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Description of key information

NOAEL = 7.02 mg/kg bw Trinickel dicitrate
LOAEL = 21.1 mg/kg bw Trinickel dicitrate
NOAEC = 0.159 mg/m3 Trinickel dicitrate
LOAEC = 0.368 mg/m3 Trinickel dicitrate

Key value for chemical safety assessment

Additional information

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 detail here.


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 observed.


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, respectively.


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 13:689-693.

Justification for classification or non-classification


There are conclusive data available, but they are not sufficient for classification.


Based on the available data, nickel hydrogencitrate has to be calssified:

EU: R48/23

CLP: STOT repeated exposure category 1 (respiratory tract, inhalation)