Naphthenic acids, cobalt salts

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

Study duration:

subchronic

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Introductory remark – read-across

 

Read-across entails the use of relevant information from analogous substances (the ‘source’ information) to predict properties for the ‘target’ substance(s) under consideration. Substances whose physicochemical or toxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a category of substances. Structural similarity is a pre-requisite for any read-across approach under REACH (ECHA Read-Across Assessment Framework, 2015).

 

In accordance with Annex XI, 1.5 of the REACH regulation and the ECHA Guidance Read-Across Assessment Framework (ECHA, 2017), the similarities may be based on:

 

1) A common functional group (i.e. chemical similarity within the group);

2) Common precursors and/or likelihood of same breakdown products through physical and/or biological processes which result in structurally-similar degradation products (i.e. similarity through (bio) transformation); or

3) A constant pattern in the changing of the potency of the properties across the group (i.e. of physical-chemical and/or biological properties).

 

Due to the absence of substance specific information for the majority of substances within the cobalt category, the approach will read-across data from representative source substances to all other members of the read-across group.

 

Due to the route-specific toxicological properties of the cobalt category substances, several read-across groups are formed as shown in the table below:

 

		Route		Read-across group
Cobalt category		oral-systemic		bioavailable cobalt substances group
			inorganic poorly soluble
			poorly soluble in aqueous solutions with organic ligand
		inhalation-local		reactive
			non-reactive

 

 

Further details on the read-across approach are given in Appendix 1.1 of the CSR for the oral systemic effects and Appendix 1.2 of the CSR for the inhalation local effects.

Naphthenic acids, cobalt salts is assigned to the read-across group for oral-systemic: poorly soluble in aqueous solutions with organic ligand.

 

 

Effects on fertility

 

In three guideline-compliant OECD 422 reproductive screening studies with members of the poorly soluble in aqueous solutions with organic ligand cobalt substances read-across group in the CD(SD) rat. The compounds tested were cobalt neodecanoate, cobalt stearate and cobalt borate neodecanoate. These studies were conducted under the US HPV program, and can be accessed at (EPA website, link to HPV program http://www.epa.gov/hpv/). 

 

While general toxicity was observed in the studies with cobalt neodecanoate and cobalt stearate (such as decreased food consumption, decreased body weight gain, and reduced weight of non-reproductive organs), there was no evidence suggesting that these substances are primary reproductive or developmental toxicants. Effects on reproductive or developmental endpoints occurred only in the presence of considerable general toxicity, suggesting that the reproductive or developmental effects were secondary to overall toxicity of the substances.

 

It is concluded that substances of the poorly soluble in aqueous solutions with organic ligand read-across group are not primary reproductive or developmental toxins, and that the DNELs based on local irritation (gastro-intestinal tract) are sufficient to prevent systemic effects.

 

Due to a lack of adverse effects on fertility, it is concluded that the conditions for proposing an extended one generation reproductive toxicity study for the read-across group “poorly soluble in aqueous solutions with organic ligand” cobalt substances are not met. Experimental testing is therefore scientifically not justified and therefore waived in accordance with the conditions laid down in Section 8.7.3 Column 1, Annex IX of regulation (EC) 1907/2006.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

Study duration:

subacute

Species:

rat

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

Developmental toxicity

Three screening for reproductive / developmental toxicity studies (in accordance with OECD 422) in rats via oral application are available for different poorly soluble in aqueous solutions with organic ligand cobalt substances. The predominant findings in the studies were as follows:

Cobalt stearate: The dose level of 5 mg/kg bw/d represents the NOAEL for toxicity in female rats based on decreased body weight and food consumption, clinical signs of toxicity, mortality, and microscopic pathology effects (degeneration/necrosis of mucosal epithelium (villous and crypt epithelium); atrophy of villi and crypts; regeneration of mucosal epithelium, and mucosal inflammation. Lesions were observed in all segments of the small intestine and in the cecum and colon. Lesions were graded as minimal to severe (grades 1 to 4) and were most severe in the jejunum, ileum, and cecum.) at 15 and/or 100 mg/kg bw/d. The no-observed-adverse-effect level (NOAEL) for systemic toxicity in males was 40 mg/kg bw/d, the highest dose level tested.

Cobalt Borate Neodecanoate: There were no test substance-related effects on mortality, body and organ weights, food consumption, haematology, clinical chemistry, neurobehavioral parameters, pathology and histopathology at any dose level. The no-observed-adverse-effect level (NOAEL) for systemic toxicity in males and females was 5 mg/kg bw/d, the highest dose level tested.

Cobalt neodecanoate: Under the conditions of this study, a no-observed-adverse-effect level (NOAEL) for systemic toxicity was not achieved due to effects on mortality, clinical signs of toxicity, body weight parameters, and food consumption parameters at all dosages in males and females. A LOAEL of 5 mg/kg bw/day (equivalent to 0.7 mg cobalt/kg bw) was determined for male and female rats. Adverse effects were observed in males and female animals already at the lowest dose, manifested as decreased weight gain, lethargy, gastro-enteropathy and subsequent secondary effects.

In summary all available studies for the read-across group poorly soluble in aqueous solutions with organic ligand cobalt substances show adverse effects as follows: (i) Decreased body weight and food consumption, clinical signs of toxicity (ii) Intestinal effects including the following diagnoses: degeneration/necrosis of mucosal epithelium (villous and crypt epithelium); atrophy of villi and crypts; regeneration of mucosal epithelium, and mucosal inflammation (iii) Effects on the haematopoietic system, being the hallmark for the bioavailable cobalt substances group were apparent only in high doses, already showing significant adverse effects in the digestive tract.

There was no evidence suggesting that these substances are primary reproductive or developmental toxicants. Effects on reproductive or developmental endpoints occurred only in the presence of considerable general toxicity, suggesting that the reproductive or developmental effects were secondary to overall toxicity of the substances.

The above discussed studies are considered in a weight of evidence that the poorly soluble in aqueous solutions with organic ligand cobalt substances are not primary developmental toxins, and that the DNELs based on local irritation (gastro-intestinal tract) are sufficient to prevent systemic effects. The severity of the gastrointestinal irritation lead to the decision to self-classify all the poorly soluble in aqueous solutions with organic ligand cobalt substances with specific target organ toxicity after repeated exposure, category 1 (STOT-RE 1, H372- GI tract). Further developmental toxicity testing is not considered to add any relevant information to the hereto negative data and is therefore waived in accordance with regulation 1907/2006 (EC), Annex XI, Section 1.2.

Justification for classification or non-classification

Based on the above discussed data, there was no evidence suggesting that the poorly soluble in aqueous solutions with organic ligand cobalt substances are primary reproductive or developmental toxicants. Effects on reproductive or developmental endpoints occurred only in the presence of considerable general toxicity, suggesting that the reproductive or developmental effects were secondary to overall toxicity of the substances. Based on the weight of evidence the classification criteria as reproductive or developmental toxicants are not met, hence no classification is proposed.