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In accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic behavior of the substance Acetic acid, chromium salt, basic (CAS 39430-51-8) was conducted to the extent that can be derived from the relevant available information on physicochemical and toxicological characteristics.

The substance Acetic acid, chromium salt, basic (molecular weight of 603.2 g/mol) is a yellow-greenish powder, which is soluble in water (675 g/L at 20 °C) and which has a log Po/w of 0.2. No vapour pressure is available, since the substance is a solid with a melting point > 400°C.

 

Absorption

Oral

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2012).

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 are favorable for oral absorption (ECHA, 2012). As the molecular weight of Acetic acid, chromium salt, basic is 603.2 g/mol, an absorption of the molecule in the gastrointestinal tract is not expected. This assumption is supported by a study performed with the source substance chromium acetate hydroxide, for which an absorption of only 0.8% of the dose after oral administration was observed (Juturu et al., 2002). Furthermore, no toxic effects of Acetic acid, chromium salt, basic were observed in an acute oral toxicity study (Seguier et al. 2008) leading to the overall conclusion, that the substance is not bioavailable and will be excreted unchanged.

 

Dermal

The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 favours dermal absorption, above 500 the molecule may be too large (ECHA, 2012). As the molecular weight of Acetic acid, chromium salt, basic is 603.2 g/mol, a dermal absorption of the molecule is unlikely.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2012). As Acetic acid, chromium salt, basic is not considered as skin irritating in humans, an enhanced penetration of the substance due to local skin damage can be excluded.

Dermal acute toxicity was assessed in an acute study (OECD 402) and an LD50 of >2000 mg/kg bw was determined (Seguier et al. 2008). No deaths and clinical signs were observed.

For substances with a log Pow around 0, poor lipophilicity will limit penetration into the stratum corneum and hence dermal absorption. Liquids and substances in solution are taken more readily than dry particulates. Dry particulates will have to dissolve into the surface moisture of the skin before uptake can begin. In addition, the substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis (ECHA, 2008). As Acetic acid, chromium salt, basic is easily soluble in water, but is a solid with a log Pow of 0.2, dermal uptake is likely to be low.

Overall, the relatively high molecular weight (>100), the log Pow value, the physical appearance and the fact that the substance is not irritating to skin implies that dermal uptake of Acetic acid, chromium salt, basic in humans is considered as limited.

 

Inhalation

As a general guide, highly volatile substances which can easily be inhaled, are those with a vapour pressure greater than 25 KPa. Substances with low volatility have a vapour pressure of less than 0.5 KPa and are not suspected to be inhaled. No vapour pressure is available for Acetic acid, chromium salt, basic, since the substance is a solid with a melting point > 400°C. Therefore, no assumption on respiratory absorption based on the volatility is possible.

However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the substance is sprayed. In humans, particles with aerodynamic diameters below 100 µm have the potential to be inhaled. Particles with aerodynamic diameters below 50 µm may reach the thoracic region and those below 15 µm the alveolar region of the respiratory tract. Moderate log Pow values (between -1 and 4) are favourlable for absorption directly across the respiratory tract epithelium by passive diffusion. Vapours of very hydrophilic substances may be retained in the mucus (ECHA, 2008). Regarding the particle size distribution of Acetic acid, chromium salt, basic (75.81 µm: 85.4%, 15.18 µm: 4.84%) and the low log Pow of 0.2, the substance can possibly be inhaled. Due to the hydrophilic character, retention in the mucus might also be possible. No acute inhalation toxicity study is available. A subchronic inhalation study with the source substance basic chromium sulphate (Derelanko et al., 1999, Section 7.5.3) has demonstrated the absence of mortality at concentrations 30 mg of Cr(III)/m³ (equivalent to 132 mg/m³ chromium triacetate). This was the highest concentration tested. General toxicity observations, observed only at the highest concentration tested, included sporadic signs of laboured breathing and depressed body weight development. Basic chromium sulphate produced severe and widespread effects in the nasal cavity, larynx, lungs, and mediastinal lymph node. Effects were characterized by accumulation of foreign material, infiltration of alveolar macrophages, septal cell hyperplasia, and granulomatous and chronic inflammation. These effects can be considered as local effects on the respiratory tract.

Accumulation and distribution

In general, the smaller the molecule, the wider the distribution. Small water-soluble molecules and ions will diffuse through aqueous channels and pores (ECHA, 2012). Since Acetic acid, chromium salt, basic has a relatively high molecular weight but is water soluble, distribution within the body might occur. Accumulation of the substance in adipose tissue is unlikely since the substance is hydrophilic, but accumulation might occur in organs. This was demonstrated for chromium acetate hydroxide (Juturu et al. 2003). Application of a single oral dose of 1000 mg/kg bw to rats statistically significantly elevated chromium concentrations were observed in liver, heart, kidneys and pancreas after dosing with chromium acetate compared to controls.

Metabolism

The water solubility of Acetic acid, chromium salt, basic suggests, that there is likely no significant metabolism. Dissolving the substance in water leads to the formation of chromium triacetate and chromium dihydroxy acetete. 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 Acetic acid, chromium salt, basic 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 substances a single positive result was observed in an in vitro MLA study. This effect was overruled by further negative results obtained in a second in vitro MLA, in an in vivo MNT and an in vivo Comet assay.

 

Excretion

Since absorption after oral uptake of Acetic acid, chromium salt is considered to be very low, most of the ingested substance will be excreted unchanged via faeces. This assumption is supported by the results of an oral repeated dose toxicity study with the source substance chromium picolinate monohydrate. In this study, reddish colored faeces were observed in high dosed animals (Rhodes et al., 2005). The effect was attributed to the reddish colour of the test substance. In addition, it was shown that after oral administration of chromium(III) picolinate monohydrate to rats about 99% of the administered Cr(III) is not absorbed but excreted via faeces (NTP, 2008). Tissue Cr does not increase over a 2-yr feeding period, so that accumulation in tissues upon prolongued exposure is excluded.

However, acetic acid, chromium salt that might be absorbed will be excreted via urine. This was shown for the source substance chromium picolinate monohydrate. After oral administration to rats the analysis of urine revealed that about 1% of the administered substance is excreted unchanged in the urine (NTP, 2008). Elevated urine chromium levels were also observed in chromium acetate hydroxide administered animals when compared to controls (Juturu et al., 2002).

Reference

ECHA Guidance on information requirements and chemical safety assessmentChapter R.7c: Endpoint specific guidance, 2012