Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

The available evidence suggests that 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

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 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.

Physico chemical characteristics

The substance is a racemate composed of 2 enantiomers having a relatively low molecular weight of 236.4 g/mol. The substance is a slightly water soluble solid (1.88 mg/L), highly lipophilic based on the octanol/water partition coefficient (log Kow = 5.09) and not volatile according to its vapour pressure (0.054 Pa at 20°C). Moreover, 99.9% of its particles have a granular size larger than 100 µm and are therefore not expected to be inhalable.

Absorption

Oral/GI 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 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 (LD50 > 2000 mg/kg bw). The combined repeated dose toxicity with the reproduction/developmental screening test using the oral route (gavage) 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/d is known to be a rat-specific lesion and therefore is not relevant for human. 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 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.

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 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 substance. Although no study was available on the substance, these assumptions are supported by the absence of systemic effects following single-dose dermal application of one of its enantiomer 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.

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. However, the vapour pressure and the granulometry of the substance 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.

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 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 combined repeated dose toxicity with the reproduction/developmental screening test 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 ST 10 C 08 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 degrees 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 substance, that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with skin cells.