Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

The available evidence suggests that the substance is bioavailable via the oral route and by inhalation if exposure occurs. Systemic absorption of this substance via dermal route is expected but only to a limited extent. The substance is expected to be mainly excreted in urine. The substance has a 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 UVCB with all its constituents having a relatively low molecular weight of 220.35[MB1] g/mol. The substance is a slightly water-soluble liquid (20.7 mg/L) and is highly lipophilic based on the octanol/water partition coefficient (Log Kow = 5.05). The substance has low volatility according to its vapour pressure (0.161 Pa at 20°C).

 

Absorption:

Oral/GI absorption:

The physical chemical characteristics described above suggest that the target substance is of adequate molecular size to participate in endogenous absorption mechanisms within the mammalian gastrointestinal tract. Being lipophilic, the target substance may be expected to cross gastrointestinal epithelial barriers even if the absorption may be limited by the inability of the substance to dissolve into gastro-intestinal fluids and hence make contact with the mucosal surface. Moreover, the absorption will be enhanced if the target substance undergoes micellular solubilisation by bile salts. Substances absorbed as micelles will enter the circulation via the lymphatic system, by passing the liver.

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

- An acute oral gavage toxicity study conducted on the target substance identified neither mortality nor clinical signs (LD50 > 5000 mg/kg bw).

- The reproduction/developmental screening study conducted on the substance using the oral route (diet) gave a NOAEL of 3750 ppm (i.e. 223 mg/kg bw/day in male rats and 225 mg/kg bw/day in female rats). Changes observed in liver and thyroid in this study were considered as normal adaptive metabolism/excretion responses following administration of a xenobiotic. In the absence of corroborative pathology or functional change of the organs these changes are considered to be not adverse. No treatment-related effects were observed in any of these studies.

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 substance being highly lipophilic (log Kow = 5.05), 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. Moreover, it is assumed that the dermal uptake is also limited by the slight water solubility of the substance. Even if the target substance is a skin irritant, which may enhance penetration, and therefore enhance the dermal uptake, the absence of systemic effects following a single-dose dermal application of the target substance up to 1000 mg/kg bw would suggest a limited systemic absorption through cutaneous barriers.

In light of these data, and the lack of specific informationon 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 = 0.161 Pa at 20°C) indicated an absence of volatility and inhalability, and therefore no exposure by inhalation is anticipated. Thus, at ambient temperature, no respiratory absorption is expected under normal use and handling of the substance.

However, when used as a vapour or as mist (droplet 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:

Systemic distribution of the substance can be predicted from its physical chemical characteristics.

Considering that the substance is lipophilic (log Pow > 4) and slightly water soluble, it is suggested that, upon systemic absorption by oral or by inhalation, the substance may be transported through the circulatory system in association with a carrier molecule such as a lipoprotein or other macromolecule.

Afterwards, based on its lipophilic character, the substance may readily cross cellular barriers or may be distributed into fatty tissues with a low potential to accumulate. Due to its lipophilic property, the substance could readily penetrate the stratum corneum following dermal exposure but then it is not expected to be systemically absorbed to a major extent.

 

Metabolism:

Specific data on metabolism of the registered substance is not available. In vitro Micronucleus and HPRT tests showed some evidence of attenuation of cytotoxicity in the presence of S9, which may indicate biotransformation by microsomal enzymes but might also just be evidence of a reduced toxicity in the presence of protein that is commonly observed in such in vitro assays.

 

Excretion:

The substance, having a molecular weight lower than 300 g/mol, is expected to be mainly excreted in urine and 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.

Following dermal exposure, highly lipophilic substances, such as the substance, that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with skin cells.