Dialuminium nickel tetraoxide

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 the Appendix 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 (Vaktskjold et al., 2006, 2007, 2008a&b).

Additional information

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

"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 aluminate, as well as to the read-across substance Ni oxide. Animal toxicokinetic data clearly demonstrate that the oral absorption of nickel from the read-across substance nickel oxide is significantly lower than from soluble forms of nickel and strongly infers that oral exposure to nickel oxide will not allow enough absorption to exceed the threshold for reproductive effects. Data from a reproductive toxicity study with Ni sulfate hexahydrate (SLI, 2000b) combined with toxicokinetic data (Ishimatsu et al. 1995) will be used to meet the data requirements.

Short description of key information:
Data from a reproductive toxicity study with the read across subtance Ni sulfate hexahydrate (SLI, 2000b) combined with toxicokinetic data with the read across substance Ni oxide (Ishimatsu et al. 1995) provide sufficient justification that nickel aluminate should not be considered a reproductive toxicant.

Effects on developmental toxicity

Description of key information

Data from a reproductive toxicity study with the read across substance Ni sulfate hexahydrate (SLI, 2000b) combined with toxicokinetic data with the read across substance Ni oxide (Ishimatsu et al. 1995) provide sufficient justification that nickel oxide should not be considered a developmental toxicant.

Additional information

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

"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 aluminate, as well as to the read across substance Ni oxide. Animal toxicokinetic data clearly demonstrate that the oral absorption of nickel from the read across substance nickel oxide is significantly lower than from soluble forms of nickel and strongly infers that oral exposure to nickel oxide will not allow enough absorption to exceed the threshold for reproductive effects. Data from a reproductive toxicity study with Ni sulfate hexahydrate (SLI, 2000b) combined with toxicokinetic data (Ishimatsu et al. 1995) will be used to meet the data requirements.

In addition, a single study was identified characterizing developmental toxicity associated with exposure to the read across substance nickel oxide in rats. No studies characterizing reproductive or teratogenic effects were found in the literature. Weischer et al (1980) evaluated the effects of a continuous, 21-day gestational inhalation exposure to NiO (unspecified calcining temperature or color) aerosols (0.8, 1.6 and 3.2 mg/m3) in rats. On gestation day 21, fetuses and fetal blood, as well as maternal blood, serum and urine were collected and evaluated for changes in body weight, organ weight, hematological assessments, urinalysis, various clinical chemistry assays, and fetal survival. Exposure related effects including significant reductions in body weight, wet weights of kidneys and lungs, hematocrit, MCV, leukocytes, and erythrocyte count were noted in maternal rats. In fetuses, body weights were reduced and leukocytes and urea in serum were increased. These data suggested that both maternal and developmental toxicities occurred in a dose-dependent fashion following a 21-day gestational inhalation exposure to NiO aerosols. However, because this study only evaluated hematological and clinical chemistry endpoints, only evaluated a single (though relevant) route of exposure, and only evaluated a single species, it is not sufficient to fully characterize potential developmental, reproductive, and/or teratogenic effects associated with exposure to nickel oxide.

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 (Vaktskjold et 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

Based on analogy approach, the available data are conclusive but not sufficient for classification.

Based on a self-classification, Ni aluminate is not classified for reproductive toxicity, developmental toxicity and teratogenicity.