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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 (Vaktskjold et al., 2006, 2007, 2008a&b).
Effect on fertility: via oral route
Dose descriptor:
NOAEL
5.1 mg/kg bw/day
Effect on fertility: via inhalation route
Dose descriptor:
NOAEC
1 mg/m³
Additional information

Due to the structural similarities of Pentanickel Octahydroxide Carbonate and Nickel Hydroxycarbonate, all information in this section is relevant for Pentanickel Octahydroxide Carbonate (see section 13 for full discussion of read-across strategy).

No studies evaluating toxicity to reproduction associated with nickel hydroxycarbonate were identified. 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 hydroxycarbonate (Appendices B1 and B2). The results of this program suggest that Ni hydroxycarbonate should be read-across from Ni sulphate only fororalsystemic exposure. This read-across is considered to be a conservative estimate for the potential toxicity of Ni hydroxycarbonate as the oral absorption of Ni ion from Ni hydroxycarbonate is likely to be lower than from Ni sulphate. This is supported by findings from acute oral toxicity studies where the NOAEL of Ni hydroxycarbonate was found to be significantly higher than that of Ni sulphate (EPSL, 2009). A background document summarizing available human data on developmental and reproductive toxicity of soluble Ni compounds is attached in Sections 7.8.1 and 7.8.2 of IUCLID and in Appendix B5 of the CSR.

Endpoint Summary Information from the 2008/2009 European Union Risk Assessment for Nickel Sulphate:

Two oral multi-generation reproduction studies and a range-finding one-generation study of nickel sulphate are available (Ambrose et al. 1976, SLI 2000a, SLI 2000b). No effects on fertility have been found in these studies following oral administration; no data are available for inhalation and dermal contact. The study by Ambrose et al. (1976) and the one-generation range-finding study (SLI 2000a) indicate NOAELs of 52-80 mg Ni/kg bw/day and 16.8 mg Ni/kg bw/day, respectively. However, the Ambrose et al. study has a limited reporting of data and the range-finding study uses only a limited number of animals (8 per group). Therefore, the most reliable NOAEL is from the recent OECD TG 416 two-generation study (SLI 2000b) where the NOAEL is the highest dose investigated, i. e. 2.2 mg Ni/kg bw/day. This value is taken forward to the risk characterization; however, it should be considered that the NOAEL is probably higher.


Short description of key information:
No effects on fertility have been found in studies following oral administration with Ni sulphate; no data are available for inhalation and dermal contact. Data regarding effects on fertility are read-across from Ni sulphate. The most reliable NOAEL is from the two-generation study (SLI 2000b) where the NOAEL is the highest dose investigated, i. e. 2.2 mg Ni/kg bw/day. A repeated dose toxicity study provides a NOAEL for effects on sperm and oestrus cyclicity of 0.45 mg Ni/m3 for inhalation exposure (Dunnick et al., 1989).

Effects on developmental toxicity

Description of key information
Data regarding developmental toxicity are read-across from Ni sulphate. No standard prenatal developmental toxicity studies with Ni-sulphate via either the oral or inhalation routes were located. Based on an interpretation in the 2008/2009 European Union Risk Assessment of Nickel Sulphate of an equivocal increase in postimplantation/perinatal lethality in F1 generation in the two-generation study (SLI 2000b) at 2.2 mg Ni /kg bw/day, the NOAEL used for developmental toxicity is set at 1.1 mg Ni/kg bw/day.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
2.54 mg/kg bw/day
Additional information

No studies evaluating toxicity to reproduction associated with nickel hydroxycarbonate were identified. A comprehensive read-across program based on bioaccessibility data in synthetic fluids andin vivoacute oral toxicity data has been conducted on a series of Ni substances including Ni hydroxycarbonate. The results of this program suggest that Ni hydroxycarbonate should be read-across from Ni sulphate for oral systemic exposure. This read-across is considered to be a conservative estimate for the potential toxicity of Ni hydroxycarbonate as the oral absorption of Ni ion from Ni hydroxycarbonate is likely to be lower than from Ni sulphate. This is supported by findings from acute oral toxicity studies where the NOAEL of Ni hydroxycarbonate was found to be significantly higher than that of Ni sulphate (341 mg Ni/kg/day vs. 36 mg Ni/kg/day) (EPSL, 2009a). A background document summarizing available human data on developmental and reproductive toxicity of soluble Ni compounds is attached in Sections 7.8 and 7.10.2 of this IUCLID and inAppendix B5of the CSR.

 

Endpoint Summary for Fertility and Developmental Toxicity

Endpoint Summary Information from the 2008/2009 European Union Risk Assessment for Nickel Sulphate:

Effects on male sex organs in rats and mice have been reported in limited studies after oral, inhalation or subcutaneous administration. These studies indicate a possible LOAEL for oral and inhalation exposure of 5.6 mg Ni/kg bw/day and 1.6 mg Ni/m3, respectively. A repeated dose toxicity study provides a NOAEL for effects on sperm and oestrus cyclicity of 0.45 mg Ni/m3for inhalation exposure [cited as Dunnick et al. 1989 in this CSR]. No effects on male sex organs including sperm quality were found in the recent oral OECD TG 416 two-generation study (SLI 2000b) and the NOAEL is therefore the highest dose studied, i. e. is 2.2 mg Ni/kg bw/day. The NOAELs for effects on male sex organs of 0.45 mg Ni /m3for inhalation exposure and 2.2 mg Ni/kg bw/day for oral administration is taken forward to the risk characterization.

The highest dose level used in the recent OECD TG 416 two-generation study (SLI 2000b) was chosen based upon the dose-response characteristics of the peri- postnatal loss previously observed in other studies, Consequently, the study high dose did not induce any signs of toxicity in the F0 animals and does not fulfil OECD TG 416 guidelines concerning the dose levels used. Therefore, the results of the study are not conclusive concerning the potential for effects of nickel sulphate on fertility or sex organs at dose levels higher than 2.2 mg Ni/kg bw/day.

No standard prenatal developmental toxicity studies with Ni-sulphate via either the oral or inhalation routes were located. The multi-generation studies and the one-generation range-finding study provide consistent evidence of developmental toxicity (stillbirth, postimplantation/perinatal death) in rats at dose levels not causing maternal toxicity. Based on the increased postimplantation/perinatal lethality in F1 generation in the OECD TG 416 two-generation study (SLI 2000b) at 2.2 mg Ni /kg bw/day, the NOAEL used for developmental toxicity for regulatory purposes is set to 1.1 mg Ni/kg bw/day. This value is taken forward to the risk characterisation.

From the background document on nickel compounds it appears that studies on nickel chloride and an unspecified nickel salt also provide evidence of increased postimplantation/perinatal lethality in rats after oral exposure. An equivocal LOAEL of 1.33 mg Ni/kg bw/day for nickel chloride has been identified and this value is higher than the NOAEL of 1.1 mg Ni/kg bw/day for nickel sulphate. Thus, looking across to data on other nickel compounds does not affect the conclusion for nickel sulphate.

There is consistent evidence of developmental toxicity (stillbirth, postimplantation/perinatal lethality) in rats at dose levels not causing maternal toxicity. The TC C&L has agreed to classify nickel sulphate as Repr. Cat. 2; R61. This classification is included in the Annex I entry in the 30th ATP.

There is a lack of standard prenatal developmental toxicity studies (OECD 414) and therefore the minimum data requirement in the revised TGD is not fulfilled. However, the minimum data requirement in the prior TGD is more than fulfilled as the multi-generation studies is more extensive than the OECD screening test for reproductive toxicity. Based on the findings of peri-/postnatal death in the multi-generation studies there is not considered to be urgent need for further testing for developmental toxicity if nickel sulphate is classified in Category 2 for developmental toxicity.

The potential for effects of nickel sulphate on fertility have not been sufficiently investigated, since the highest dose level in the recent OECD TG 416 two-generation study did not induce any signs of toxicity in the adult animals. Therefore, to be able to draw clear conclusions regarding the potential for effects of nickel sulphate on fertility further studies using higher dose levels would be relevant. However, there is no reason to expect that such testing would lead to lower NOAELs than the ones already determined for fertility and developmental effects. Therefore, the results of such testing are unlikely to influence the outcome of the risk assessment.

No standard prenatal developmental toxicity studies with Ni-sulphate via either the oral or inhalation routes were located. The multi-generation studies and the one-generation range-finding study provide consistent evidence of developmental toxicity (stillbirth, postimplantation/perinatal death) in rats at dose levels not causing maternal toxicity. Based on the increased postimplantation/perinatal lethality in F1 generation in the two-generation study (SLI 2000) at 2.2 mg Ni /kg bw/day, the NOAEL used for developmental toxicity for is set to 1.1 mg Ni/kg bw/day.

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/m3 in the low exposure group to 0.15-0.33 mg Ni/m3 in 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

Ni hydroxycarbonate is classified as Cat 2:R61 and Repr. 1B;H360D in the 1st ATP to the CLP Regulation. Background information is provided in the discussion sections above and in the background document attached to Sections 7.8.1 and 7.8.2 of IUCLID and Appendix B5 to the CSR.