Naphthenic acids, nickel salts

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No toxicity data on adverse effects on sexual function and fertility with naphthenic acids, nickel salts are available, thus the reproductive toxicity will be addressed with existing data on the individual moieties nickel and naphthenate. Naphthenic acids, nickel salts is not expected to impair fertility, since both assessment entities nickel and naphthenic acid has not shown adverse effects in relevant and reliable toxicity studies in animals.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

Effect on fertility: via inhalation route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

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). 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.

In addition, 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 IUCLID and in Appendix B7 of the CSR.

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

No effects on fertility have been found in studies following oral administration; 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 (10 mg nickel sulphate hexahydrate/kg bw/day). A repeated dose toxicity study provides a NOAEC for effects on sperm and oestrus cyclicity of 0.45 mg Ni/m3 (2.0 mg nickel sulphate hexahydrate/m3) for inhalation exposure (Dunnick et al., 1989).

Naphthenate

A key combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in Wistar rats was performed by oral gavage with Naphthenic acids in corn oil (HPVIS, 2010). There were 3 test material treated groups (100, 300 and 900 mg/kg bw) along with a vehicle treated group (corn oil) each in 12 animals/sex/group. Male rats were dosed during premating, mating and afterwards for 28 days in total and females were dosed during premating, mating, gestation and up to day 3 post partum. In this section, only reproductive toxicity parameters are discussed; further info on repeated & developmental parameters is given in Section 7.5.1 and 7.8.2. Target organ findings were identified at the dose of 900 mg/kg bw, whereas 100 mg/kg bw was considered as the NOAEL for systemic toxicity.

No reproductive effects were identified up to 900 mg/kg bw . There were no weight differences in any of the other organs nor any pathological changes in the reproductive organs up to the highest dose tested (900 mg/kg/day). The NOAEL for mating and reproductive organ effects was 900 mg/kg/day.

 

There was also a reproductive toxicity study in male New Zealand White rabbits dermally exposed to 2 mL undiluted Calcium naphthenate for 6 hours daily for 5 days each week over 10 weeks (Dix and Cassidy, 1983). Half of the males of each group were killed and necropsied after mating. The remaining males were weighed weekly and necropsied approximately 12 weeks later. Macroscopic and microscopic examinations of the male reproductive tracts were carried out on all rabbits. The females were necropsied on day 29 of gestation. Numbers of corpora lutea, total implantations, pre-and post-implantation losses and numbers of viable foetuses were recorded. Calcium naphthenate in carrier oil did not show any effect on the reproduction when applied dermally on male rabbits. Since the naphthenate ion is considered as the toxic entity of the whole molecule read across of these findings to naphthenic acid is justified. Although no effects were observed, supporting the main study, the data were limited and the study was disregarded for risk assessment.

 

 A supporting combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in Wistar rats was performed by oral gavage with Naphthenic acids in corn oil (HPVIS, 2010). There were 3 test material treated groups (100, 300 and 900 mg/kg bw) along with a vehicle treated group (corn oil) each in 12 animals/sex/group. Male rats were dosed during premating, mating and afterwards for 28 days in total and females were dosed during premating, mating, gestation and up to day 3 post partum. In this section, only developmental toxicity parameters are discussed: (further info on repeated & reproductive parameters is given in Section 7.5.1 and 7.8.1). Target organ findings were identified at the dose of 300 and 900 mg/kg bw, whereas 100 mg/kg bw was considered as the NOAEL for systemic toxicity. Treatment of Sprague-Dawley rats with refined naphthenic acids had no apparent effects on mating and did not produce malformations at the highest dose tested (900 mg/kg/day). There were significant reductions in number of offspring, number live born and offspring body weights at 300 and 900 mg/kg, which were considered secondary findings at the maternally toxicity dose levels. The overall no observed adverse effect level was 100 mg/kg/day.

 

A disregarded study was available in pregnant female Wistar rats dosed at 6 and 60 mg/kg bw with Naphthenic acids obtained from Athabasca oil sands (AOS) from 14 days prior to pairing and continued throughout the mating and gestational periods until study termination on post-natal day 3 (Rogers, 2003). Reproductive toxicity testing demonstrated dramatic effects on female fertility at an oral dosage of 60 mg/kg/day during pre-breeding, breeding and gestation. While control and low dose (6 mg/kg/day) animals achieved 93 (13/14) and 100% (13/13) reproductive success, respectively, only 7% (1/14) of females dosed at 60 mg/kg/d successfully bore a litter. Total cholesterol of the latter group was 30% lower than controls. Mating and ovulation were comparable amongst control and dose groups, while fetal malformations were not apparent in any offspring. Results suggest that the dose-related infertility may be associated with poor embryonic implantation, an effect that might be secondary to depressed sex hormone production requiring cholesterol as a precursor.

 

Available data suggest values that warrant no classification for reproductive and developmental toxicity under Regulation 1272/2008 (CLP).

Naphthenic acids, nickel salts

Since no reproductive/developmental toxicity screening study is available specifically for naphthenic acids, nickel salts, information on the assessment entities nickel and naphthenate will be used for the hazard assessment and when applicable for the risk characterisation of naphthenic acids, nickel salts. Naphthenic acids, nickel salts is not expected to impair fertility of male or female animals, since none of the assessment entities showed effects on fertility in relevant and reliable animal studies.

For further information on the toxicity of the individual moieties, please refer to the relevant sections in the IUCLID and CSR.

Effects on developmental toxicity

Description of key information

No toxicity data on adverse effects on developmental toxicity with naphthenic acids, nickel salts are available, thus the reproductive toxicity will be addressed with existing data on the assessment entities nickel and naphthenate. Naphthenic acids, nickel salts is expected to be developmentally toxic, since the assessment entity nickel has shown adverse effects in a two-generation reproductive toxicity study.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

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 PNDT studies of nickel sulphate were identified. A comprehensive read-across program based on bioaccessibility data in synthetic fluids validated by in vivo acute oral toxicity data has been conducted on a series of Ni compounds including Ni sulphate. The results of this program suggest that the developmental toxicity effects of Ni sulphate should be read-across from Ni chloride for oral and/or inhalation systemic exposure (Appendices B1 and B2). 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 B7 of the CSR.

Data requirements for nickel sulphate are fulfilled by the results of a two-generation study with nickel sulphate and by reading across the results from a rat prenatal developmental toxicity (PNDT) study with nickel chloride. A weight of evidence analysis indicates that a PNDT in a second species (e.g. rabbit) is not necessary. This is based on the negative results of the PNDT study of soluble nickel compounds; the results of the human epidemiological studies showing no developmental effects (such as malformations) in highly exposed workers (see below); and the fact that rapidly dividing tissues were not affected in other toxicological studies (e.g. no effects of soluble nickel in bone marrow in the micronucleus assay (Oller and Erexson, 2007).  These studies indicate that a second PNDT study is not justified.

It is important to note that while developmental effects in general could include also malformations, the nickel effects are specific and limited to post implantation loss and perinatal mortality. These Ni effects would not be detected with a PNDT study but are detected with one- or two-gen studies, even if these studies are usually conducted to examine fertility effects. 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. Regarding teratogenicity effects, soluble nickel chloride was not shown to cause malformations or teratogenicity effects (RTI, 1988b). 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:

No standard prenatal developmental toxicity studies with Ni-sulphate via either the oral or inhalation routes were located. 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 (5 mg nickel sulphate hexahydrate/kg bw/day).

Naphthenate

A key combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in Wistar rats was performed by oral gavage with Naphthenic acids in corn oil (HPVIS, 2010). There were 3 test material treated groups (100, 300 and 900 mg/kg bw) along with a vehicle treated group (corn oil) each in 12 animals/sex/group. Male rats were dosed during premating, mating and afterwards for 28 days in total and females were dosed during premating, mating, gestation and up to day 3 post partum. In this section, only reproductive toxicity parameters are discussed; further info on repeated & developmental parameters is given in Section 7.5.1 and 7.8.2. Target organ findings were identified at the dose of 900 mg/kg bw, whereas 100 mg/kg bw was considered as the NOAEL for systemic toxicity.

No reproductive effects were identified up to 900 mg/kg bw . There were no weight differences in any of the other organs nor any pathological changes in the reproductive organs up to the highest dose tested (900 mg/kg/day). The NOAEL for mating and reproductive organ effects was 900 mg/kg/day.

 

There was also a reproductive toxicity study in male New Zealand White rabbits dermally exposed to 2 mL undiluted Calcium naphthenate for 6 hours daily for 5 days each week over 10 weeks (Dix and Cassidy, 1983). Half of the males of each group were killed and necropsied after mating. The remaining males were weighed weekly and necropsied approximately 12 weeks later. Macroscopic and microscopic examinations of the male reproductive tracts were carried out on all rabbits. The females were necropsied on day 29 of gestation. Numbers of corpora lutea, total implantations, pre-and post-implantation losses and numbers of viable foetuses were recorded. Calcium naphthenate in carrier oil did not show any effect on the reproduction when applied dermally on male rabbits. Since the naphthenate ion is considered as the toxic entity of the whole molecule read across of these findings to naphthenic acid is justified. Although no effects were observed, supporting the main study, the data were limited and the study was disregarded for risk assessment.

 

 A supporting combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in Wistar rats was performed by oral gavage with Naphthenic acids in corn oil (HPVIS, 2010). There were 3 test material treated groups (100, 300 and 900 mg/kg bw) along with a vehicle treated group (corn oil) each in 12 animals/sex/group. Male rats were dosed during premating, mating and afterwards for 28 days in total and females were dosed during premating, mating, gestation and up to day 3 post partum. In this section, only developmental toxicity parameters are discussed: (further info on repeated & reproductive parameters is given in Section 7.5.1 and 7.8.1). Target organ findings were identified at the dose of 300 and 900 mg/kg bw, whereas 100 mg/kg bw was considered as the NOAEL for systemic toxicity. Treatment of Sprague-Dawley rats with refined naphthenic acids had no apparent effects on mating and did not produce malformations at the highest dose tested (900 mg/kg/day). There were significant reductions in number of offspring, number live born and offspring body weights at 300 and 900 mg/kg, which were considered secondary findings at the maternally toxicity dose levels. The overall no observed adverse effect level was 100 mg/kg/day.

 

A disregarded study was available in pregnant female Wistar rats dosed at 6 and 60 mg/kg bw with Naphthenic acids obtained from Athabasca oil sands (AOS) from 14 days prior to pairing and continued throughout the mating and gestational periods until study termination on post-natal day 3 (Rogers, 2003). Reproductive toxicity testing demonstrated dramatic effects on female fertility at an oral dosage of 60 mg/kg/day during pre-breeding, breeding and gestation. While control and low dose (6 mg/kg/day) animals achieved 93 (13/14) and 100% (13/13) reproductive success, respectively, only 7% (1/14) of females dosed at 60 mg/kg/d successfully bore a litter. Total cholesterol of the latter group was 30% lower than controls. Mating and ovulation were comparable amongst control and dose groups, while fetal malformations were not apparent in any offspring. Results suggest that the dose-related infertility may be associated with poor embryonic implantation, an effect that might be secondary to depressed sex hormone production requiring cholesterol as a precursor.

 

Available data suggest values that warrant no classification for reproductive and developmental toxicity under Regulation 1272/2008 (CLP).

 

 

 

Naphthenic acids, nickel salts

Since no reproductive/developmental toxicity screening study is available specifically for naphthenic acids, nickel salts, information on the individual moieties nickel and naphthenate will be used for the hazard assessment and when applicable for the risk characterisation of naphthenic acids, nickel salts. Naphthenic acids, nickel salts is expected to be developmentally toxic, since the assessment entity nickel has shown adverse effects in a two-generation reproductive toxicity study. For further information on the toxicity of the individual moieties, please refer to the relevant sections in the IUCLID and CSR.

Justification for classification or non-classification

Naphthenic acids, nickel salts is expected to impair fertility or development, since the moiety nickel has shown adverse effects in a two-generation reproductive toxicity test. Thus, naphthenic acids, nickel salts is classified according to regulation (EC) 1272/2008 as toxic for reproduction Repr 1B (H360D). The classification for naphthenic acids, nickel salts will be read-across from the classification of nickel sulfate.