Registration Dossier

Administrative data

Description of key information

Value used for CSA:

NOAEL (oral, systemic, animal): 550 mg/kg bw(96 mg Ni/kg bw/day) (EPSL, 2008)

LOAEL (oral, systemic, human data; read-across): 0.012 mg Ni (Ni ion)/kg bw/day released from metallic nickel in water and food contact material (Nielsen et al 1999)

NOAEC (inhalation, systemic, animal; read-across): 0.53 mg NiSO4.6H2O/L air (120 mg Ni/m3) (EPSL, 2009)

LOAEC (inhalation, local, animal; read-across): 0.7 mg Ni/m3(DNEL calculation is based on 16-day repeated dose study-Benson et al, 1988; no acute data was available)

An acute local inhalation DNEL is derived based on the lung effects (e.g. lung inflammation) associated with nickel sulphate inhalation.  The shortest-term study available examining those effects in animals is a 16-day repeated exposure study.  An adjustment factor was derived to extrapolate the results from the repeated exposure study to an equivalent effect concentration in a 4 hr acute exposure.  SeeAppendix C3for more information.

(Oral, local values are not applicable; Dermal, local or systemic, values are not applicable)

Key value for chemical safety assessment

Additional information

Two studies were available to characterize the acute toxicity of nickel sulphamate, both studies reported on lethality following oral exposure. However, only the information provided by EPSL (2008) was of high quality and reliability; the full study report was not available for the other studies and thus the data was difficult to interpret (NRC 1952, NIOSH 2008).

EPSL (2008) conducted an OECD guideline-based acute toxicity up and down procedure in female rats in an effort to estimate the oral LD50. To do so, nickel sulphamate crystals (nickel sulphamate tetrahydrate) were administered via oral gavage as a 60% w/w mixture in distilled water to seven female animals at doses of 175, 550, 2000 mg/kg (administered in this sequence according to the guideline). Animals exposed to 175 or 550 mg/kg of the test substance survived, gained weight, and generally did not demonstrate any signs of gross toxicity, adverse effects, or abnormal behavior throughout the 14-day observation period. All three animals exposed to 2000 mg/kg died within three hours. The oral LD50 was calculated using the maximum likelihood method and was estimated to be 1098 mg/kg body weight in female rats (95% CI of 550 mg/kg to 2000 mg/kg).

Data on acute inhalation toxicity of Ni sulphamate are read-across from Ni sulphate. A comprehensive read-across assessment was recently completed based on bioaccessibility data in synthetic lung fluids of various nickel compounds combined in vivo verification data for three source nickel substances (Henderson et . al, 2014). The read-across paradigm presented in a summary document in Section 7.2.2 and Appendix B2 of the CSR enables grouping of target Ni substances for classification purposes according to bioaccessibility in interstitial fluid as demonstrated. The outcome of this assessment indicates that Ni sulphamate should be read-across from Ni sulphate for acute inhalation toxicity. Ni sulphate hexahydrate has been shown to have an acute inhalation LC50 of 2.48 mg NiSO4/L and a NOAEC of 0.53 mg NiSO4.6H2O/L air (120 mg Ni/m3) (EPSL, 2009). Therefore, application of this read-across paradigm suggests that Ni sulphamate should be classified as Acute Tox 4; H332.

Information regarding the acute toxicity of nickel (II) sulphamate following intraperitoneal (i. p.) exposure was also reported as raw data in a publication summarizing biological tests (NRC 1952, NIOSH 2008). The International Nickel Company submitted the raw data used in the NRC summary table. In early 2009, company representatives were contacted for verification of the raw data; however, the company was not able to provide any supporting documents or primary reports in relation to the data included in the 1952 NRC publication. Thus, information was limited to that primarily provided by the NRC publication, which was a secondary source. NRC (1952) only provided mortality findings but did not provide information regarding study design, species, dosing, etc. and thus interpretation of the data provided is difficult. Mortality data reported indicated that mice were exposed intraperitoneally to 31.3 to 500 mg/kg nickel (II) sulphamate (5 doses total); no animals died in the three low dose groups (31.3, 62.5 and 125 mg/kg), two of three animals died in the 250 mg/kg dose group, and all five animals died in the 500 mg/kg group. No i. p. LD50, or other interpretation of the data was reported. The usefulness of this data is very limited given (a) the lack of information available from primary sources, and (b) intraperitoneal exposure is not a relevant route of exposure for this compound.

There are no available data on which to evaluate acute dermal toxicity. However, acute toxicity is expected to be low in view of the poor absorption by this route. As oral and inhalation routes of exposure are more relevant and data for these have been provided. Testing for acute dermal toxicity is therefore waived based on this information.

The following information is taken into account for any hazard / risk assessment:

ORAL: In a GLP, guideline-based study, the acute oral LD50 of Ni sulphamate was determined in female rats using the up and down procedure. Statistical evaluation of mortality data resulting from exposures ranging from 175 to 2000 mg/kg indicated an oral LD50 of 1098 mg/kg body weight and a NOAEL of 550 mg/kg (or 96 mg Ni/ kg bw/day). Based on this newly generated data, Ni sulphamate now has a harmonized classification as Acute Tox. 4; H302 according to the 14th ATP to the CLP Regulation.

INHALATION: Data are read-across from Ni sulphate. The outcome of a recently completed read-across assessment based on bioaccessibility and in vivo animal data for various nickel comounds indicates that Ni sulphamate should be read-across from Ni sulphate for acute inhalation toxicity. Ni sulphate hexahydrate has been shown to have an acute inhalation LC50 of 2.48 mg NiSO4/L and a NOAEC of 0.53 mg NiSO4.6H2O/L air (120 mg Ni/m3)

Therefore, application of this read-across paradigm suggests that Ni sulphamate should be classified as Acute Tox 4; H332.

DERMAL: No risk characterisation will be conducted for acute dermal toxicity. Acute systemic effects are not relevant due to the very low dermal absorption of nickel. Acute local effects are covered by the long term DNEL based on prevention of dermal sensitization.

Justification for classification or non-classification

Ni sulphamate has not previously been classified for acute oral or inhalation toxicity in the EU. However, a recently completed OECD-guideline compliant study reported an oral LD50=1098 mg/kg Ni sulphamate. Based on this newly generated data, Ni sulphamate now has a harmonized classification as Acute Tox. 4; H302 according to the 14th ATP to the CLP Regulation.

In addition, a comprehensive read-across assessment was recently completed based on bioaccessibility data in synthetic lung fluids of various nickel compounds combinedin vivoverification data for three source nickel substances. The read-across paradigm presented in a summary document in Section 7.2.2 andAppendix B2of the CSR enables grouping of target Ni substances for classification purposes according to bioaccessibility in interstitial and/or lysosomal fluid as demonstrated. The outcome of this assessment indicates that Ni sulphamate should be read-across from Ni sulphate for acute inhalation toxicity. Therefore, application of this read-across paradigm suggests that Ni sulphamate should be classified as Acute Tox 4; H332.