NTP Study Reports
Abstract for TR-454 - Nickel Sulfate Hexahydrate
TR-454
Toxicology and Carcinogenesis Studies of
Nickel Sulfate Hexahydrate (CAS No. 10101-97-0) in F344 Rats and
B6C3F1 Mice (Inhalation Studies)
Chemical Formula: NiSO4 · 6H2O
Nickel sulfate hexahydrate is
used in nickel plating, as a mordant in dyeing and printing textiles,
as a blackening agent for zinc and brass, and in the manufacture
of organic nickel salts. Nickel sulfate hexahydrate was nominated
by the National Cancer Institute to the NTP as part of a class
study of nickel compounds for which there was little information
on the toxic and carcinogenic effects of inhalation exposure.
Male and female F344/N rats and B6C3F1 mice were exposed to nickel
sulfate hexahydrate (greater than 98% pure) by inhalation for
16 days, 13 weeks, or 2 years. Genetic toxicology studies were
conducted in L5178Y mouse lymphoma cells.
16-DAY STUDY IN RATS
Groups of five male and five female
F344/N rats were exposed to 0, 3.5, 7, 15, 30, or 60 mg nickel
sulfate hexahydrate/m3 (equivalent to 0, 0.7, 1.4,
3.1, 6.1, or 12.2 mg nickel/m3). Rats were exposed
on weekdays only, for a total of 12 exposure days during a 16-day
period. Additional groups of four or five male and female F344/N
rats were exposed to 0, 3.5, 15, or 30 mg nickel sulfate hexahydrate/m3for tissue
burden studies. In the core study, two 60 mg/m3
males, one 30 mg/m3 female, and all 60 mg/m3females
died before the end of the study. Final mean body weights of all
exposed groups of males and females were significantly lower than
those of the controls, as were mean body weight gains of male
rats. Clinical findings included increased rates of respiration
and reduced activity levels in rats in all exposure groups, except
those exposed to 3.5 mg/m3. Absolute lung weights of
60 mg/m3 males and of all exposed groups of females
were significantly greater than those of the controls, as were
the relative lung weights of all exposed groups of males and females.
Inflammation (including degeneration and necrosis of the bronchiolar
epithelium) occurred in the lungs of all exposed groups of males
and females. Atrophy of the olfactory epithelium occurred in the
nasal passages of all exposed groups of males (except 60 mg/m3)
and in 15, 30, and 60 mg/m3 females. Lymphoid hyperplasia
in the bronchial or mediastinal lymph nodes was observed in 30
mg/m3 males and in 60 mg/m3 males and females.
The concentration of nickel in the lungs of all exposed groups
of males and females was greater than in control animals.
16-DAY STUDY IN MICE
Groups of five male and five female
B6C3F1 mice were exposed to 0, 3.5, 7, 15, 30, or 60 mg nickel
sulfate hexahydrate/m3. Mice were exposed on weekdays
only, for a total of 12 exposure days during a 16-day period.
Additional groups of five male and five female B6C3F1 mice were
exposed to 0 or 3.5 mg nickel sulfate hexahydrate/m3for
tissue burden studies. All core study mice exposed to 7 mg/m3 or greater died before
the end of the study; all control
and 3.5 mg/m3mice survived to the end of the study.
Final mean body weights and weight gains of 7, 15, 30, and 60
mg/m3males and females were significantly less than
those of the controls, and clinical findings in these groups included
emaciation, lethargy, and rapid respiration rates. Absolute and
relative lung weights of male and female mice exposed to 7 mg/m3 or greater were
significantly greater than those of the
controls. Only tissues from mice exposed to 0, 3.5, or 7 mg/m3 were examined
histopathologically. Inflammation occurred
in the lungs of 3.5 and 7 mg/m3 males and females;
necrosis of the alveolar and bronchiolar epithelium was a component
of the inflammation in 7 mg/m3males and females. In
addition, atrophy of the olfactory epithelium of the nasal passages
was observed in 3.5 mg/m3 males and females. Nickel
concentrations in the lungs of mice exposed to 3.5 mg/m3
were greater than those in the controls.
13-WEEK STUDY IN RATS
Groups of ten male and ten female
F344/N rats were exposed to 0, 0.12, 0.25, 0.5, 1, or 2 mg nickel
sulfate hexahydrate (equivalent to 0, 0.03, 0.06, 0.11, 0.22,
or 0.44 mg nickel/m3), 5 days per week for 13 weeks.
Additional groups of six male and six female F344/N rats were
exposed to 0, 0.12, 0.5, or 2 mg nickel sulfate hexahydrate/m3for tissue burden
studies. In the core study, one 2 mg/m3male rat died before the end of the study; all
other males
and all females survived until the end of the study. Final mean
body weights and body weight gains of all exposed groups were
similar to those of the controls. There were no significant clinical
findings noted during the study. Exposure-related increases
in neutrophil and lymphocyte numbers occurred and were most pronounced
in female rats. 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. 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/m3or
greater. Atrophy of the olfactory epithelium occurred in males
and females exposed to 0.5, 1, and 2 mg/m3and in 0.25
mg/m3females. 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.
13-WEEK STUDY IN MICE
Groups of ten male and ten female
B6C3F1 mice were exposed to 0, 0.12, 0.25, 0.5, 1, or 2 mg nickel
sulfate hexahydrate, 5 days per week for 13 weeks. Additional
groups of up to five or six male and female B6C3F1 mice were exposed
to 0, 0.12, 0.5, or 2 mg nickel sulfate hexahydrate/m3for
tissue burden studies. In the core study, four control males,
three control females, and one 0.12 mg/m3male died
before the end of the study; the deaths were not considered to
be chemical related, and all other mice survived to the end of
the study. The final mean body weights and body weight gains of
all exposed groups were similar to those of the controls. There
were no chemical-related clinical findings. Hematology changes
similar to those reported in female rats occurred in female mice,
but the mice were minimally affected. The absolute and relative
lung weights of 1 mg/m3males and 2 mg/m3males
and females were significantly greater than those of the controls.
Increased numbers of alveolar macrophages occurred in all males
and females exposed to 0.5 mg/m3or greater. Chronic
active inflammation and fibrosis occurred in 1 and 2 mg/m3males and females. Lymphoid
hyperplasia of the bronchial
lymph node and atrophy of the olfactory epithelium in the nasal
passages were observed in 2 mg/m3males and females.
Nickel concentration in the lung of 2 mg/m3females
was significantly greater than in control animals.
2-YEAR STUDY IN RATS
Groups of 63 to 65 male and 63
to 64 female rats were exposed to nickel sulfate hexahydrate by
inhalation at concentrations of 0, 0.12, 0.25, or 0.5 mg/m3
(equivalent to 0, 0.03, 0.06, or 0.11 mg nickel/m3).
Animals were exposed for 6 hours plus T90 (8 minutes) 5 days per
week for 104 weeks. Five male and five female rats from each group
were evaluated at 7 months for histopathology; an additional seven
males and seven females from each group were evaluated at 7 months
for nickel tissue burden in the lung and kidney; and five males
and five females from each group were evaluated at 15 months for
alterations in hematology, nickel tissue burden in the lung and
kidney, and histopathology.
Survival, Body Weights,
Clinical Findings, and Hematology
The survival rates of all exposed
groups of males and females were similar to those of the controls.
Mean body weights of 0.5 mg/m3female rats were slightly
lower (6% to 9%) than those of the controls throughout the second
year of the study; final mean body weights of all exposed groups
of males and 0.12 and 0.25 mg/m3females were similar
to those of the controls. There were no clinical findings or hematology
differences that were considered to be related to nickel sulfate
hexahydrate administration.
Pathology Findings
No exposure-related neoplasms
occurred in male or female rats exposed by inhalation to nickel
sulfate hexahydrate for 2 years. Increased incidences of inflammatory
lung lesions were generally observed in all exposed groups of
male and female rats at the end of the study. The incidences of
chronic active inflammation, macrophage hyperplasia, alveolar
proteinosis, and fibrosis were markedly increased in male and
female rats exposed to 0.25 or 0.5 mg/m3. Increased
incidences of lymphoid hyperplasia in the bronchial lymph nodes
occurred in 0.5 mg/m3male and female rats at the end
of the 2-year study. The incidences of atrophy of the olfactory
epithelium in 0.5 mg/m3males and females were significantly
greater than those in controls at the end of the study.
Tissue Burden Analyses
Lung nickel burdens in exposed
male and female rats were greater than those in the controls at
the 7- and 15-month interim evaluations, and lung nickel
burdens values increased with increasing exposure concentration.
2-YEAR STUDY IN MICE
Groups of 80 male and 80 female
mice were exposed to nickel sulfate hexahydrate by inhalation
at concentrations of 0, 0.25, 0.5, or 1 mg/m3 (equivalent
to 0, 0.06, 0.11, or 0.22 mg nickel/m3). Animals were
exposed for 6 hours plus T90 (8 minutes) 5 days per week for 104
weeks. Five male and five female mice from each group were evaluated
at 7 months for histopathology; five males and five females from
each group were evaluated at 7 months for nickel tissue burden
in the lung and kidney; five males and five females from each
group were evaluated at 15 months for alterations in hematology
and histopathology; and five males and five females from each
group were evaluated at 15 months for nickel tissue burden in
the lung and kidney.
Survival, Body Weights,
Clinical Findings, and Hematology
The survival rates of all exposed
groups of males and females were similar to those of the controls.
The mean body weights of 1 mg/m3males and of all exposed
groups of females were lower than those of the controls during
the second year of the study. There were no clinical findings
or hematology differences considered to be related to chemical
exposure.
Pathology Findings
Inflammatory lesions of the lung
generally occurred in all exposed groups of male and female mice
at the end of the 2-year study. These lesions included macrophage
hyperplasia, chronic active inflammation, bronchialization (alveolar
epithelial hyperplasia), alveolar proteinosis, and infiltrating
cells in the interstitium. Incidences of macrophage hyperplasia
and/or lymphoid hyperplasia occurred in the bronchial lymph nodes
of most of the 1 mg/m3males and females and in some
0.5 mg/m3females at the end of the 2-year study.
Atrophy of the olfactory epithelium was observed in 0.5 and 1
mg/m3males and in all exposed groups of females at
the end of the 2-year study.
Tissue Burden Analyses
At the 7- and 15-month
interim evaluations, lung nickel burden parameters measured in
control and exposed groups were below the limit of detection.
Absolute lung weights of 0.5 and 1 mg/m3lung burden
study females were significantly greater than those of the controls
at 15 months.
GENETIC TOXICOLOGY
Nickel sulfate hexahydrate (500
to 800 g/mL) was tested for induction of trifluorothymidine resistance
in L5178Y mouse lymphoma cells. A positive response was observed
in the absence of S9. The test was not performed with S9.
CONCLUSIONS
Under the conditions of these
2-year inhalation studies, there was no evidence of carcinogenic
activity of nickel sulfate hexahydrate in male or female F344/N
rats exposed to 0.12, 0.25, or 0.5 mg/m3 (0.03, 0.06,
or 0.11 mg nickel/m3). There was no evidence of
carcinogenic activity of nickel sulfate hexahydrate in male
or female B6C3F1 mice exposed to 0.25, 0.5, or 1 mg/ m3
(0.06, 0.11, or 0.22 mg nickel/m3).
Exposure of rats to nickel sulfate
hexahydrate by inhalation for 2 years resulted in increased incidences
of chronic active inflammation, macrophage hyperplasia, alveolar
proteinosis, and fibrosis of the lung; lymphoid hyperplasia of
the bronchial lymph node; and atrophy of the olfactory epithelium.
Exposure of mice to nickel sulfate hexahydrate by inhalation for
2 years resulted in increased incidences of chronic active inflammation,
bronchialization (alveolar epithelial hyperplasia), macrophage
hyperplasia, interstitial infiltration, and alveolar proteinosis
of the lung; lymphoid and macrophage hyperplasia of the bronchial
lymph node; and atrophy of the olfactory epithelium.
Synonyms: Blue salt; hexahydrate,
nickel (2+) salt; nickel monosulfate hexahydrate; nickel (2+)
sulfate hexahydrate; nickel (II) sulfate hexahydrate; nickel sulphate
hexahydrate; nickelous sulfate hexahydrate; nickelous sulphate
hexahydrate; single nickel salt, sulfuric acid
Report Date: July 1996
Pathology Tables, Survival and Growth Curves from NTP 2-year Studies
Target Organs & Incidences from 2-year Studies
You may link to the full technical report in pdf format ( Note: A print ready copy of the document is presented in Portable Document Format (pdf) which requires the Acrobat Reader plug-in -- download a free copy of the reader.)
Web page last updated on October 11, 2007