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Description of key information

ORAL: The outcome of a read-across assessment based on bioaccessibilty indicates that Nickel oxyhydroxide could be read-across from Nickel dihydroxide. 
In a GLP, guideline-based study, the acute oral LD50 of Nickel dihydroxide was determined to be 5,000 mg/kg body weight (95% PL confidence interval of 3,390 mg/kg to 5,800 mg/kg).
INHALATION: The outcome of a recently completed read-across assessment based on bioaccessibility and in vivo animal data for various nickel compounds indicates that Nickel dihydroxide should be read-across from Nickel oxide. According the read-across assessment and the data on bioavailability Nickeloxyhydroxide could also be read-across from Nickeloxide.
DERMAL: No risk characterisation will be conducted for acute dermal toxicity, following the approach taken in the European Union Risk Assessment for Nickel and Nickel Compounds (2008-2009). Acute systemic effects are not relevant due to the very low dermal absorption of nickel. Although nickel dihydroxide carries a classification as “irritant” (Xi; R38 at concentrations above 20%; Skin Irrit. 2:H315 in the 1st ATP to the CLP Regulation), more recent data (EPSL 2008a) do not support this classification. In either case, the long term DNEL based on prevention of dermal sensitization will be sufficiently protective from any possible acute local dermal effects associated with exposure to nickel dihydroxide.The same is applicable for Ni oxyhydroxide.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Dose descriptor:
LD50
Value:
5 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Dose descriptor:
LC50
Value:
5 080 mg/m³

Additional information

A comprehensive read-across assessment for acute oral toxicity was recently completed based on the bioaccessibility data in simulated gastric fluid of thirteen nickel compounds combined within vivoverification data for eleven source nickel substances (IUCLID section 7.2.1 and Appendix B1 of this CSR).The bioaccessibility of Ni in the target substance Nickeloxyhydroxide was tested in simulated gastric fluid but not proven inin vivostudies, as all Nickel oxides are far beyond classification.The LD50 of the Nickel compounds shown to release < 30% nickel ions in the bioaccessibility studies is much higher than the limit dose. Therefore no oral acute toxicity test was conducted for Ni oxyhydroxide which releases 29.38 %. The bioaccessibility approach enables grouping of target Ni substances for classification purposes according to bioaccessibility in simulated gastric fluid. Samples releasing <48% nickel ion in gastric fluid can be read-across to 2 source compounds (Nickel oxide green and Nickel subsulfide). These substances would carry no classifications for the endpoints of oral and reproductive toxicity. Substances belonging to this group are Nickel hydroxide, Nickel oxyhydroxide and Nickel sulfide.The outcome of this assessment indicates that Ni oxyhydroxide could be read-across from Ni dihydroxide.

Two studies investigating acute oral toxicity of Ni dihydroxide were chosen to read-across to Ni oxyhydroxide. Both studies identified evaluated mortality as the primary endpoint. The most robust study characterizing such was conducted by EPSL (2009a). In this GLP, guideline-based study (OECD Guideline #425), the acute oral LD50 was determined in female rats using the up and down procedure. Statistical evaluation of mortality data resulting from exposures ranging from 3,200 to 6,000 mg/kg indicated an oral LD50 of 5,000 mg/kg body weight (95% PL confidence interval of 3,390 mg/kg to 5,800 mg/kg). In addition to mortality, animals exposed to 5,000 mg/kg nickel dihydroxide or higher exhibited clinical and behavioral adversities as well as discolored intestines upon necropsy. Reagan (1996) also evaluated the acute oral toxicity in young rats. Animals were exposed to single doses ranging from 1000 mg/kg to 5000 mg/kg (five dose groups) and monitored for up to 15 days. Resulting oral LD50 values were 1515 mg/kg, 1565 mg/kg, and 1540 mg/kg in males, females, and both sexes combined, respectively. Therefore, the most relevant study to characterize acute toxicity of Ni dihydroxide and to read-across to Ni oxyhydroxide is the EPSL (2009a). This study indicated that the LD50 associated with oral exposure is 5,000 mg/kg in rats.

A comprehensive read-across assessment for inhalation toxicity was recently completed based on bioaccessibility data in synthetic lung fluids of various nickel compounds combined with in vivo verification data for three source nickel substances. The bioaccessibility-based paradigm presented in a summary document in Section 7.2.2 and in Appendix B2 of this CSR enables grouping of target Ni substances for classification purposes according to bioaccessibility in interstitial fluid. Oxidic nickel compounds that release less than 1% Ni per gram sample in interstitial fluid could be read-across from green Ni oxide and hence carry no classification for acute inhalation toxicity. Nickeloxyhydroxide releases only 0.72 % Ni per gram sample in interstitial fluid and thus can be read-across from green Nickel oxide and Ni dihydroxide. The LC50 of Ni oxide was determined to be 5.08 mg/l (EPSL, 2009b).

There are no available data to evaluate acute dermal toxicity of Ni oxyhydroxide. However, acute toxicity is expected to be low in view of the poor absorption by this route. In addition, please note the following in regards to REACH endpoint requirements identified in Column 2 of the REACH Annex VIII which state,

"in addition to the oral route (8.5.1), for substances other than gases, the information mentioned under 8.5.2 to 8.5.3 [inhalation and dermal acute toxicity] shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure. If there is only one route of exposure, information for only that route need be provided”.  The rules for adaptation also state that, “Testing by the dermal route is appropriate if…(1) inhalation of the substance is unlikely…”.  

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.

Justification for classification or non-classification

A recently completed in vivo acute oral toxicity study concluded that Ni dihydroxide has an LD50=5,000 mg/kg suggesting it should not be classified for this endpoint. Based on the results of the bioaccessibility studies in simulated gastric fluid this data can be read-across to Ni oxyhydroxide.

 

Data from a recently conducted read-across assessment concluded that Ni dihydroxide may not warrant the existing harmonized classification according to the 1st ATP to the CLP Regulation. Although application of this read-across paradigm suggests no classification for acute inhalation toxicity is warranted, the in vitro data are not sufficient to justify declassification of Ni dihydroxide for this endpoint and no proposal for a change in classification is extended at this time. A summary of this program is provided in Section 7.2.2 of IUCLID and as Appendix B2 to the CSR. The current harmonized classification of Ni dihydroxide is read across to Ni oxyhydroxide.

 

Ni dihydroxide is not classified for acute dermal toxicity according to the 1st ATP to the CLP Regulation. This data is read-across to Ni oxyhydroxide.