carcinoma (combined) and an increased incidence of benign pheoalveolar/ chromocytoma of the adrenal medulla.

 

Exposure of male and female rats to nickel subsulfide by inhalation for 2 years resulted in inflammation, hyperplasia, and fibrosis in the lung; inflammation and atrophy of the olfactory epithelium in the nose; and hyperplasia in the adrenal medulla (females).