Nickel(2+) propionate

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

May 1988 to May 1990

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

May 1988 to May 1990

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

other: reference to same study, different species (mouse)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

GLP compliance:

yes

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, USA.
- Age at study initiation: 6-week old
- Weight at study initiation: ~108-133 g
- Fasting period before study: not reported
- Housing: individually housed
- Diet: ad libitum, except during exposure
- Water: ad libitum, except during exposure

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.2-29.6°C
- Humidity (%): 8-99%
- Air changes (per hr): 9-21/hour
- Photoperiod (hrs dark / hrs light): 12-h light/dark photo cycle

IN-LIFE DATES: June 1988 to June 1990

Route of administration:

inhalation: aerosol

Type of inhalation exposure (if applicable):

whole body

Vehicle:

other: distilled and deionized water

Remarks on MMAD:

MMAD / GSD: MMAD =2.08-2.52 µm

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Stainless steel multitiered whole exposure chambers (Hazleton, Aberdeen, MD, USA)
- Source and rate of air: High-efficiency particulate air filter (Flanders, Washington, DC)
- System of generating particulates/aerosols: Aerosols were generated by nebulization of test substance solutions (62.1 g/L in distilled and deionized water)
- 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.
- 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)


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. Aerosol size was determined using cascade impactors.

Duration of treatment / exposure:

6 h / d

Frequency of treatment:

5 days per week for a period of 2 years

Dose / conc.:

0 mg/m³ air (nominal)

Dose / conc.:

0.125 mg/m³ air (nominal)

Dose / conc.:

0.25 mg/m³ air (nominal)

Dose / conc.:

0.5 mg/m³ air (nominal)

No. of animals per sex per dose:

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

Control animals:

yes, concurrent no treatment

Details on study design:

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

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were observed twice daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: conducted at the start of the study, weekly for 13 weeks, monthly during the remainder of the study, and at the end of the study period.

BODY WEIGHT: Yes
- Time schedule: conducted at the start of the study, weekly for 13 weeks, monthly during the remainder of the study, and at the end of the study period.

HAEMATOLOGY: Yes
- Blood was collected from the retroorbital sinus of as many as five male and five female mice at the 15-month interim evaluation.
- Hematology: hematocrit, hemoglobin, erythrocytes, mean erythrocyte volume, mean erythrocyte hemoglobin, mean erythrocyte hemoglobin concentration, reticulocytes, total leukocytes and differential, and nucleated erythrocytes.

Sacrifice and pathology:

GROSS PATHOLOGY/HISTOPATHOLOGY: Yes
Necropsy was performed on all animals.
The following organs were weighed at 7- and 15-months: brain, right kidney, liver, lung, spleen, and thymus.

Complete histopathology was performed on all mice. Gross lesions and tissues examined included: adrenal gland, bone, brain, clitoral gland, epididymis or oviduct, esophagus, heart, gallbladder, large intestine (including cecum, colon, rectum), small intestine (including duodenum, jejunum, ileum), kidneys, larynx, liver, lung, lymph nodes, mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate, salivary gland, seminal vesicle, skin, spleen, stomach, testis, thymus, thyroid gland, trachea, urinary bladder, and uterus.

Other examinations:

Ni levels in lung tissues were analyzed

Statistics:

The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958). Dose-related effects were analyzed using Cox's (1972) method for testing two groups for equality, and Tarone's (1975) life table test to identify dose-related trends. Organ and body weight data were analyzed using the parametric multiple comparison procedures of Dunnett (1955) and Williams (1971, 1972).

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The final mean body weights compared to the control group per 0.125 mg/m3, 0.25 mg/m3 and 0.5 mg/m3 exposure groups were 99 %, 101 % and 98 %, respectively for the male rats and 97 %, 97 % and 94 % for the females, respectively.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Lung weights in exposed animals were greater than controls, this was considered to be related to inflammatory lung reactions that occurred in response to test substance exposure. At 15 months, the lung weights of in the high exposure group was 33-41 % more compared to the control.

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

A spectrum of exposure-related nonneoplastic respiratory tract lesions seen after exposure included focal alveolar/bronchiolar hyperplasia, inflammation, and/or fibrosis of the lung and lymphoid hyperplasia of the lung-associated lymph nodes. Atrophy of the olfactory epithelium was also seen after exposure.

Histopathological findings: neoplastic:

no effects observed

Details on results:

ORGAN WEIGHTS:
Significant organ weight changes reported:
-increased relative lung weights of 0.25 and 0.5 mg/m3 males at 7-month evaluation.
-increased relative and absolute lung weights of 0.5 mg/m3 females at 7-month evaluation.
-increased relative and absolute lung weights of 0.5 mg/m3 males and females at 15-month evaluation.

HAEMATOLOGY:
There were no substance-related hematology differences or clinical findings reported. Lung Ni levels were significantly higher in Ni-exposed rats relative to the control animals. Lung Ni levels increased with increasing Ni exposure levels.

HISTOPATHOLOGY: NON-NEOPLASTIC
Significantly-increased incidences of non-neoplastic lung lesions reported for 2-year study:
-chronic active lung inflammation of 0.25 and 0.5 mg/m3 rats.
-macrophage hyperplasia of 0.25 and 0.5 mg/m3 rats.
-alveolar proteinosis of 0.25 and 0.5 mg/m3 rats.
-fibrosis of 0.25 and 0.5 mg/mg3 rats.

Result (carcinogenicity): negative

Dose descriptor:

LOAEL

Effect level:

0.25 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: chronic active lung inflammation

Remarks on result:

other: equivalent to 0.056 mg Ni/m3

Key result

Dose descriptor:

NOAEC

Effect level:

0.125 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects

Remarks on result:

other: equivalent to 0.027 mg Ni/m3

Key result

Critical effects observed:

no

Conclusions:

No evidence of carcinogenic activity of the test substance nickel sulfate hexahydrate as aerosol has been revealed in rats in this 2-years inhalation study. The NOAEL was determined to be ca. 0.125 mg/m3 air, equivalent to 0.027 mg Ni/m3 air.

Data source

Reference

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.

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

nickel(2+);sulfate;hexahydrate

EC Number:

600-152-3

Cas Number:

10101-97-0

Molecular formula:

H12NiO10S

IUPAC Name:

nickel(2+);sulfate;hexahydrate

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: ad libitum during non-exposure periods
- Water: 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:

water

Remarks on MMAD:

MMAD / GSD: MMAD =2.08-2.52 µm

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Stainless steel multitiered whole exposure chambers (Hazleton, Aberdeen, MD, USA)
- Source and rate of air: High-efficiency particulate air filter (Flanders, Washington, DC)
- System of generating aerosols: Aerosols were generated by nebulization of test substance solutions (62.1 g/L in distilled and deionized water)
- 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)

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. Aerosol size was determined using cascade impactors.

Duration of treatment / exposure:

6h /d

Frequency of treatment:

5 d/wk, 2 yr

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

1 mg/m³ air (nominal)

Doses / concentrations 2

Dose / conc.:

0.5 mg/m³ air (nominal)

Doses / concentrations 3

Dose / conc.:

0.25 mg/m³ air (nominal)

Doses / concentrations 4

Dose / conc.:

0.125 mg/m³ air (nominal)

Doses / concentrations 5

Dose / conc.:

0 mg/m³ air (nominal)

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

Examinations

Observations and examinations performed and frequency:

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

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

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, 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, embedded in paraffin, sectioned, and stained with hematoxylin and eosin for microscopic examination.
HISTOPATHOLOGY: Yes. Complete histopathology was performed on high-exposure and control groups and to a no-effect level in target tissues.

Other examinations:

Ni concentration in the lungs

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:

effects observed, treatment-related

Description (incidence and severity):

The final mean body weights compared to the control group per 0.125 mg/m3, 0.25 mg/m3 and 0.5 mg/m3 exposure groups were 99 %, 101 % and 98 %, respectively for the male rats and 97 %, 97 % and 94 % for the females, respectively.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Lung weights in exposed animals were greater than controls, this was considered to be related to inflammatory lung reactions that occurred in response to test substance exposure. At 15 months, the lung weights of in the high exposure group was 33-41 % more compared to the control.

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

A spectrum of exposure-related nonneoplastic respiratory tract lesions seen after exposure included focal alveolar/bronchiolar hyperplasia, inflammation, and/or fibrosis of the lung and lymphoid hyperplasia of the lung-associated lymph nodes. Atrophy of the olfactory epithelium was also seen after exposure.

Histopathological findings: neoplastic:

no effects observed

Details on results:

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 µg Ni/g lung.

Effect levels

1

Dose descriptor:

LOAEC

Effect level:

0.25 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: chronic active lung inflammation

Remarks on result:

other: equivalent to 0.056 mg Ni/m3

2

Key result

Dose descriptor:

NOAEC

Effect level:

0.125 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects

Remarks on result:

other: equivalent to 0.027 mg Ni/m3

Target system / organ toxicity

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

0.25 mg/m³ air

System:

respiratory system: lower respiratory tract

Organ:

lungs

Treatment related:

yes

Applicant's summary and conclusion

Conclusions:

The NOAEL of the test substance as aerosol was found to be 0.125 mg/m3 air.