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Description of key information

No repeated dose toxicity study with fatty acids, C9-13-neo-, copper salts is available, thus the repeated dose toxicity will be addressed with existing data on the individual assessment entities copper and neodecanoate. As detailed in the RAAF report, neodecanoic is considered as representative of fatty acids, C9-13 -neo-. Adverse findings were observed in relevant and reliable repeated dose toxicity studies with the assessment entity copper. However, no adverse effects were observed with the assessment entity neodecanoic 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:
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 adverse effect observed

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.

Neodecanoate

Repeated dose toxicity, oral:

Seven male and seven female rats were exposed to 0; 10; 30; 100, or 300 mg/kg/day propanoic acid, 2,2-dimethyl- (CAS# 75-98-9) by oral gavage for 28 consecutive days (Shell Research Ltd., 1990). No treatment related changes were observed in body weight, food intake, haematology, or histopathology. The only clinical signs seen in this study were a shaking of heads, sneezing, dark nasal discharge, immediately after dosing 100 and 300 mg/kg/day. This behaviour could result from a mild irritant effect of the volatile acidic test compound. Slight increase of alkaline phosphatise, cholesterol and bilirubin levels at the 100 and 300 mg/kg/day dose levels, and slight increase of alkaline phosphatise and cholesterol levels in the plasma of females at the 30 mg/kg/day dose level. Increase in kidney and liver weight was observed in the 300 mg/kg/day group. None of these changes correlated with histopathological effects. These findings were considered adaptive changes and not indicative of a treatment-related adverse effect. The no observed adverse effect level (NOAEL) in this study was 300 mg/kg.

Five male and five female rats were exposed to 0; 10; 55; or 300 mg/kg/day fatty acids, C9-C13 neo (CAS# 68938-07-8) by oral gavage for 28 consecutive days (Shell Internationale Petroleum Maatschappij, 1994). There were no mortalities. Increased salivation was observed after dosing in rats receiving 300 mg/kg. No treatment related changes were observed in body weight, food consumption, haematology, or clinical chemistry. In males receiving 300 mg/kg, kidney weight increased and necropsy revealed an abnormal appearance of the kidney. A dose-related hyaline droplet was noted in males at all treatment levels. The findings in the kidney of the treated males are species and sex specific and not considered relevant to humans. The NOAEL in this study was 300 mg/kg.

Dermal

In a repeated-dose dermal study, neodecanoic acid was applied repeatedly (once daily for 10 applications with a rest period on days 5 and 6) to the skin of rabbits at doses of 0.5 or 2.5 ml/kg (400 or 2280 mg/kg/day).  All animals survived the exposure.  Wheezing was noted in one animal at the 0.5 ml dose level.  Animals at the lower dose level generally showed an overall body weight gain while those at the high level showed terminal weight losses.  The low level animals generally showed slight erythema and moderate atonia and desquamation following the first or fourth application and during the remainder of the study.  At the high level, moderate erythema and moderate or marked atonia and desquamation were present in all animals.  In addition, slight edema was present following the fifth application and slight fissures or cracks were observed in several animals following the last seven applications.  The exposed skin also became hypersensitive to the touch.  There were no indications of systemic toxicity attributed to exposure.

 

A repeated dose dermal toxicity study was conducted for propanoic acid, 2,2-dimethyl- (CAS# 75-98-9) in male rabbits (Hazelton Laboratories Inc., 1964). Test material in isopropyl alcohol solution was repeatedly applied to the shaved intact skin of albino rabbits 5 days/week for two weeks (for a total of 10 applications) at doses of 30 or 300 mg/kg/day. Slight to moderate irritation at the low dose and moderate to marked irritation at the high dose was observed. Slight or moderate erythema, atonia, and desquamation were seen at the low dose. At the high dose, skin irritation consisted of moderate erythema, slight to marked edema, moderate or marked atonia and desquamation. Some dermal necrosis at the site of application was seen in three rabbits and persisted throughout the study. Control animals that received only the solvent (isopropyl alcohol) showed slight irritation. There were no signs of systemic toxicity attributable to dermal absorption of propanoic acid, 2,2-dimethyl-. The NOAEL for systemic toxicity in this study was 300 mg/kg.

 

Carboxylic acid, C6-8 neo (CAS# 95823-36-2) was applied at 55.4 mg/kg and 553.7 mg/kg to the shaved intact skin of rabbits for 10 applications (Hazleton Laboratories, Inc., 1964). No treatment related effects were observed on behaviour of clinical signs during the in-life phase of the study. Gross pathology of the animals in all dose groups did not reveal any abnormalities. Repeated application of carboxylic acid C6-8 neo did produce marked skin irritation with some dermal necrosis at the site of application in the high dose group. Since no systemic effects were observed in this study, the NOAEL for systemic effects following subchronic dermal application of carboxylic acid, C6-8 neo was 553.7 mg/kg.

 

Members of the Neo acid C5 to C28 Category have a low order of toxicity under conditions of repeat exposure by oral and dermal routes. In addition, they display a consistent degree of subchronic toxicity by either oral or dermal route of exposure. No classification for repeated dose toxicity is indicated according to the classification, labelling, and packaging (CLP) regulation (EC) No 1272/2008.

 

Fatty acids, C9-13-neo-, copper salts

Since no repeated dose toxicity study is available specifically for fatty acids, C9-13-neo-, copper salts, information on the individual assessment entities copper and neodecanoate will be used for the hazard assessment and when applicable for the risk characterisation of fatty acids, C9-13-neo-, copper salts. As detailed in the RAAF report, neodecanoic is considered as representative of fatty acids, C9-13 -neo-. For the purpose of hazard assessment of fatty acids, C9-13-neo-, copper salts, the point of departure for the most sensitive endpoint of each moiety will be used for the DNEL derivation. In case of neodecanoic acid in fatty acids, C9-13-neo-, copper salts, the NOAEL of 75 mg/kg bw/day for the reproductive 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 fatty acids, C9-13-neo, copper salts, toxicological relevant findings were observed in repeated dose toxicity studies with copper. No adverse effects were observed for the moiety neodecanoic 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.