Naphthenic acids, nickel salts

Endpoint summary

Description of key information

No repeated dose toxicity study with naphthenic acids, nickel salts is available, thus the repeated dose toxicity will be addressed with existing data on the individual moieties nickel and naphthenate.

In relevant and reliable repeated dose toxicity studies for both assessment entities of naphthenic acids, nickel salts, toxicological relevant findings were observed in studies with nickel as well as naphthenic acid.

There are several studies that have investigated the repeated toxicity of nickel sulphate via oral and inhalation routes of exposure. Only one set of studies investigating the effects of repeated exposure via the dermal route was identified. The target organ for toxicity caused by repeated exposure to nickel sulphate depends on the route of exposure.

For the moiety nickel, chronic lung inflammation including lung fibrosis was observed that results from long-term exposure via inhalation to a concentration of 0.056 mg Ni/m³ or 0.25 mg nickel sulphate hexahydrate/m³. A NOAEC of 0.12 mg/m³ (0.027 mg Ni/m³, MMAD = 2.5 µm) was identified for these effects (Dunnick et al., 1995).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Nickel

Repeated dose toxicity: oral

In a 3-6-month drinking water study by Vyskocil et al. (1994a), increased urinary albumin was detected in female rats exposed to 6.8 mg Ni/kg bw/day. In a 13-week study conducted by Obone et al. (1999), a LOAEL of 11 mg Ni/kg bw/day was identified for nickel sulphate hexahydrate given in drinking water. At this exposure level, a 4% reduction in body weight and increases in relative organ weights were observed. The NOAEL for these effects was 4.5 mg Ni/kg bw/day. A more recent 90-day study, by gavage, showed 8% body weight reduction at 7-11 mg Ni/kg bw/day (Benson et al., 2002). A 2-year chronic rat study conducted by Ambrose et al. (1976) examined the effects of nickel sulphate hexahydrate administered to rats in the diet. Effects on body weights were also observed in this study, with a NOAEL of 10 mg Ni/kg bw/day and a LOAEL of 100 mg Ni/kg bw/day identified for these effects. The same researchers conducted a 2-year study in dogs (Ambrose et al., 1976), and identified a NOAEL of 75 mg Ni/kg bw/day and a LOAEL of 188 mg Ni/kg bw/day for decreased body weight, lung granulomas, and bone marrow hyperplasia. However, because of the small group size (3 dogs/sex) it is possible that this study missed effects at the lower dose exposure levels.

A more recent 2-year OECD 451 carcinogenicity study found decreased body weight gains ranging from 4% to 12% in rats (males and females combined) following oral gavage administration of 2.2 to 11 mg Ni/kg bw/day. Survival was reduced in a dose-related manner, achieving statistical significance at the two highest dose levels in females (Heim et al., 2007).

The kidney has been identified as a target organ for oral toxicity of nickel (e.g., albuminuria) although marked histopathological kidney damage after oral exposure has not been observed (TERA, 1999). A mouse study showed mild tubular nephropathy but at higher dose levels. The increases in urinary albumin were observed at approximately the same dose level as the reduction in body weight. Various effects on the immune system have also been reported after oral exposure to nickel sulphate. The immune effects have been observed at dose levels above those causing body weight loss. Therefore, the LOAEL of 6.7 mg Ni/kg bw/day based on reduced body weight and increased mortality together with a NOAEL of 2.2 mg Ni/kg bw/day from the chronic Heim et al. (2007) study is taken forward to the risk characterisation for oral repeated dose toxicity.

A summary of the chronic oral toxicity of Ni compounds can be found in the attached background document entitled, "Background-Oral Chronic Exposure Effects" (Section 7.5.1 of IUCLID) and in Appendix B5 of the CSR.

 

Repeated dose inhalation

There are several inhalation studies ranging from 12 days to 24 months of exposure that have examined the effects of repeated exposure to nickel sulphate in rats and mice. These studies identified the target organ for toxicity effects of inhalation exposure to nickel sulphate as the respiratory tract, with effects seen in the nose and the lungs.

Following inhalation of nickel sulphate the most serious toxicity effects observed in the respiratory tract are chronic inflammation and fibrosis. The most relevant and sensitive studies to assess chronic effects are the 2-year rat inhalation studies with nickel sulphate hexahydrate (NTP, 1996a; Dunnick et al., 1995). Rats appeared to be more sensitive to the toxicity effects of nickel sulphate by inhalation than mice. Chronic lung inflammation in rats including lung fibrosis was observed at a concentration of 0.056 mg Ni/m3 or 0.25 mg nickel sulphate hexahydrate/m3, with a NOAEC of 0.027 mg Ni/m3 identified for these effects. Although macrophage hyperplasia was detected at the exposure level of 0.027 mg Ni/m3, this effect was considered an adaptive effect and not an adverse toxicity effect. The LOAEC for repeated dose toxicity via inhalation of 0.056 mg Ni/m3 and the NOAEC of 0.027 mg Ni/m3 are used in the risk characterization of nickel sulphate.

Nickel sulphate fulfils the criteria for classification for repeated dose toxicity via inhalation since chronic lung inflammation including lung fibrosis results from long-term exposure via inhalation to a concentration of 0.056 mg Ni/m3 or 0.25 mg nickel sulphate hexahydrate/m3. Ni sulfate was classified as STOT RE 1;H372 in the 1st ATP to the CLP.

 

Repeated dose toxicity: dermal

One set of studies describing toxicity effects after repeated exposure through the skin has been identified (Mathur et al. 1977; 1991; 1992; 1993; 1994) A NOAEL of 40 mg Ni/kg was identified in the Mathur et al. (1977) study for local effects on skin and systemic effects in testis and liver. However, due to the methodological limitations of this study, a NOAEL for toxicity effects via the dermal route is not carried forward to the risk characterisation.

Naphthenate

A key study for repeated dose toxicity (HPVIS, 2010) is available as a 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. 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. Reproductive & developmental parameters are discussed in Section 7.8.1 and 7.8.2.

At the lowest dose of 100 mg/kg bw, no effects were observed both in male and female rats. At the 300 and 900 mg/kg bw doses, there were no relevant effects on clinical chemistry (only slight incidental findings) and neurobehaviour at all dose levels. Further effects at the medium and high doses are described:

-  Two mortalities and clinical observations were seen in high dose females; clinical observations in some high dose group males.

-   Body weight gain at the high dose was reduced for less than 10% in males and 4% in females versus control groups, associated with reduced food consumption in both groups.

-   Slightly reduced hemoglobin in males, however not in females.

-   Increased liver weight in males and females of medium and high dose groups; significant increase in kidney weight in males of medium and high dose group.

-   Pale kidneys in the high dose males and reduction in the number of corpora lutea in the high dose females (not statistically significant).

-   Hyaline-droplets in high dosed male kidneys (not relevant for humans); liver hepatocellular hypertrophy in high dosed males & females (adaptive); and thyroid gland epithelial hypertrophy and cytoplasmatic vacuolation in (mid) and high dosed males & females (considered compensatory related to the increased metabolic capacity of the liver and more rapid turnover of thyroid hormones).

In conclusion, the dose levels of 300 and 900 mg/kg bw were considered to be toxic in male and female parents with overall NOAEL for systemic toxicity of 100 mg/kg bw, whereas NOAEL for neurotoxicity was 900 mg/kg bw, both in male and female rats.

 

A supporting 90 -day oral gavage rat study was available, which was conducted with a mixture of naphthenic acids isolated from Athabasca oil sands (AOS) in female Wistar rats dosed at 0.6, 6, or 60 mg/kg bw, 5 days per week (Rogers et al., 2002). Results confirmed the liver as a potential target organ: relative liver weight in the high-dose group was increased, biochemical analysis revealed elevated blood amylase and hypocholesterolemia in high-dose rats, and hepatic glycogen accumulation in 42% of animals in this group. The latter study was disregarded for further risk assessment. The oil sands extracts used in testing described in Rogers et al. (2002) was composed of a greater proportion of higher molecular weight Naphthenic acid isomers than the registered substance. Three and four ring constituents comprised 38% of their test sample whereas they totalled 7% of the registered (and HPV) substance. The higher molecular weight naphthenic acid constituents in the oil sands extracts may have implications to the interpretation of effects. Rogers drew attention to the fact that the material he had isolated from oil sands had properties that differed from those of commercial materials that he was using for standards. In fact, there were differences in toxic properties and possible contaminants present in the samples of Rogers or methodological differences which were not representative for the commercial products, so the extent to which these are due to differences in the test protocols is not known (EPA, 2012).

 

Naphthenic acids, nickel salts

Since no repeated dose toxicity 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. For the purpose of hazard assessment of naphthenic acids, nickel salts, the point of departure for the most sensitive endpoint of each moiety will be used for the DNEL derivation.The repeated dose toxicity for naphthenic acids, nickel salts will be addressed based on the toxicological information for the assessment entity nickel, which is classified as STOT-RE Cat. 1 via the inhalation route due to a chronic lung inflammation including lung fibrosis that results from long-term exposure via inhalation to a concentration of 0.056 mg Ni/m3 or 0.25 mg nickel sulphate hexahydrate/m3. A NOAEC of 0.12 mg/m³ (0.027 mg Ni/m3, MMAD = 2.5 µm) was identified for these effects (Dunnick et al., 1995).

Justification for classification or non-classification

The repeated dosetoxicity for naphthenic acids, nickel salts will be addressed based on the toxicological information for the assessment entity nickel, which is classifiedas STOT-RE Cat. 1 (H372) via the inhalation route.