Nickel bis(2-ethylhexanoate)

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Additional information

Read-across approach

Selected endpoints for the human health hazard assessment are addressed by read-across, using a combination of data on the metal cation and the organic acid anion. This way forward is acceptable, since metal carboxylates are shown to dissociate to the organic anion and the metal cation upon dissolution in aqueous media. No indications of complexation or masking of the metal ion through the organic acid were apparent during the water solubility and dissociation tests (please refer to the water solubility and dissociation in sections 4.8 and 4.21 of IUCLID). Once the individual transformation products of the metal carboxylate become bioavailable (i.e., in the acidic environment in the gastric passage or after phagocytosis by pulmonary macrophages), the “overall” toxicity of the dissociated metal carboxylate can be described by a combination of the toxicity of these transformation products, i.e., the metal cation and carboxylate anion according to an additivity approach.

 

Nickel bis(2-ethylhexanoate) is the nickel salt of 2-ethylhexanoic acid, which readily dissociates to the corresponding divalent nickel cation and monovalent 2-ethylhexanoate anions. The nickel cation and the 2-ethylhexanoate anion are considered to represent the overall toxicity of nickel bis(2-ethylhexanoate) in a manner proportionate to the free acid and the metal (represented by one of its readily soluble salts). 

 

A detailed justification for the read-across approach is added as a separate document in section 13 of IUCLID.

 

Toxicity to reproduction - effects on fertility

No toxicity data on adverse effects on sexual function and fertility with nickel bis(2-ethylhexanoate) are available, thus the reproductive toxicity will be addressed with existing data on the dissociation products as detailed in the table below. 

 

Table: Summary of toxicity data on adverse effects on sexual function and fertility of nickel bis(2 -ethylhexanoate) and the individual constituents.

	nickel ion	2-ethylhexanoic acid (CAS# 149-57-5)	nickel bis(2 -ethylhexanoate) (CAS# 4454-16-4)
Reproductive toxicity study	NOAEL(Rat; F0 + F1) = 2.2 mg Ni/kg bw/day   not classified	NOAEL(rat; F1) = 100 mg/kg bw/day NOAEL(rat; P) = 300 mg/kg bw/day   not classified	no data   not classified

 

Nickel

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). While some effects have been reported in studies in mice with soluble nickel (e.g. Pandey and Srivastava, 2000), the European Union Risk Assessment Report (EU RAR) in 2008 did not consider the data sufficient to classify soluble nickel compounds for fertility effects. 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.

 

2-Ethylhexanoic acid

2-Ethylhexanoic acid was administered via drinking water to an unspecified number of male and female rats at 0, 100, 300, or 600 mg/kg bw/day. There were no deaths. The relative epididymal weights in high-dose males were significantly increased, but no histological changes were noted. A slight, but not statistically significant increase in the number of abnormal sperm was noted in the highest two dose groups; however, the incidence per animal was not provided. Treated groups required more time to successfully complete mating, and the mean litter size in high-dose pregnant females was significantly reduced. The mean pup weights in the high-dose group were significantly lower on postnatal day 7 and 14. Mean fetal weight per litter and mean placental weights were significantly reduced in the mid- and high-dose groups. Clubfoot was the only skeletal malformation; changes in skeletal variations were also noted (wavy ribs, reduced cranial ossification, and twisted hind legs). Corrected maternal body weights at termination and weight gains of high-dose females were significantly reduced. Physical development of the eyes, teeth and hair appeared to be slightly later in the pups from the high-dose groups; the significance of this finding is unclear since no data were presented on the length of gestation in treated and control dams. The high-dose of 600 mg/kg bw/day significantly reduced overall water consumption and body weights in female animals. The NOAEL for reproductive effects in parental animals was 300 mg/kg bw/day; this effect occurred in the presence of maternal toxicity. The NOAEL for F1 offspring was 100 mg/kg bw/day. Based on these results, 2-ethylhexanoic acid is not likely to cause effects on fertility but is likely to be a developmental toxicant. The developmental toxicity of 2-ethylhexanoic acid is at least partially related to disruption of Zn metabolism and distribution in the mother, and that higher zinc levels in the mothers leads to lower developmental toxicity in offspring.

 

Nickel bis(2-ethylhexanoate)

Since no toxicity data on adverse effects on sexual function and fertility is available for Nickel bis(2-ethylhexanoate), information on the individual constituents nickel and 2-ethylhexanoic acid will be used for the hazard assessment and, when applicable, for the risk characterisation of nickel bis(2-ethylhexanoate). For the purpose of hazard assessment of nickel bis(2-ethylhexanoate), the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation. For nickel, a NOAEL of 2.2 mg/kg bw/day is selected and for 2-ethylhexanoic acid in nickel bis(2-ethylhexanoate), the NOAEL of 100 mg/kg bw/day for the reproductive toxicity in the F1 offspring will be used.

 

Nickel bis(2-ethylhexanoate) is not expected to show adverse effects on sexual function and fertility, since the two constituents nickel and 2-ethylhexanoic acid have not shown clear adverse effects on sexual function and fertility in relevant bioassays. Thus, nickel bis(2-ethylhexanoate) is not to be classified according to regulation (EC) 1272/2008 as reproductive toxicant: fertility impairment. Further testing is not required. For further information on the toxicity of the individual constituents, please refer to the relevant sections in the IUCLID and CSR.

Effects on developmental toxicity

Additional information

Read-across approach

Selected endpoints for the human health hazard assessment are addressed by read-across, using a combination of data on the metal cation and the organic acid anion. This way forward is acceptable, since metal carboxylates are shown to dissociate to the organic anion and the metal cation upon dissolution in aqueous media. No indications of complexation or masking of the metal ion through the organic acid were apparent during the water solubility and dissociation tests (please refer to the water solubility and dissociation in sections 4.8 and 4.21 of IUCLID). Once the individual transformation products of the metal carboxylate become bioavailable (i.e., in the acidic environment in the gastric passage or after phagocytosis by pulmonary macrophages), the “overall” toxicity of the dissociated metal carboxylate can be described by a combination of the toxicity of these transformation products, i.e., the metal cation and carboxylate anion according to an additivity approach.

 

Nickel bis(2-ethylhexanoate) is the nickel salt of 2-ethylhexanoic acid, which readily dissociates to the corresponding divalent nickel cation and monovalent 2-ethylhexanoate anions. The nickel cation and the 2-ethylhexanoate anion are considered to represent the overall toxicity of nickel bis(2-ethylhexanoate) in a manner proportionate to the free acid and the metal (represented by one of its readily soluble salts). 

 

A detailed justification for the read-across approach is added as a separate document in section 13 of IUCLID.

 

Toxicity to reproduction - developmental toxicity

No toxicity data on adverse effects on development of the offspring with nickel bis(2-ethylhexanoate) are available, thus the reproductive toxicity will be addressed with existing data on the dissociation products as detailed in the table below. 

 

Table: Summary of toxicity data on adverse effects on development of the offspring for nickel bis(2 -ethylhexanoate) and the individual constituents.

	nickel ion	2-ethylhexanoic acid (CAS# 149-57-5)	nickel bis(2 -ethylhexanoate) (CAS# 4454-16-4)
pre-natal developmental toxicity study	NOAEL(Rat; dev) = 1.1 mg Ni/kg bw/day Category 1b, H360d	NOAEL(rat; mat.)= 250 mg/kg   NOAEL(rat; dev)= 100 mg/kg   Category 2, H361d	no data   Category 1b, H360d

 

Nickel

Data requirements for nickel are fulfilled by the results of a two-generation study with nickel sulphate, 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.

 

2-Ethylhexanoic acid

2-Ethylhexanoic acid was administered via drinking water to an unspecified number of male and female rats at 0, 100, 300, or 600 mg/kg bw/day. There were no deaths. The relative epididymal weights in high-dose males were significantly increased, but no histological changes were noted. A slight, but not statistically significant increase in the number of abnormal sperm was noted in the highest two dose groups; however, the incidence per animal was not provided. Treated groups required more time to successfully complete mating, and the mean litter size in high-dose pregnant females was significantly reduced. The mean pup weights in the high-dose group were significantly lower on postnatal day 7 and 14. Mean fetal weight per litter and mean placental weights were significantly reduced in the mid- and high-dose groups. Clubfoot was the only skeletal malformation; changes in skeletal variations were also noted (wavy ribs, reduced cranial ossification, and twisted hind legs). Corrected maternal body weights at termination and weight gains of high-dose females were significantly reduced. Physical development of the eyes, teeth and hair appeared to be slightly later in the pups from the high-dose groups; the significance of this finding is unclear since no data were presented on the length of gestation in treated and control dams. The high-dose of 600 mg/kg bw/day significantly reduced overall water consumption and body weights in female animals. The NOAEL for reproductive effects in parental animals was 300 mg/kg bw/day; this effect occurred in the presence of maternal toxicity. The NOAEL for F1 offspring was 100 mg/kg bw/day. Based on these results, 2-ethylhexanoic acid is not likely to cause effects on fertility but is likely to be a developmental toxicant. The developmental toxicity of 2-ethylhexanoic acid is at least partially related to disruption of Zn metabolism and distribution in the mother, and that higher calcium levels in the mothers leads to lower developmental toxicity in offspring. Based on the above given information, 2-ethylhexanoic acid was classified as toxic for reproduction, developmental toxicity category 2 (H361d).

 

Nickel bis(2-ethylhexanoate)

Nickel bis(2-ethylhexanoate) is legally classified as Repr. 1B, H360D as per the 1st ATP of CLP regulation. Since no reproductive toxicity study is available for nickel bis(2-ethylhexanoate), information on the individual constituents nickel and 2-ethylhexanoic acid will be used for the hazard assessment and, when applicable, for the risk characterisation of nickel bis(2-ethylhexanoate). For the purpose of hazard assessment of nickel bis(2-ethylhexanoate), the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation. For nickel, a NOAEL of 1.1 mg/kg bw/day is selected and for 2-ethylhexanoic acid, the NOAEL of 100 mg/kg bw/day for the developmental toxicity in the F1 offspring will be used.

Justification for classification or non-classification

Nickel bis(2-ethylhexanoate) is legally classified as Repr. 1B, H360D as per the 1st ATP of CLP regulation.