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Key value for chemical safety assessment

Effects on fertility

Description of key information

There are no data on fertility effects of registered nickel nitrate itself. However, in guidance-compliant reproductive studies, soluble nickel compounds have not been shown to cause adverse fertility effects (SLI, 2000a,b; Smith et al., 1993). Since nickel nitrate shares the solubility characteristics of the tested compounds, and these effects are related to the amount of nickel systemically available after exposure, the negative evidence from these soluble nickel compounds can be considered for nickel nitrate as well. The EU C&L Health Effects Working Group discussed this point in 2004 and agreed that soluble nickel compounds should not be classified for fertility effects.

A comprehensive read-across program based on water solubility and bioaccessibility data in synthetic fluids validated byin vivotoxicokinetics andacute oral toxicity data has been conducted on a series of Ni compounds. The results of this program suggest that soluble nickel compounds should be read-across from Ni sulphate and Ni chloride for oral and inhalation systemic exposure (Appendices B1andB2). 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 inAppendixB4of the CSR.Data requirements for nickel nitrate are therefore fulfilled by reading across the negative results from fertility studies with soluble nickel compounds.While some effects have been reported in studies in mice with soluble nickel (e.g. Pandey and Srivastava, 2000), theEuropean Union Risk Assessment Report(EU RAR) in 2008 did not consider the data sufficient to classify soluble nickel compounds for fertility effects.

 

 

The following information is taken into account for any hazard / risk assessment:

Data regarding effects on fertility are read-across from Ni sulphate. No effects on fertility have been found in studies following oral administration with Ni sulphate; no data are available for inhalation and dermal contact. The most reliable NOAEL is from the two-generation study (SLI 2000a,b) 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/m3for inhalation exposure (Dunnick et al., 1989).

Value used for CSA (route: oral):NOAEL: 6.8 mg nickel nitrate/kg bw/day

Value used for CSA (route: inhalation):NOAEC: 1.4 mg nickel nitrate/m³ air

 

Effect on fertility: via oral route
Dose descriptor:
NOAEL
6.8 mg/kg bw/day
Effect on fertility: via inhalation route
Dose descriptor:
NOAEC
1.4 mg/m³

Effects on developmental toxicity

Description of key information

No robust studies that characterized the reproductive toxicity (developmental toxicity) of nickel nitrate were identified.A comprehensive read-across program based on water solubility and bioaccessibility data in synthetic fluids validated byin vivotoxicokinetics and acute oral toxicity data has been conducted on a series of Ni compounds including Ni nitrate. The results of this program suggest that soluble nickel compounds should be read-across from Ni sulphate (and chloride) for oral and/or inhalation systemic exposure (Appendices B1andB2). 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 inAppendix B4of the CSR.

Data requirements for nickel nitrate are fulfilled by a rat prenatal developmental toxicity (PNDT) study with nickel chloride (RTI, 1988b) and a mouse (PNDT) study with nickel chloride (Saini et al., 2013). In the rat study, no evidence of teratogenic effects was reported in a multi-generational study where the F2b generation was subjected to a classical teratology assessment (RTI, 1988a,b). The F2b generation was delivered by Caesarean section on gestation day 20 and were examined for external, internal, and skeletal malformations mimicking the protocol of a stand-alone PNDT study, but with extended exposure of the parental animals. This F2b cohort showed no exposure-related adverse effects. The lack of adverse effects in the F2b generation, examined on gestation day 20, indicated that the developmental effects in the other generational cohorts (i.e., perinatal mortality) were expressed during the perinatal or postnatal periods and not during gestation (RTI, 1988a,b).

Saini et al. (2013) studied the effects of oral (gavage) exposure during gestation (GD6-13) of Swiss albino mice to Ni chloride hexahydrate at doses of 0, 46, 92 and 185 mg Ni/kg b.w. per day. Maternal toxicity (decrease feed consumption, water intake and b.w.) was observed at doses ≥ 92 mg Ni/kg b.w. per day and fetotoxicity (decreases in b.w.), embryotoxicity (decrease in the number of live fetuses/dam, increases in post-implantations losses and resorptions at high dose), and teratogenicity (malformations such as open eyelids, club foot, umbilical hernia, ophthalmic anomalies, hydrocephaly, reduced ossification, dose-dependent increase in skeletal anomalies) were observed at doses ≥ 92 mg/kg b.w. per day (microphthalmia already at 46 mg/kg b.w. per day). The NOAEL for maternal toxicity was 46 mg Ni/kg b.w. per day and the LOAEL for developmental toxicity was 46 mg Ni/kg b.w. per day.

The multi-generation studies and the one-generation range-finding study provide consistent evidence of developmental toxicity (stillbirth, post-implantation/perinatal death) in rats at dose levels not causing maternal toxicity. Based on the increased post-implantation/perinatal lethality in F1 generation in an OECD TG 416 two-generation study (SLI 2000a,b) at 2.2 mg Ni /kg bw/day, the NOAEL used for developmental toxicity for regulatory purposes is set at 1.1 mg Ni/kg bw/day. This value is taken forward to the risk characterisation.

The following information is taken into account for any hazard / risk assessment:

Data regarding developmental toxicity are read-across from Ni chloride and Ni sulphate to Ni nitrate (see (Appendices B1andB2). The existing studies on soluble nickel compounds provide consistent evidence of developmental toxicity (stillbirth, post-implantation/perinatal death) in rats at dose levels not causing maternal toxicity. No standard PNDT studies with Ni nitrate via either the oral or inhalation routes were located. Regarding teratogenicity effects,nickel chloride was shown to cause malformations in a PNDT study in mice at higher doses (Saini et al., 2013).Human data from reproductive epidemiological studies of female refinery workers with high exposures to water soluble nickel compounds (and insoluble ones) have not demonstrated adverse developmental effects such as: 1) male newborns with genital malformations, 2) spontaneous abortions, 3) small-for-gestational-age newborns, or 4) musculosketal effects in newborns of female refinery workers exposed to nickel. The data in these manuscripts showed no correlation between nickel exposures (urinary levels as high as 30-fold over background) and observed reproductive impairment.Based on the increased post-implantation/perinatal lethality in F1 generation in an OECD TG 416 two-generation study (SLI 2000a,b) at 2.2 mg Ni /kg bw/day, the NOAEL used for developmental toxicity for regulatory purposes is set at 1.1 mg Ni/kg bw/day.

Value used for CSA (route: oral):NOAEL: 3.4 mg nickel nitrate/kg bw/day

 

Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
3.4 mg/kg bw/day

Toxicity to reproduction: other studies

Description of key information

A reproductive study of female refinery workers hasnotdemonstrated 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). Researchers created a birth registry for all births occurring in the region of a Russian nickel refinery at Monchegorsk during the period of the study, which included information on 22,836 newborns and 2,793 pregnancy outcomes surveyed for spontaneous abortions (Vaktskjoldet al.2007; 2008a). They also reconstructed the exposures (using air and urinary nickel measurements) for the female workers at the refineries so as to be able to link specific pregnancy outcomes with occupational exposures via inhalation and systemically bioavailable doses of nickel (i.e.urinary nickel levels). The study culminated in a series of manuscripts by Vaktskjoldet al.(2006, 2007, 2008a,b) describing the results of the investigation. The study demonstrated nickel compound and metal exposure was not associated with adverse pregnancy outcome for 1) male newborns with genital malformations, 2) spontaneous abortions, 3) small-for-gestational-age newborns, or 4) musculoskeletal effects in newborns of female refinery workers exposed to nickel. The data in these manuscripts showed no correlation between nickel exposures (urinary levels as high as 30-fold over background[1]) and observed reproductive impairment. It is important to note thatgenital malformations are considered as one of the most sensitive endpoints for human developmental toxicity while spontaneous abortion in humans would most closely approximate the observation of perinatal lethality associated with nickel exposure in rodents. Further evidence that nickel compound and metal exposure was not adversely affecting the reproduction of these women was provided by the lack of a “small-for-gestational-age” finding and also the lack of an association of male genital malformations with nickel exposure. Both of these findings are considered “sentinel” effects (i.e., sensitive endpoints) for reproductive toxicity in humans.

 

The work by Vaktskjoldet al.(2006, 2007, 2008a,b) is important in demonstrating that no hazard for reproductive impairment from nickel compound and metal exposure exists under the conditions of the study, which were extremely high exposure levels which are no longer present in current refinery operations.[2]Thus, the reproductive effects observed in rats 1) may not be relevant to humans or 2) may not have been observed in the exposed human population because even the highest achievable female workers’ exposure (179 µg Ni/l in urine) is lower than those achieved in rats at the LOAEL for reproductive effects (2300 µg Ni/L in urine). In either case, for classification and risk assessment purposes, the relevance of the positive results in rats with soluble nickel compounds (at what seem to be unachievable human exposures) needs to be considered together with the negative results in human studies at Monchegorsk (for the highest exposed human population) in a weight of evidence approach. At the very least, the data indicates that humans do not appear to be greatly more sensitive to reproductive effects of nickel ion than rats. While the exact mode of action for the perinatal mortality effects of Ni ion are not known, the existing data demonstrates that these are clearly threshold-mediated effects. Because the study correlated the systemically available nickel levels to reproductive outcomes, the lack of reproductive toxicity effects is relevant to nickel compounds and nickel metal. Importantly, the results from human studies showing no reproductive toxicity effects due to nickel compound and metal exposure reported by Vaktskjoldet al.were not available at the time when nickel compounds were classified as Cat. 1B reproductive toxicants.

 

The mode of action for the reproductive toxicity of soluble nickel ion observed in rodents is not currently known; thus its relevancy for humans is also unknown. What is known is that epidemiological studies of female workers exposed to the highest attainable levels of water soluble nickel compounds (via inhalation) and who had urinary nickel levels up to 30-fold above backgroundfailedto show an association between exposures to nickel and observed adverse reproductive effects. To place the animal and human results in context, we can compare the urine nickel levels in the workers’ cohort with the urine levels in rat reproductive studies. Background urinary nickel levels in the female Monchegorsk population had a geometric mean of 5.9 µg/l, the low exposure refinery workers had urinary levels up to 70 µg/l (~12-fold increase in urinary levels) and the high exposure workers had urinary levels between 70 and 179 µg/l (up to 30-fold increase in urinary levels). Urinary levels of 70 µg/l in low exposure workers corresponded to approximately 160 µg soluble nickel inhalable exposure/m3(>1000-fold over ambient air levels).

Comparison of the exposures in female workers to the exposure of rats can be made. In a rat oral study with nickel sulfate (100% bioaccessible nickel), blood and urinary nickel levels were measured after two years of exposure to 2.2 to 10 mg Ni/kg (Heim et al., 2007; Rush, 2005). A linear dose-response between oral intake of nickel and urinary nickel levels was found. An exposure of 2.2 mg Ni/kg corresponded to a mean urine value of 2300 µg Ni/L (males + females) with blood peak levels of ~70 µg Ni/l. Thus, the rat urinary nickel level at the LOAEL for reproductive developmental effects (2.2 mg Ni/kg) is 33-fold and 13-fold higher than those measured in Low and High exposure nickel refinery workers, respectively. Likewise, the rat urinary nickel level at the NOAEL for developmental effects (1.1 mg Ni/kg) are expected to be 16.5-fold and 6.5-fold higher than those measured in Low and High exposure nickel refinery workers, respectively. 

Thus, the reproductive effects observed in rats 1) may not be relevant to humans or 2) may not have been observed in the exposed human population because even the highest achievable human exposures are lower than those at which adverse reproductive effects have been observed in rats. In either case, the relevance of the positive results in rats (at unachievable human exposures) needs to be considered together with the negative results in human studies at Monchegorsk (for the highest exposed human population).  

These data show that while a reproductive “hazard” from nickel ion systemic exposure can be demonstrated in animals, this hazard has not been demonstrated in humans.

 

The full document summarizing these data in humans is attached in Sections 7.8 and 7.10.2 of IUCLID and inAppendixB4to the CSR.

The following information is taken into account for any hazard / risk assessment:

A summary document is attached in sections 7.8.1, 7.8.2, and 7.10.2 of IUCLID and inAppendixB4of the CSR discussing human assessments of reproductive impairment associated with soluble nickel exposures as a worst case scenario. In summary, there was a lack of a correlation between nickel exposure and observed (sex organ and skeletal) malformations in the human reproductive studies of nickel-exposed workers reviewed above (Vaktskjold et al., 2006, 2007; 2008a,b). Specific endpoints, their assessment methods, and the number of subjects included: genital malformations in newborns of female nickel-refinery workers were examined with a register-based, nested case-control study (n= 103 cases; 23,038 controls); small-for-gestational-age newborns of female refinery workers exposed to nickel were examined with a register-based, nested case-control study (n= 2,096 cases; 20,740 controls); spontaneous abortions among nickel-exposed female refinery workers were examined with a case-control study (n=184 cases, 1,691 controls); and maternal nickel exposure and congenital musculoskeletal defects were examined with register-based, nested case-control study (n=341 cases, 22,624 controls). In all studies, nickel exposure was not associated with adverse pregnancy outcome for any of the endpoints examined. Such large studies provide adequate statistical power to support a conclusion to exclude the risk of reproductive effects (e.g. malformations) from exposure to the chemical (EMA/CHMP Guideline, 2006). 


[1]Background urinary nickel levels in female Monchegorsk population had a geometric mean of 5.9 µg/l, the low exposure refinery workers had urinary levels up to 70 µg/l (~12-fold increase in urinary levels) and the high exposure workers had urinary levels between 70 and 179 µg /l (up to 30-fold increase in urinary levels). Urinary nickel levels are better indicators of fetal exposure, as they account for systemically absorbed nickel ion from occupational and non-occupational sources (e.g. diet) by all routes of exposure.

[2]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.

Justification for classification or non-classification

Due to consistent evidence of developmental toxicity (stillbirth, post-implantation/perinatal death) at dose levels not causing maternal toxicity in multi-generation studies in rats in similarly soluble nickel compounds (e.g. nickel chloride and nickel sulphate), Ni nitrate is classified as Repr. 1B; H360D in the 1st ATP to the CLP Regulation.