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Description of key information

The available evidence suggests that the substance is bioavailable via the oral, dermal and inhalation route. The substance is expected to be mainly excreted in urine.The substance has low potential to bioaccumulate.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

In accordance with the section 8.1.1 of Annex VIII of Regulation (EC) No 1907/2006 (REACH), the toxicokinetic profile of the substance (i.e. absorption, distribution, metabolism and elimination) was derived from the relevant available information collated in the dossier. The physical chemical characteristics of the registered substance, the results obtained from acute, repeated-dose, and reproductive toxicity studies, as well as information gained from genotoxicity assays were used to predict its toxicokinetic behaviour.

 

Physical-chemical properties:

The substance is a mono-constituent, having a relatively low molecular weight of 178.2 g/mol. The substance is a highly water soluble solid/powder (13700 mg/L) and is moderately lipophilic based on the octanol/water partition coefficient (Log Kow = 1.95). The substance has low volatility according to its vapour pressure (0.178 Pa at 25°C).

 

Absorption:

Oral/GI absorption

The physical chemical characteristics described above suggest that the registered substance is of adequate molecular size to participate in endogenous absorption mechanisms within the mammalian gastrointestinal tract. Being lipophilic, the registered substance may be expected to cross gastrointestinal epithelial barriers where the absorption may be potentiated by the ability of the substance to dissolve into gastro-intestinal fluids and hence make contact with the mucosal surface.

These hypotheses are supported by oral systemic effects, as summarized below:

- In an acute oral gavage toxicity study, narcotic effects (ataxia, lethargy and loss of righting reflex) were observed at 2000 mg/kg bw.

 

The observation of systemic effects even if limited indicates the oral bioavailability of the substance and/or its metabolites.

In light of these data, and the lack of specific information, the substance was assumed to be 100% bioavailable by oral route for the purpose of human health risk assessment.

 

Dermal absorption

Regarding dermal absorption, the registered substance being lipophilic, the rate of uptake into the stratum corneum is expected to be high while the rate of penetration is likely to be limited by the rate of transfer between the stratum corneum and the epidermis. It is assumed that the dermal uptake is also potentiated by the high water solubility of the substance.Moreover, enhanced skin penetration is expected to occur since the substance is a skin corrosive.

In light of these data, and the lack of specific information on the substance, a dermal absorption of 100% was conservatively assumed for the purposes of human health risk assessment.

 

Respiratory absorption

The potential for inhalation toxicity was not evaluated in vivo.

The vapour pressure of the substance (Vp = 9.2 Pa at 25°C) indicated a low volatility. However, a fraction of this substance can be inhaled as dust particles (27% <105µm, 4.2%<11µm, 1.8% <4.5µm) with a non-negligible thoracic fraction (<11µm) of 4.2%. Therefore exposure by inhalation is anticipated. Thus, at ambient temperature, significant respiratory absorption is expected under normal use and handling of the substance.

Moreover, when used as a vapour in aerosol, the substance is expected to be directly absorbed across the respiratory tract epithelium by passive diffusion.

In light of these data, and the lack of specific information on respiratory absorption, the substance was conservatively assumed to be 100% bioavailable by inhalation for the purposes of human health risk assessment.

 

Distribution:

Any material that is absorbed will be distributed via the blood to the liver, and other organs and tissues. The very high water solubility of the substance would promote the distribution in the body via the water channels. The rate at which very hydrophilic molecules diffuse across membranes could limit their distribution. Afterwards, based on its moderate lipophilic character, the substance may readily cross cellular barriers or may be distributed into fatty tissues with a low potential to accumulate (Log Kow<4).

Clear signs of central nervous system (CNS) effects (narcosis) in the acute oral toxicity study by gavage indicate that the substance and/or its metabolites has distributed to the CNS.

 

Metabolism:

Specific data on metabolism of the registered substance is not available.

Due to the presence and high activity of different enzymes in liver, the registered substance is expected to undergo different transformations such as: [Ref.[1]]

-        Reduction of the carbonyl group to hydroxyl controlled by aldo-keto reductase (EC-1.1.1)

-        Oxidative O-delkylation controlled by cytochrome P-450 enzyme systems (EC-1.14.14.1, CYP1A1/2 and CYP2B1/2) which is very reactive in liver as compared to skin.

-        Oxidation of aldehyde group to carboxylic acid controlled by ALDH.

-        Detoxification reactions such as glucuronidation on the hydroxyl group and reaction of glycine with the COOH group forming “hippuric type” compounds

 

Excretion:

The registered substance, having a molecular weight lower than 300 g/mol, is expected to be mainly excreted in urineand no more than 5-10% may be excreted in bile. Any substance that is not absorbed from the gastro-intestinal tract, following oral ingestion, will be excreted in the faeces.

 

Hydrolysis:

The hydrolytic properties of the Target substance have been determined and it is not hydrolysed at physiological pH (i.e. pH=7) or below (pH = 2 and 5).

Reference:

[1] Expert review of capability of Calone to metabolise in skin and liver (see the attached document in IUCLID Section 7.4)