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Description of key information

The substance is bioavailable via oral route. Limited systemic absorption via inhalation and dermal route is anticipated.  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

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 behavior of the substance.

Physico chemical characteristics

The substance is a multi-constituent substance composed of 4 isomers having a relatively low molecular weight of 270.37 g/mol. The substance is slightly water soluble (11.6 mg/L), highly lipophilic based on the octanol/water partition coefficient (log Kow = 4.5,) and not volatile according to its vapour pressure (0.053 Pa at 20°C). The hydrolysis study concluded that the substance is hydrolytically unstable at pH 7 and pH 9, with half-lives at 25°C being 994h and 18.1h, respectively. At pH 4.0 the substance can be considered as a hydrolytically stable compound (half-life > 1 year at +25°C). Hence, the substance 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, 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 undergo micellular solubilisation by bile salts. Substances absorbed as micelles will enter the circulation via the lymphatic system, bypassing the liver.

The acute oral gavage toxicity studies identified only slight evidence of systemic toxicity, i.e. neither mortality nor macroscopic effects but ataxia and/or hunched posture was noted in all animals two to four hours after dosing with hunched posture noted in all females one day after dosing (LD0 ≥ 2000 mg/kg bw). The NOAEL was set at the highest achievable dietary dose tested in the 28-day (851 or 953 mg/kg bw/day for males or females, respectively) and 90 -day (657 or 781 mg/kg bw/day for males or females, respectively) repeated dose toxicity study, the reproductive/developmental screening study (698 mg/kg bw/day in males) and the pre-natal developmental toxicity study using the oral route (1012 mg/kg bw/day). The lack of significant adverse findings following repeated oral dosing may be due to limited gastrointestinal absorption of the test material and/or its metabolites, or due to a very low inherent toxicity of the substance. 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 = 4.5), 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 the 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 (0.053 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.

Excretion

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. Urinary excretion is supported by microscopic kidney changes identified as increased incidence and severity of hyaline droplets in tubules and basophilic tubules was seen in treated males, together with increased kidney weights in males. 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.