1-Butanone, 3-(dodecylthio)-1-[(1R,2S)-2,6,6-trimethyl-3-cyclohexen-1-yl]-, rel-

Endpoint summary

Description of key information

The available evidences suggest that limited systemic absorption of the substance can be anticipated by oral and dermal route and by inhalation if exposure occurs. The substance will cross cellular barriers or will be distributed into fatty tissues. The substance is expected to be excreted in the bile. The substance has a high potential to bioaccumulate.

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 substance, 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 registered substance is a multi-constituent substance, composed of four isomers having a quite high molecular weight of 394.71 g/mol. The substance is insoluble in water (< 0.5 µg/L), highly lipophilic based on the octanol/water partition coefficient (log Kow = 9.5) and not volatile according to its vapour pressure (0.0075 mPa at 25°C).

Absorption:

Oral/GI absorption:

The physical chemical characteristics described above suggest that the registered substance is of adequate molecular size (MM < 500 g/mol) to participate in endogenous absorption mechanisms within the mammalian gastrointestinal tract. Being highly 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 registered substance undergoes micellular solubilisation by bile salts. Substances absorbed as micelles will enter the circulation via the lymphatic system, bypassing the liver. In an acute oral gavage toxicity study conducted on the registered substance, no adverse effects were identified at 2000 mg/kg bw (i.e. no mortality, no clinical signs, and no macroscopical findings). A 28-day repeated dose study and a reproduction/developmental toxicity screening test conducted on the substance using the oral route (gavage) gave a NOEL of 1000 mg/kg bw/day. No treatment-related effects were observed in these two studies. The lack of adverse findings following oral dosing may be due to limited or absent gastrointestinal absorption of the registered substance and/or its metabolites, or to a very low inherent toxicity of the substance and/or its metabolites.

Dermal absorption:

Regarding the dermal absorption, The substance being highly lipophilic (log Kow = 9.5), the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across skin. Moreover, the dermal uptake will also be limited by the insolubility of the substance in water. Uptake into the stratum corneum itself may be slow considering also the quite high molecular weight (around 400 g/mol). However, the registered substance being identified as a skin sensitizer, some uptake must occur although it may only be a small fraction of the applied dose inducing sensitisation. Moreover, enhanced skin penetration is not expected since the substance is not a skin irritant or corrosive.

These assumptions are supported by the absence of systemic effects following single-dose dermal application of the registered susbtance up to 2000 mg/kg bw which would suggest a limited systemic absorption through cutaneous barriers.

Respiratory absorption:

The potential for inhalation toxicity was not evaluated in vivo. However, considering the absence of volatility of the registered substance no exposure by inhalation is anticipated. Thus, at ambient temperature, no respiratory absorption is expected under normal use and handling of the substance.

However, if used as a vapour or as mist (droplet aerosol), the substance is expected to enter respiratory tract. The substance being highly lipophilic (log P > 4) and insoluble in water (< 1 mg/L), it is then expected to be taken up by micellar solubilisation. Considering this pathway of absorpion into the circulation, it is expected that no adverse findings could be observed by comparison with the absence of effects following oral dosing in the acute and repeated dose toxicity study. Moreover, as the substance is not classified to skin and to eyes, no respiratory irritation is expected that could enhance the absorption by inhalation.

Distribution:

Systemic distribution of the substance can be predicted from its physical chemical characteristics. Considering that the substance is highly lipophilic and water insoluble, 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 high potential to accumulate.

Metabolism:

Physiological responses, like liver enzyme induction or limited liver enlargement, were not observed in the available studies, suggesting that there was no need for increased metabolic activity following exposure to the substance.

Excretion:

The registered substance is not water-soluble and has a molecular weight higher than 300, therefore it is not expected to be excreted in urine. Biliary excretion is likely to be the route of excretion after inhalation, dermal and oral routes of exposure.