3-ethoxy-1,1,5-trimethylcyclohexane

Endpoint summary

Description of key information

The available evidence suggests that the substance is bioavailable via the oral route. Systemic absorption of this substance via inhalation and dermal routes 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 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 registered substance (i.e. absorption, distribution, metabolism and elimination) was derived from the relevant available information collated in the dossier. The physical chemical characteristics of 3-Ethoxy-1,1,5-trimethylcyclohexane, 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

3-Ethoxy-1,1,5-trimethylcyclohexane (D) has a relatively low molecular weight of 170.3 g/mol. The substance is considered as low water soluble liquid (27 mg/L) and volatile according to its vapour pressure (220 Pa at 25°C). Furthermore, 3-Ethoxy-1,1,5-trimethylcyclohexane has low potential for bioaccumulation since it is moderately lipophilic based on the octanol/water partition coefficient (log Kow = 3.91).

Absorption

The physical chemical characteristics described above suggest that 3-Ethoxy-1,1,5-trimethylcyclohexane is of adequate molecular size to participate in endogenous absorption mechanisms within the mammalian gastrointestinal tract. Being rather lipophilic than hydrophilic, it may be expected to cross gastrointestinal epithelial barriers and the absorption may be enhanced by the ability of 3-Ethoxy-1,1,5-trimethylcyclohexane to dissolve into gastro-intestinal fluids and hence make contact with the mucosal surface. 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 (diet) gave a NOAEL of 1000 mg/kg bw/day (highest dose level tested, 15000 ppm). Increased liver and kidney weight and several clinical biochemistry changes (higher total protein, albumin, sodium, creatinine and cholesterol and lower glucose and total bilirubin in males, and higher bile acids and cholesterol and lower alkaline phosphatase activity in females) were considered to be part of an adaptive response to an increase in metabolic demand at the highest dose. The lack of significant adverse findings following oral dosing may be due to a very low inherent toxicity of 3-Ethoxy-1,1,5-trimethylcyclohexane. However, the observation of non-adverse systemic effects, indicates the oral bioavailability of 3-Ethoxy-1,1,5-trimethylcyclohexane and/or its metabolites.

Regarding the dermal absorption, being lipophilic (log Kow = 3.91), the rate of uptake of 3-Ethoxy-1,1,5-trimethylcyclohexane into the stratum corneum is expected to be high while its low water solubility is not in favour of a high rate of transfer between the stratum corneum and the epidermis. Moreover, the vapour pressure should limit the absorption. Although no study was available on 3-Ethoxy-1,1,5-trimethylcyclohexane, these assumptions are supported by the absence of systemic effects following a single-dose dermal application of 3-Ethoxy-1,1,5-trimethylcyclohexane up to 2000 mg/kg bw which would suggest a limited systemic absorption through cutaneous barriers. Moreover, enhanced skin penetration is not expected since 3-Ethoxy-1,1,5-trimethylcyclohexane is not a skin irritant or corrosive. However, 3-Ethoxy-1,1,5-trimethylcyclohexane is skin sensitiser in LLNA showing that dermal penetration occurs leading to sufficient amount of substance for sensitisation even if it should be very low. Indeed, this is demonstrated in the LLNA where the SI is just above the cut-off limit at the highest concentration (89%). Moreover, using AIHA’s IH SkinPerm tool (developed by American Industrial Hygiene Association) filled in with the physico-chemical properties described above, dermal absorption in human is low (5.5%), estimated at below 0.055 mg. Morever, almost 83% of substance evaporation occurs at 8-hours workday following instantaneous 1 mg deposition of substance (on 1 cm2) or with the deposition over 8-hour time scenario, respectively.

https://www.aiha.org/publications-and-resources/TheSynergist/AIHANews/Pages/French-Research-Institute-Features-AIHA's-IH-SkinPerm-Tool-Online.aspx with the tool "IHSkinPerm_V1.24b"

Exposure to vapour by inhalation is possible based on the volatility of 3-Ethoxy-1,1,5-trimethylcyclohexane (220 Pa at 25°C). Therefore, the potential for toxicity by inhalation is anticipated. However, both the partition coefficient (3.91) and the low water solubility (27 mg/L) of 3-Ethoxy-1,1,5-trimethylcyclohexane, are not favourable for absorption by inhalation. Moreover, considering that 3-Ethoxy-1,1,5-trimethylcyclohexane is not skin and eye irritant, no respiratory irritation is anticipated that could increase inhalation absorption.

Distribution

Systemic distribution of 3-Ethoxy-1,1,5-trimethylcyclohexane can be predicted from its physical chemical characteristics. Considering that the substance is lipophilic (log Kow 3.91) and lower water soluble, it is suggested that, upon systemic absorption, 3-Ethoxy-1,1,5-trimethylcyclohexane 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 based on the partition coefficient.

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. This liver induction confirmed that a non-negligible part of 3-Ethoxy-1,1,5-trimethylcyclohexane can be absorbed in gastrointestinal tract.

Elimination

3-Ethoxy-1,1,5-trimethylcyclohexane having a molecular weight lower than 300 g/mol, it is expected to be mainly excreted in urine and may be slightly excreted in bile. It is expected that 3-Ethoxy-1,1,5-trimethylcyclohexane is excreted unchanged or as their glucuronide and sulfate conjugates. The substance amount that may not be absorbed from the gastro-intestinal tract, following oral ingestion, will be excreted in the faeces.

Following dermal exposure, lipophilic substances, such as 3-Ethoxy-1,1,5-trimethylcyclohexane, that have penetrated the stratum corneum but not totally penetrated the viable epidermis based on limited rate, be sloughed off with skin cells.

 

3-Ethoxy-1,1,5-trimethylcyclohexane is bioavailable via oral route. Limited systemic absorption via inhalation and dermal route are anticipated. The substance will cross cellular barriers or may be distributed into fatty tissues. 3-Ethoxy-1,1,5-trimethylcyclohexane is expected to be mainly excreted in urine as unchanged or as their glucuronide and sulfate conjugates.

The bioavailability of 3-Ethoxy-1,1,5-trimethylcyclohexane should be limited following exposure by inhalation and by dermal route.