Nickel bis(dihydrogen phosphate)

Endpoint summary

Description of key information

Value used for CSA (read-across from Nickel sulphate or Nickel ion):

NOAEL (oral, systemic, animal): 100 mg NiSO₄.6H₂O/kg bw(22 mg Ni/kg bw/day) (FDRL, 1983)

LOAEL (oral, systemic, human data): 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): 0.53 mg NiSO₄.6H₂O/L air (120 mg Ni/m³) (EPSL, 2009b)

LOAEC (inhalation, local, animal data): 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.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Additional information

No reliable studies were available to characterize the acute oral toxicity of nickel bis(dihydrogen phosphate), so data on acute inhalation toxicity of Ni bis(dihydrogen phosphate) are read-across from Ni sulphate study. A comprehensive read-across assessment was recently completed based on bioaccessibility data in synthetic gastric fluid of various nickel compounds combined in vivo verification data for three source nickel substances. The read-across paradigm presented in a summary document in IUCLID Section 7.2.1 and Appendix B1 of the CSR enables grouping of target Ni substances for classification purposes according to bioaccessibility in gastric fluid as demonstrated. This assessment supports that Ni bis(dihydrogen phosphate) should be read-across from Ni sulphate for acute oral toxicity, based on similar bioaccessibility data after 2 hours in gastric fluid: % nickel content release by nickel sulphate and nickel bis(dihydrogen phosphate) was 95.6% and 93.4%, respectively. Ni sulphate hexahydrate has been shown to have an acute oral LD₅₀ of 361.9 mg NiSO₄/kg/bw (EPSL, 2009a) and a NOAEL of 100 mg NiSO₄.6H2O/kg (or 22 mg Ni/kg) (FDRL, 1983). Therefore, application of this read-across paradigm suggests that Ni bis(dihydrogen phosphate)should be classified as Acute Tox 4; H302. 

 

No reliable studies were available to characterize the acute inhalation toxicity of nickel bis(dihydrogen phosphate), so data on acute inhalation toxicity of Ni bis(dihydrogen phosphate) 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. The read-across paradigm presented in a summary document in IUCLID 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. This assessment supports that Ni bis(dihydrogen phosphate) should be read-across from Ni sulphate for acute inhalation toxicity based on use of Ni sulphate as a worst case scenario and the most conservative estimate of potential respiratory 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, 2009b). Therefore, application of this read-across paradigm suggests that Ni bis(dihydrogen phosphate)should be classified as Acute Tox 4; H332.

 

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: Data are read-across from Ni sulphate. In a GLP, guideline-based study, the acute oral LD₅₀ of Ni sulphate was determined in female rats using the up and down procedure. Statistical evaluation of mortality data resulting from exposures ranging from 159 to 2000 mg/kg indicated an oral LD₅₀ of 361.9 mg/kg body weight. These newly generated data demonstrate via read-across that Ni bis(dihydrogen phosphate) should be classified as Acute Tox. 4; H302.

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 bis(dihydrogen phosphate) 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 bis(dihydrogen phosphate) 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 bis(dihydrogen phosphate) has not previously been classified for acute oral or inhalation toxicity in the EU. However, comprehensive read-across assessments were recently completed based on bioaccessibility data in synthetic gastric and lung fluids of various nickel compounds combined in vivo verification data for three source nickel substances. The read-across paradigms presented in summary documents in Appendix B1 and Appendix B2 of the CSR enables grouping of target Ni substances for classification purposes according to bioaccessibility in gastric, interstitial and/or lysosomal fluid as demonstrated. The outcome of this assessment indicates that Ni bis(dihydrogen phosphate) should be read-across from Ni sulphate for acute oral and inhalation toxicity. Therefore, application of this read-across paradigm suggests that Ni bis(dihydrogen phosphate) should be classified as Acute Tox 4; H302 and H332.