Nickel(III) oxy hydroxide

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

A summary document is attached in sections 7.8.1, 7.8.2, and 7.10.2 of IUCLID and in Appendix B5 of the CSR discussing human assessments of reproductive impairment associated with soluble nickel exposures as a worst case scenario.  In summary, a reproductive study of female refinery workers in Russia has not demonstrated an association between relatively high soluble nickel exposures (worst case scenario with higher blood and urinary levels) and the following reproductive outcomes: genital malformations (hypospadias and cryptorchidism), spontaneous abortions, small-for-gestational-age newborns, and skeletal malformations (see IUCLID section 7.10.2: Vaktskjold et al., 2006, 2007, 2008a&b).

Effect on fertility: via oral route

Dose descriptor:

NOAEL

10 mg/kg bw/day

Additional information

According to the 2008/2009 European Union Risk Assessment for Nickel (Human Health section, p. 207):

There are no studies with metallic nickel with respect to reproductive toxicity. The developmental toxicity of nickel compounds is related to the systemic available nickel and therefore the effect should be considered as relevant for metallic nickel as well. However, the potential release and absorption of nickel from metallic nickel is substantially lower than for the soluble compounds via all routes, and the C&L Health Effects Working Group have agreed that metallic nickel should not be classified for this effect.

 

The same concept applies to Ni oxyhydroxide. As the oral bioaccessibility of Ni oxyhydroxide is comparable to Ni dihydroxide animal toxicokinetic data are read-across from Ni dihydroxide. The data clearly demonstrate that the oral absorption of nickel is significantly lower than from more soluble forms of nickel and strongly infers that oral exposure to nickel oxyhydroxide will not allow enough absorption to exceed the threshold for fertility effects. Data from a reproductive toxicity study with Ni sulphate hexahydrate (SLI, 2000b) combined with acute oral toxicity data of Ni dihydroxide (EPSL, 2009a) will be used to meet the data requirements. In addition, a 13-week inhalation study with nickel sulphate hexahydrate conducted by Dunnick et al (1989) did not identify any adverse effects on sperm and oestrus cycle at exposure levels as high as 0.45 mg Ni/m³. 

Short description of key information:
There are no data available on the effect of Ni oxyhydroxide on fertility. Data from a reproductive toxicity study with Ni sulfate hexahydrate (SLI, 2000b) combined with acute oral toxicity data of Ni dihydroxide (EPSL, 2009a) provide sufficient justification that nickel oxyhydroxide would not cause effects on fertility.

Effects on developmental toxicity

Description of key information

There are no data available on the developmental toxicity of Ni oxyhydroxide. Data from a reproductive toxicity study with Ni sulfate hexahydrate (SLI, 2000b) combined with acute oral toxicity data of Ni dihydroxide (EPSL, 2009a) provide sufficient information regarding the developmental toxicity of nickel oxyhydroxide. Ni oxyhydroxide is not expected to cause developmental toxicity and should not be be classified as Repro.1B, H360D. But there is no change to the existing classification proposed in this registration file.

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

10 mg/kg bw/day

Additional information

Data from a reproductive toxicity study with Ni sulfate hexahydrate (SLI, 2000b) combined with acute oral toxicity data of Ni dihydroxide (EPSL, 2009) provide sufficient information regarding the reproductive and developmental toxicity of Ni oxyhydroxide. A comprehensive read-across program based on bioaccessibility data in synthetic fluids and in vivo acute oral toxicity data has been conducted on a series of Ni substances including Ni oxyhydroxide. The results of this program and the evaluation of the studies conducted with Ni sulfate hexahydrate suggest that Ni oxyhydroxide should not be classified as Repro. 1B, H360D.

While no change to the existing classification is proposed within this registration file, a complete summary of the testing program including results and discussion are provided in Section 7.8 of IUCLID and as Appendix B1 in this CSR.

According to the 2008/2009 European Union Risk Assessment for Nickel (Human Health section, p. 207):

There are no studies with metallic nickel with respect to reproductive toxicity. The developmental toxicity of nickel compounds is related to the systemic available nickel and therefore the effect should be considered as relevant for metallic nickel as well. However, the potential release and absorption of nickel from metallic nickel is substantially lower than for the soluble compounds via all routes, and the C&L Health Effects Working Group have agreed that metallic nickel should not be classified for this effect.

The same concept applies to Ni oxyhydroxide. Animal toxicokinetic data and results of a recently completed acute oral toxicity study on Ni dihydroxide clearly demonstrate that the oral absorption of nickel from nickel dihydroxide is significantly lower than from more soluble forms of nickel and strongly infers that oral exposure to nickel dihydroxide will not allow enough absorption to exceed the threshold for developmental toxicity.

Based on the data on oral bioaccessibility of Ni oxyhydroxide the data of Ni dihydroxide can be used for read-across to Ni oxyhydroxide leading to the assumption that there is not enough absorption of Ni to exceed the threshold for developmental toxicity. Therefore Ni oxyhydroxide is not expected to cause developmental toxicity.

Toxicity to reproduction: other studies

Additional information

A reproductive study of female refinery workers has not demonstrated an association between relatively high soluble nickel exposures (worst case scenario with higher blood and urinary levels) and the following reproductive outcomes: genital malformations (hypospadias and cryptorchidism), spontaneous abortions, small-for-gestational-age newborns, and skeletal malformations(Vaktskjoldet al., 2006, 2007, 2008a&b).  Genital malformations are considered as one of the most sensitive endpoints for human developmental toxicity while spontaneous abortions may be the closest human equivalent outcome to the effects seen in animals. The geometric means of the workers’ exposures in this study ranged from 0.03-0.084 mg Ni/m³in the low exposure group to 0.15-0.33 mg Ni/m³in the high exposure group. 

 

These data demonstrate that a weight-of-evidence approach to the evaluation of reproductive toxicity of nickel substances is needed. While a reproductive “hazard” from nickel exposure can be demonstrated in animals, there is no demonstrable “risk” of reproductive impairment in the single female occupational cohort that can be confirmed to have been consistently exposed to high levels of nickel. Consequently, the risk of reproductive impairment from occupational nickel exposure is exceedingly small and the risk for the general population is almost non-existent.

Justification for classification or non-classification

A comprehensive read-across program based on bioaccessibility data in synthetic fluids and in vivo acute oral toxicity data has been conducted on a series of Ni substances including Ni dihydroxide and Ni oxyhydroxide. The results of this program suggest that Ni dihydroxide should not be classified as Repr. 1B;H360D. While no change to the existing classification is proposed within this registration file, a complete summary of the testing program including results and discussion are provided in Section 7.8 of IUCLID and as Appendix B1 in the accompanying CSR. Because there are no data to disprove the toxicity to reproduction Ni oxyhydroxide is classified as Repro.1B;H360D as worst case assumption.