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Administrative data

Link to relevant study record(s)

Description of key information

The substance is bioavailable via oral route. Limited systemic absorption via inhalation and dermal route is anticipated. It will cross cellular barriers or will be distributed into fatty tissues. It is expected to be mainly excreted in urine.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

There is no specific requirement to generate toxicokinetic information in REACH. Therefore, the toxicokinetic profile of the substance (i.e. absorption, distribution, metabolism and elimination) was derived from the relevant available information. The physical chemical characteristics of the substance, the results obtained from acute and repeated-dose toxicity studies, as well as information gained from genotoxicity assays were used to predict the toxicokinetic behaviour of the substance.

Physico chemical characteristics:

The substance is a multi-constituent, each isomer having a relatively low molecular weight of 284.44 g/mol. The substance is slightly water soluble (4.7 mg/L), highly lipophilic based on the octanol/water partition coefficient (log Kow = 4.68) and not volatile according to its vapour pressure (17.2 Pa at 20°C). The hydrolysis study concluded that it is hydrolytically unstable at pH 9, with half-life at 25°C being 224h. At pH 4.0 and 7.0 the test substance can be considered as a hydrolytically stable compound. Hence, it showed a slight degree of hydrolysis under alkaline conditions such as those which may be observed in the intestine while no or limited hydrolysis would occur at acidic pH such as in the stomach.

Absorption:

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, it 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. However, an acute oral gavage toxicity studies identified no evidence of systemic toxicity, i.e. neither mortality nor clinical/macroscopic effects (LD0 ≥ 2000 mg/kg bw). The 28-day and the 90 -day repeated dose and the one-generation toxicity studies using the oral route (gavage) gave a NOAEL of 1000 mg/kg bw/day. The effects observed in the liver were considered to be a physiological adaptation and therefore non-adverse. The effects seen in kidneys were consistent with spontaneous and current findings in rats and were therefore non-adverse. The lack of significant adverse findings following oral dosing may be due to limited gastrointestinal absorption of the test material and/or its metabolites, or to a very low inherent toxicity of the parent. However, the observation of systemic effects, even if of very low toxicological concern, indicates the oral bioavailability of the substance and/or its metabolites.

Regarding the dermal absorption, the substance being lipophilic (log Kow = 4.68), 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. These assumptions are supported by the absence of systemic effects following single-dose dermal application of test substance up to 2000 mg/kg bw which would suggest a limited systemic absorption through cutaneous barriers. Moreover, 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. However, the vapour pressure of the substance (17.2 Pa at 20°C) 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

Distribution

Systemic distribution of the substance can be predicted from its physical chemical characteristics. Considering that the substance is highly lipophilic (log Pow >4) 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 low potential to accumulate.

Metabolism

The results of the repeated oral toxicity study in the rat showed liver changes that are consistent with the increased metabolism associated with detoxification of a xenobiotic. Moreover, the liver induction confirmed that a non-negligible part of the substance can be absorbed in gastrointestinal tract.

Elimination

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 this substance, that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with skin cells.