Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

The substance is bioavailable via oral route. Limited systemic absorption via dermal route is anticipated. Absorption via inhalation is not expected.  The substance will cross cellular barriers or will be distributed into fatty tissues. The substance is expected to be mainly excreted in urine.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

In accordance with the section 8.8.1 of Annex VIII in REGULATION (EC) No 1272/2008, 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 source and the target substance, the results obtained from acute and repeated-dose toxicity studies, skin sensitation test, as well as information gained from genotoxicity assays on the source or the target substances were used to predict the toxicokinetic behaviour of the substance.

Physico chemical characteristics:
The substance is a multi-constituent substance composed of 2 isomers having a relatively low molecular weight of 226.4 g/mol. Based on data on the source substance, the substance is expected to be slightly water soluble (125-285 µg/L – source substance), highly lipophilic based on the octanol/water partition coefficient (log Pow = 5.79 – source substance) and not volatile according to its vapour pressure (0.194 Pa at 25°C – source substance).

The physical chemical characteristics described above suggest that the substance is of adequate molecular size to participate in endogenous absorption mechanisms within the mammalian gastrointestinal tract. Being lipophilic, the 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 substance undergoes micellular solubilisation by bile salts. Substances absorbed as micelles will enter the circulation via the lymphatic system, bypassing the liver. Even if neither mortality nor clinical/macroscopic effects were identified in the acute oral gavage toxicity study, the observation of systemic effects in the combined repeated dose toxicity study with the reproduction / developmental screening test using the oral route (diet), which suggests very low toxicological concern of the substance, indicates the oral bioavailability of the substance itself and/or its metabolites.
Regarding the dermal absorption, the substance being highly lipophilic (log Kow = 5.79 – from source substance), the rate of transfer between the stratum corneum and the epidermis is anticipated to be slow and will limit absorption across skin. However, the substance being identified as a skin sensitizer, some uptake must occur although it may only be a small fraction of the applied dose. Enhanced skin penetration is not expected since the substance is not a skin irritant or corrosive.
The potential for inhalation toxicity was not evaluated in vivo using animals exposed by inhalation. However, the vapour pressure of the substance (0.194 Pa at 25°C – from source substance) indicated an absence of volatility 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

Systemic distribution of the substance can be predicted from its physical chemical characteristics. Considering that the substance is highly lipophilic (log Pow >4 – from source substance) and slightly water soluble, it is suggested that, upon systemic absorption, 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 will readily cross cellular barriers or will be distributed into fatty tissues with a potential to accumulate. Distribution of the substance via dermal route is supported by the positive response in the skin sensitisation test on the source substance, which suggests that the test material binds to carrier proteins in the circulatory system.

An increase in the liver weights and in the minimal centrilobular hepatocellular hypertrophy observed in the combined repeated dose toxicity study with the reproduction / developmental screening study performed on the source substance indicates the liver metabolism of this compound, albeit constituting an adaptive response of no toxicological concern. The results of the in vitro genotoxicity studies available for both the source and the target substances show that genotoxicity was not induced in the presence of S9 metabolising system because the source and target substances were negative in each of mutagenicity tests.

The substance having a molecular weight lower than 300, it 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.