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Description of key information

The available evidence suggests that the substance is bioavailable via oral route. Systemic absorption of this substance via inhalation and dermal route is expected but to a limited extent. Although available toxicological information suggest that the substance is of very low toxicological concern, the substance may cross cellular barriers or may be distributed into fatty tissues. The substance is metabolised in the liver. The substance is expected to be mainly excreted in urine.

Key value for chemical safety assessment

Bioaccumulation potential:
high 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 target 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 target and the source substance (its racemate form), 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 target substance is a reaction mass composed of the source substance (racemate) and another isomer (cf. Iuclid section 13 for read-across justification. All isomers have a relatively low molecular weight of 236.4 g/mol.

The target substance is a slightly water soluble pasty solid (1.87 mg/L for the racemate, 4.97 mg/L for the isomer) and is highly lipophilic based on the octanol/water partition coefficient (log Kow = 5.09, data for the racemate). The water solubility and log Kow data for the source substance are considered to be relevant to assess the toxicokinetic behaviour of the target substance as no significant difference is anticipated between the isomers. The target substance is unlikely to be volatile according to its vapour pressure (0.236 Pa at 25°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, bypassing the liver. The acute oral gavage toxicity study performed on the target substance identified some evidence of systemic toxicity, such as hunched posture, ataxia and lethargy up to four days after dossing at the highest dose level (2000 mg/kg bw/day. However, neither mortality nor macroscopic effects were observed (LD50 > 2000 mg/kg bw). The combined repeated dose toxicity with the reproduction/developmental screening test using the oral route (gavage) performed on the source substance gave a NOAEL of 800 mg/kg bw/day (highest dose level tested). Increased liver weight, biochemical changes (bilirubin, cholesterol, protein) and liver hypertrophy were considered to be part of an adaptive response to an increase in metabolic demand. The induced hyaline droplet nephropathy observed in male rats at 800 and 400 mg/kg bw/day is known to be a lesion specific to adult male rats and therefore is not relevant for human. The lack of significant treatment-related 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 source substance, this could also be said of the target substance. However, the observation of systemic effects, even if of very low toxicological concern, indicates the oral bioavailability of the source substance as well as the target 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 the dermal absorption, the target substance being lipophilic (log Kow = 5.09), 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 target substance. These assumptions are supported by the absence of systemic effects following single-dose dermal application of the source substance up to 2000 mg/kg bw which would suggest a limited systemic absorption through cutaneous barriers. Moreover, enhanced skin penetration is not expected to occur since the target substance is not a skin irritant or 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 physical state (pasty substance) and the vapour pressure of the substance (VP = 0.236 Pa at 25°C) indicated an absence of volatility and inhalability. Thus, at ambient temperature, no respiratory absorption is expected under normal use and handling of the substance.

However, 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:

Systemic distribution of the target substance can be predicted from its physical chemical characteristics as well as from information on its surrogate. Considering that the substance is highly lipophilic (log Pow >4) and slightly water soluble, it is suggested that, upon systemic absorption, the target 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.

Metabolism:

The results of the combined repeated dose toxicity with the reproduction/developmental screening test repeated oral toxicity study in the rat on the source substance showed liver changes that are consistent with the increased metabolism associated with detoxification of a xenobiotic. Moreover, the liver induction suggests that a limited amount of the source substance can be absorbed in the gastrointestinal tract. Therefore, the same metabolism pathway is expected to be followed for the target substance.

Excretion:

The target substance having a molecular weight lower than 300 g/mol, the substance 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 with the source substance (increased degree of severity of hyaline inclusions along with an increased incidence and severity of tubular basophilia). 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 target substance, that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with skin cells.

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