Nickel dihydroxide

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: NTP studyy, 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:

see details in remarks on material and methods

GLP compliance:

not specified

Test material

Test material information

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
- Physical state: blue-green crystalline powder
- Analytical purity: 98.8% ± 0.8%
- Lot/batch No.: M06288
- Storage condition of test material: room temperature

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Simonsen Laboratories
- Age at study initiation: 7 weeks
- Weight at study initiation: males: 131 - 138 g; females: 106 - 112 g
- Housing: single in stainless stee
- Diet: NIH-07 open formula rat and mouse ration (Zeigler Brothers, Inc., Gardners, PA), available ad libitum,
- Water: tap water ad libitum
- Acclimation period: 19-22 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.1-27.6 °C
- Humidity (%): 43 - 76 %
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Remarks on MMAD:

MMAD / GSD: no data

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:

90 days

Frequency of treatment:

6 h per day, 5 days per week for 13 weeks.

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 0.12, 0.25, 0.5, 1, or 2 mg/m3
Basis:
nominal conc.

No. of animals per sex per dose:

10

Control animals:

yes

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: initially, weekly and at the end of the study

BODY WEIGHT: Yes
- Time schedule for examinations: initially, weekly and at the end of the study

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: Yes
- Time schedule for collection of blood: no data
- Anaesthetic used for blood collection: Yes (identity) / No / No data
- Animals fasted: No data
- How many animals: all
- Parameters xamined: hematocrit, hemoglobin, erythrocytes, mean erythrocyte volume, mean erythrocyte hemoglobin concentration, reticulocytes, total leukocytes and differential, and nucleated erythrocytes.

CLINICAL CHEMISTRY: No dat

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER: Organs weighed were brain, heart, thymus, right kidney, liver, lung, right testis.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes; complete histopathology was performed on 0 and 2 mg/m3 rats. In addition to gross lesions and tissue masses, the tissues examined included: adrenal gland, bone, brain, clitoral gland, epididymis or oviduct, esophagus, heart, large intestine (cecum, colon, rectum), small intestine(duodenum, jejunum, ileum), kidneys, larynx, liver, lung, lymph nodes(bronchial, mandibular, mediastinal, mesenteric), mammary gland, nose, ovary, pancreas, pancreatic islets, parathyroid gland, pituitary gland, preputial gland, prostate, salivary gland, seminal vesicle, skin, spleen, stomach(forestomach and glandular), testis, thymus, thyroid gland, trachea, urinary bladder, and uterus. In addition, the following organs were examined from selected exposure groups of rats: lung, nose, and respiratory tract lymph nodes (bronchial and mediastinal)

Results and discussion

Results of examinations

Details on results:

CLINICAL SIGNS AND MORTALITY
In the core study, one 2 mg/m3 male rat died before the end of the study; all other males and all females survived until the end of the study.
There were no significant clinical findings noted during the study.

BODY WEIGHT AND WEIGHT GAIN
Final mean body weights and body weight gains of all exposed groups were similar to those of the controls.
HAEMATOLOGY
Exposure-related increases in neutrophil and lymphocyte numbers occurred and were most pronounced in female rats.
ORGAN WEIGHTS
With the exception of 0.12 mg/m3rats, absolute and relative lung weights of all exposed groups were generally significantly greater than those of the controls.

HISTOPATHOLOGY: NON-NEOPLASTIC
Exposure-related increases in the incidence and severity of inflammatory lesions (alveolar macrophages, chronic inflammation, and interstitial infiltration) occurred in the lungs of all exposed groups of males and females. Lymphoid hyperplasia of the bronchial and/or mediastinal lymph nodes occurred in males exposed to 0.5 mg/m3 or greater. Atrophy of the olfactory epithelium occurred in males and females exposed to 0.5, 1, and 2 mg/m3and in 0.25 mg/m3 females.

OTHER FINDINGS
The concentration of nickel in the lungs of 0.5 and 2 mg/m3 rats was greater than that in the lungs of control animals at 4, 9, and 13 weeks for males and at 13 weeks for females.

Nickel sulfate hexahydrate had no significant effects on sperm morphology or vaginal cytology.

Effect levels

Dose descriptor:

NOEC

Effect level:

0.25 mg/m³ air

Sex:

male/female

Basis for effect level:

other: nasal toxicity

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

In the present 13-week studies, the no-effect level for lung alveolar hyperplasia and inflammation and olfactory epithelial atrophy was 0.25 mg/m3 (equivalent to 0.06 mg nickel/m3) in rats. The no-effect level for nasal toxicity was approximately 0.25 mg/m3 for rats Respiratory toxicity produced by nickel sulfate hexahydrate in rats and mice occurs at or below the present threshold limit value levels of water-soluble nickel salts (0.1 mg nickel/m3) (ACGIH, 1993). Chronic active inflammation of the lung was considered to be potentially life threatening because of the possibility of reduced lung function.