Chromium tris((2-ethylhexanoate)

Endpoint summary

Description of key information

According to Annex VIII (section 8.8) and ECHA guidance document on information requirements and chemical safety assessment - chapter R.7c (ECHA, 2017), assessment of the toxicokinetic behaviour of a substance can be derived from the relevant available information including physicochemical and toxicological properties.

Chromium 2-ethylhexanoate is a green sticky paste which has a limited water solubility (< 1 ppm Chromium at 30°C), its log Pow was estimated to be 7.64. No vapour presure information is available since no melting point was observed from - 80°C to 600°C. Acute oral and dermal toxicity studies were performed on the substance with no observable effect. Corrosion and irritation studies carried out with the substance gave also negative results. LLNA test came back negative. No mutagenicity was observed in an Ames test.

Additional information

Absorption

Oral

Generally, the smaller the molecule the more easily it may be taken up. Molecular weights below 500 are favourable for absorption whereas molecular weights above 1000 do not favour absorption. Molecular weight of Chromium 2-ethylhexanoate is 481.6 g/mol. Therefore, the absorption via oral route cannot be excluded.

However, the water solubility of Chromium 2-ethylhexanoate was determined to be < 1 ppm Cr at 30°C rendering the dissolution in gastrointestinal fluids and subsequent absorption unlikely. Consistent with this, there were no toxic effects observed in an acute oral toxicity study leading to the overall conclusion that the absorption of Chromium 2-ethylhexanoate via oral route is limited.

On the other hand, the source substance (Chromium picolinate monohydrate) is readily absorbed and consistent with worst-case assumption in that between 25 and 55% 14C of the orally administered Chromium picolinate monohydrate was excreted in the urine (NTP, 2010).

Dermal

Molecular weight of the substance is 481.6 g/mol. Molecular weight less than 100 favours dermal uptake whereas above 500 the molecule may be too large. Therefore, a dermal absorption of Chromium 2-ethylhexanoate may be possible.

In-vitro skin irritation/corrosion studies showed that the substance is neither corrosive, nor irritant for the skin. As a consequence, an enhanced penetration of the substance due to damage to the skin surface is excluded.

An acute dermal toxicity study carried out on the substance does not show any sign of toxicity. Absence of signs of systemic toxicity could indicate that absorption has not occurred.

Skin sensitization study carried out also on the target substance came back negative, confirming that the dermal update may be minimum.

Inhalation

Absorption via inhalation route is not anticipated due to the physical form of the substance. The pure substance is a sticky paste which is not volatile and not likely to form aerosol.

Accumulation and distribution

In general, the smaller the molecule, the wider the distribution. Since the molecule is lipophilic (log P > 0), it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues.

Based on log Pow estimated to be 7.64, there is the potential for the substance to accumulate in individuals that are frequently exposed (e.g. daily at work) to that substance. Once exposure stops, the concentration within the body will decline at a rate determined by the half-life of the substance. Lipophilic substances will tend to concentrate in adipose tissue and depending on the conditions of exposure may accumulate.

However, a guideline compliant OECD 417 study conducted with source substance Chromium picolinate shows that 99% of the Chromium (III) is excreted via faeces (NTP, 2010). In this 2-year study, it is demonstrated that the Chromium present in tissue does not increase during the study period, showing that there is no accumulation of Chromium in tissue. The remaining 1% Chromium picolinate absorbed via oral route is excreted unchanged by urine as shown by analysis.

Metabolism

Evidence for differences in toxic potencies due to metabolic changes can be derived for instance from in vitro genotoxicity tests conducted with or without metabolic activation. No effects with the substance were observed in a bacterial reverse mutation assay, indicating no reactivity of the substance or its metabolites under the test conditions. For the read-across substance Chromium picolinate a single positive result was observed in an in vitro mammalian cell gene mutation test (OECD 476). This effect was overruled by further negative results obtained in a second in vitro mammalian cell gene mutation test (OECD 476) with Niacin-bound chromium, in an in vivo mammalian erythrocyte micronucleus test (OECD 474) and an in vivo Comet assay, both performed with Chromium picolinate.

Excretion

In an oral subchronic toxicity study conducted with the source substance Chromium picolinate monohydrate, reddish colored faeces were observed in high dosed animals (Rhodes et al., 2005). This reddish color came from the color of the tested substance and shows that most of the ingested substance was excreted unchanged via faeces.

In addition, a guideline compliant OECD 417 study conducted with source substance Chromium picolinate shows that 99% of the Chromium (III) is excreted via faeces (NTP, 2010). In this 2-year study, it is demonstrated that the Chromium present in tissue does not increase during the study period, showing that there is no accumulation of Chromium in tissue. The remaining 1% Chromium picolinate absorbed via oral route is excreted unchanged by urine as shown by analysis.

Reference

Guidance on Information Requirements and Chemical Safety Assessment - Chapter R.7c - Endpoint specific guidance - version 3.0 from June 2017 (ECHA).