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EC number: 227-873-2
CAS number: 6018-92-4
Oral:NOAEL = 7.02 mg/kg bw Trinickel dicitrateLOAEL = 21.1 mg/kg bw Trinickel dicitrateInhalation:NOAEC = 0.159 mg/m3 Trinickel dicitrateLOAEC = 0.368 mg/m3 Trinickel dicitrate
There are no repeated dose toxicity studies
for Trinickel dicitrate. However, extensive data exist for the
read-across substance nickel sulphate.
Parts of the data are taken from the EU-RAR
for nickel sulphate, dated 2008.
In the EU-RAR seven (out of eight)
repeated-dose toxicity studies after oral exposure have been commented
on. Of these, the two most sensitive studies are described in more
A 90-day oral gavage study in rats using
nickel sulphate hexahydrate has been performed as a range-finding study
for a 2-year carcinogenicity study (Heim et al. 2007). The study was
performed according to GLP. Groups of 10 male and 10 female rats were
dosed with 0, 50, 75, 100, 125, and 150 mg/kg bw/day of nickel sulphate
hexahydrate. Because of significant weight loss in males at the high
doses early in the study, the 125 and 150 mg/kg bw/day doses were
reduced to 30 and 15 mg/kg bw/day, respectively, on day 28 for males
only. One female rat in the 150mg/kg bw/day group was found dead on
study day 44, the cause of death could not be established. Clinical
observations included post-dosing salivation and decreased activity,
most pronounced during the first two weeks and in the highest dose
groups. A variety of statistically decreased absolute or increased
relative organ weights were noted in the treated rats. These effects
were not accompanied by histopathological changes. The only significant
adverse effects seen in this study were weight loss in all dosed groups
(8-13% lower body weight compared to controls). No notable macroscopic
or microscopic changes were observed. There was no dose level without
effect on body weight. Therefore, the LOAEL was 30 mg/kg bw/day (reduced
from 125 mg/kg bw/day at day 28) for males and 50 mg/kg bw/day for
females. The values correspond to 21.1 and 35.15 mg nickel
hydrogencitrate/kg bw/day in males and females, respectively.
The same authors (Heim et al. 2007) reported
a two-year oral (gavage) OECD 451 carcinogenicity study with nickel
sulphate hexahydrate in Fischer rats. Groups of 60 male and 60 female
rats were dosed with 0, 10, 30 and 50 mg/kg bw/day of nickel sulphate
hexahydrate once daily for 104 weeks. In males a statistically
significant and dose-related reduced body-weight gain was observed in
the dosed groups (5%, 11%, and 12% respectively) compared to the control
group. Similarly, in females a dose-related reduced body weight gain
(4%, 8% and 10% respectively) was observed when compared to controls but
only achieved statistical significance in mid- and high-dose females.
The reduced body weight gain had no correlation with the amount of food
consumed. Survival of the females was reduced in a dose related manner
and reached the level of statistical significance at the two highest
dose levels. The mortality rates for the females at the end of the study
were 23%, 33%, 43% and 45% at 0, 10, 30 and 50 mg/kg bw/day of nickel
sulphate hexahydrate, respectively. There was no apparent
treatment-related effect on survival in males (mortality rates 60%, 48%,
50% and 57% at 0, 10, 30 and 50 mg/kg bw/day of nickel sulphate
hexahydrate, respectively). No non-neoplastic microscopic findings,
which could be attributed to administration of the test substance, were
Long-term studies of toxicity after oral
exposure have been conducted in rats, mice and dogs. Mainly non-specific
indications of toxicity, such as decreased survival and decreased body
weight, have been observed. In addition, increased urinary albumin
(indicator of diminished kidney function), mild tubular nephrosis
(Vyskocil et al. 1994), as well as immunosuppressive effects (Dieter et
al. 1988) have been observed.
No reliable data available.
The EU-RAR states 13 studies on repeated
dose toxicity via inhalation in rats and mice.
In the study by Dunnick et al. (1989),
groups of ten males and ten female F344/N rats were exposed to nickel
sulphate hexahydrate in concentrations of 0, 0.12, 0.25, 0.5, 1, or 2
mg/m3, 6h/day, 5 days per week for 13 weeks. Additional
groups of five male and female rats were exposed to nickel sulphate
hexahydrate in concentrations of 0, 0.12, 0.5, or 2 mg/m3 for
tissue burden studies (For details refer to IUCLID chapter 7.1.). In
this study, one high dose male 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
neutrophile and lymphocyte numbers occurred and were most pronounced in
female rats. With the exception of low dose rats, 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. Atrophy of the olfactory
epithelium occurred in males and females exposed to 1 and 2 mg nickel
sulphate hexahydrate/m3. The NOAEC/LOAEC for inflammation is
0.25/0.5 mg/m3nickel sulphate hexahydrate. These values
correspond to 0.18 and 0.36 mg Trinickel dicitrate/m3,
The rat appears more sensitive than the
mouse to the toxic effects after inhalation exposure. The respiratory
system was the primary target organ with severe effects occurring in
both the lungs (chronic inflammation and fibrosis) and the nose (atrophy
of olfactory epithelium).
Dieter MP, Jameson CW, Tucker AN, Luster MI,
French JE, Hong HL, Boorman GA (1988): Evaluation of tissue disposition,
myelopoietic, and immunological responses in mice after long-term
exposure to nickel sulfate in the drinking water. J. Toxicol. Environ.
Health 24: 357-372.
Vyskočil A, Viau C, Cĭžková M (1994b):
Chronic nephrotoxicity of soluble nickel in rats. Human & Exp Tox
There are conclusive data available, but
they are not sufficient for classification.
Based on the available data, nickel
hydrogencitrate has to be calssified:
CLP: STOT repeated exposure category 1
(respiratory tract, inhalation)
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