Nickel sulphate

Endpoint summary

Description of key information

Value used for CSA:

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 adequate 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.  See Appendix C3 for more information.

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

Additional information

Two independent acute oral toxicity studies in rats exist for nickel sulphate hexahydrate (Nickel sulphate hexahydrate is the most water-soluble form, which results in the highest systemic concentration).

The EPSL (2009) study is a high quality, well-documented study reporting an LD50 for acute oral toxicity of 361.9 mg NiSO₄•6H₂O/kg in female rats. A much older high quality study (using a protocol that was removed from use in 2002) by FDRL (1983) found an LD50 for acute oral toxicity of 325 mg NiSO₄•6H₂O/kg for males and 275 mg NiSO₄•6H₂O/kg for females. The LD50s in this older study were estimated using a hand-drawn plot on graph paper.  With more technical tools now available, more accurate calculation using the raw data for this study in the toolhttps://www.aatbio.com/tools/ld50-calculator resulted in LD50s of 325 mg NiSO₄•6H₂O /kg for males, 281 mg NiSO₄•6H₂O/kg for females, and 319 mg NiSO₄•6H₂O /kg for males and females combined.

 

The following should be considered in using a weight of evidence approach to derive the acute oral toxicity classification:

1. Data for females from the two independent studies (361.9 mg NiSO₄•6H₂O/kg and 281 mg NiSO₄•6H₂O/kg), the average value (321.4 mg NiSO₄•6H₂O /kg) is greater than the 300 mg/kg cutoff value for category 3, making it category 4 for acute oral toxicity classification.

2. Data for females and males combined in the FDRL study also supports category 4 acute toxicity classification, with the value of 319 mg NiSO₄•6H₂O/kg being higher than the cutoff value for category 3. Because the number of deaths of males and females varied at different doses, the value cannot simply be averaged, and must be calculated using the raw data from both genders.

Taken together, the data from the two independent studies support an acute oral toxicity LD50 of over 300 mg/kg leading to a classification of acute oral tox category 4. This classification is consistent with the current European Union harmonized acute toxicity classification of the same category. A background document describing the use of Ni sulphate as a source substance for read-across to other nickel compounds for acute oral toxicity has been attached to Section 7.2.1 of IUCLID and included in the CSR as Appendix B1. 

An LC₅₀ for acute inhalation toxicity of 2.48 mg NiSO₄.6H₂O/L air for males and females has been identified from the EPSL (2009b) study. A background document describing the use of Ni sulphate as a source substance for read-across to other nickel compounds for acute inhalation toxicity has been attached to Section 7.2.2 and included in the CSR as Appendix B2.

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:

ACUTE ORAL TOXICITY: An LD₅₀ for acute oral toxicity of over 300 mg NiSO₄.6H₂O was identified from the EPSL (2009a) and FDRL (1983) studies. A NOAEL for acute oral toxicity of 100 mg NiSO₄.6H₂O/kg bw (22 mg Ni/kg bw/day) was identified from the FDRL (1983) study and can be used for the risk characterization.

ACUTE INHALATION TOXICITY: An LC₅₀ for acute inhalation (systemic) toxicity of 2.48 mg NiSO₄.6H₂O/L air and a NOAEC was identified as 0.53 mg NiSO₄.6H₂O/L air (120 mg Ni/m³) from the EPSL(2009b) study. A LOAEC for acute inhalation (local) toxicity of 0.7 mg Ni/m³ was idendified from the Benson et al (1988) 16-day repeated dose study (no adequate acute data was available).

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

A newly conducted GLP OECD guideline compliant study reported an LD₅₀=361.9 mg/kg for Ni sulphate hexahydrate. An older FDRL (1983) study had a newly calculated LD50 of 319 mg/kg for Ni sulphate hexahydrate. Taken together, both studies support classification for acute oral toxicity as Acute Tox. 4; H302 under the 1st ATP to the CLP Regulation (EPSL, 2009a). 

 

As data were not available at the time of classification, the European Union Risk Assessment based the classification for acute inhalation toxicity on read-across from the oral data. However, a newly conducted GLP OECD guideline compliant study reported an LC₅₀=2.48 mg/L for Ni sulphate hexahydrate, which confirm the classification as Acute Tox. 4: H332 for acute inhalation toxicity under the 1st ATP to the CLP Regulation (EPSL, 2009b).