2-ethylhexanoic acid, copper salt

Endpoint summary

Description of key information

No repeated dose toxicity study with 2-ethylhexanoic acid, copper salt is available, thus the repeated dose toxicity will be addressed with existing data on the individual assessment entities copper and 2-ethylhexanoic acid. In relevant and reliable repeated dose toxicity studies for both moieties of 2-ethylhexanoic acid, copper salt, toxicological relevant findings were observed in repeated dose toxicity studies with copper. No adverse effects were observed for the moiety 2-ethylhexanoic acid. 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

Dose descriptor:

NOAEC

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no 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

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.

 

2-ethylhexanoic acid

Several repeated oral dose studies for 2-ethylhexanoic acid were available for assessment. A diet containing 0.5% 2-ethylhexanoic acid caused no adverse effect in rats in a 13 week feeding study (dose levels were 0, 0.1, 0.5, or 1.5%, calculated NOAEL ca. 300 mg/kg bw/day). No adverse effect was observed in mice receiving a diet containing 0.5 % 2-ethylhexanoic acid in a 13 week feeding study (dose levels were 0, 0.1, 0.5, or 1.5%). The NOAEL was calculated to be 200 mg/kg bw/day. Both NOAELs were based on reduced food consumption and a decreased rate of body weight gain in the high dose groups. In both studies, all toxicity observed at higher concentrations (changes in clinical chemistry, absolute and relative organ weights, microscopic changes in kidney liver and fore stomach) was reversible within 28 days after exposure ceased.

Based on the absence of any (severe) adverse effects at low doses in subacute and semichronic toxicity study with a.o. rats, classification for repeated dose toxicity is not warranted according toEU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.

 

2-ethylhexanoic acid, copper salt

Since no repeated dose toxicity study is available specifically for 2-ethylhexanoic acid, copper salt, information on the individual assessment entities copper and 2-ethylhexanoate will be used for the hazard assessment and when applicable for the risk characterisation of 2-ethylhexanoic acid, copper salt. For the purpose of hazard assessment of 2-ethylhexanoic acid, copper salt, the point of departure for the most sensitive endpoint of each moiety will be used for the DNEL derivation. In case of 2-ethylhexanoic acid in 2-ethylhexanoic acid, copper salt, the NOAEL of 100 mg/kg bw/day for the developmental 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

No adverse effects were observed for the assessment entities 2-ethylhexanoic acid. Adverse effects were observed in repeated dose toxicity studies with copper. The 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.