Naphthenic acids, copper salts

Endpoint summary

Description of key information

No repeated dose toxicity study with naphthenic acids, copper salts is available, thus the repeated dose toxicity will be addressed with existing data on the individual assessment entities copper and naphthenic acid. In relevant and reliable repeated dose toxicity studies for both moieties of naphthenic acids, copper salts, toxicological relevant findings were observed in studies with copper as well as naphthenic acid. However, classification criteria are not met since no severe adverse effects were observed at the guidance value, oral for a Category 1 classification of 10 mg/kg bw/day and at the guidance value for a Category 2 classification of 100 mg/kg bw/day, hence no classification required.

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:

no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

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

Copper

Repeated dose toxicity: oral

From studies in which humans were supplemented with copper for 12 weeks, it was concluded that copper homeostasis ensures that copper overload does not occur under normal circumstances. Due to absence of adverse effects the No observed Adverse Effect Level (NOAEL) was set at 10 mg/day. Using the uncertainty factor of two, a Tolerable Upper Intake Level (UL) of 5 mg/day was established for adults and used for the quantitative risk assessment. There are also many studies in the public domain dealing with the repeat and chronic toxicity of copper compounds via the oral route to several animal species via oral application. However, these studies did not meet the higher quality criteria (1 or 2) under the REACH quality criterion selection and will therefore not be used in the risk assessment and will not be described in this document. 

 

Repeated dose inhalation

The 28 days repeated dose inhalation study on Cu2O was used as highly reliable study and read-across to copper. The study was carried out according to OECD Guideline 412. Further additional study endpoints were measurements of copper levels in lung tissue, lung lavage fluid, liver, brain, as well as wet/dry lung weight ratio and clinical chemistry and cytology of bronchoalveolar lavage fluid of all animals. The additional study endpoints were designed to aid in the interpretation of any test substance effects.

 

The overarching findings of this study were the exposure level-dependent appearance of macrophages in the lung, an increase in neutrophil number in BALF as well as in blood, and an increase in LDH and protein levels in the BALF. An increase in inflammation scores (neutrophil-dominated inflammation) was observed in the lung (the highest score being “mild”), and there was a decrease in the wet/dry lung weight ratio (highest exposure level only). Some nasal findings were reported for the high and medium-high exposures in the males.

 

Repeated dose toxicity: dermal

 This study is usually required when the dermal route of exposure is significant and the compound is known to be toxic by the dermal route and can penetrate through intact skin. The need to conduct this study with copper or copper compounds must therefore be considered not necessary as although the dermal route of exposure is the most significant route there is no evidence to indicate that copper or copper compounds can cause toxicity or indeed pass through intact skin at significant levels. Acute dermal toxicity studies showed no toxic effects up to and including the highest dose tested. Therefore an accurate and realistic determination of dermal toxicity can be derived from available sub-chronic oral exposure studies, permissible systemic copper levels and in vitro dermal penetration studies on copper and copper compounds.

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, copper salts

Since no repeated dose toxicity study is available specifically for naphthenic acids, copper salts, information on the individual assessment entities copper and naphthenate will be used for the hazard assessment and when applicable for the risk characterisation of naphthenic acids, copper salts. For the purpose of hazard assessment of naphthenic acids, copper salts, the point of departure for the most sensitive endpoint of each moiety will be used for the DNEL derivation. In case of naphthenic acid in naphthenic acids, copper salts, the NOAEL of 100 mg/kg bw/day for the repeated dose toxicity will be used. In case of copper the Tolerable Upper Intake Level (UL) of 5 mg/kg bw/day based on human data will be used.

Justification for classification or non-classification

In relevant and reliable repeated dose toxicity studies for both assessment entities of naphthenic acids, copper salts, toxicological relevant findings were observed. However, classification criteria are not met since no severe adverse effects were observed at the guidance value, oral for a Category 1 classification of 10 mg/kg bw/day and at the guidance value for a Category 2 classification of 100 mg/kg bw/day, hence no classification required.