2-tert-butylcyclohexyl ethyl carbonate

Endpoint summary

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 in a read-across approach from the relevant available information on the target substance collated in the dossier and information on the source substance, 2-tert-butylcyclohexyl acetate (source substance). The physical chemical characteristics of both 2-tert-butylcyclohexyl ethyl carbonate and source substance, the results obtained from acute, the repeated-dose and reproductive toxicity studies from 2-tert-butylcyclohexyl ethyl acetate, as well as information gained from genotoxicity assays were used to predict the toxicokinetic behaviour of the target substance.

See the attached documents for the molecular structures of the target and source substances.  Target substance  Source substance  2-tert-butylcyclohexyl ethyl carbonate 2-tert-butylcyclohexyl acetate

                                                            

Physico chemical characteristics

2-tert-butylcyclohexyl ethyl carbonate has a relatively low molecular weight of 228.3 g/mol. The substance is slight soluble in water soluble liquid (10.9 mg/L) and less dense, with moderate surface active properties. Furthermore, it is low volatile according to its vapour pressure (2.2 Pa at 25°C). Even if the substance has low viscosity (17 mPa), no aspiration hazard is assumed based on the acute toxicity study in which no aspiration induced effect was observed. Finally, 2-tert-butylcyclohexyl ethyl carbonate is moderately hydrophobic based on the octanol/water partition coefficient (log Kow = 4.4).

 

Absorption

The physical chemical characteristics described above suggest that 2-tert-butylcyclohexyl ethyl carbonate is of adequate molecular size to participate in endogenous absorption mechanisms within the mammalian gastrointestinal tract. Being rather hydrophobic than hydrophilic, it may be expected to cross gastrointestinal epithelial barriers.

Based on the chemical structure of 2-tert-butylcyclohexyl ethyl carbonate (target substance), 2-tert-butylcyclohexyl acetate has been identified as a relevant analogue (source substance) for the target substance (see the read-across justification document, section 13). Indeed, The target substance and the source substance share a common basic structure (2-tert butylcyclohexyl) excepted carbonate and acetate groups. Moreover, 2-tert cyclohexanol could be generated from both substances following acidic hydrolysis as explained below.

Indeed, 2-tert-butylcyclohexyl ethyl carbonate could be hydrolysed in the stomach (low pH) to 2-tert butyl cyclohexanol and ethanol. Moreover, under these conditions, the carbonate functional group could turn into carbonic acid (H2CO3) and carbon dioxide, both being in a state of equilibrium in following the equation:

CO2_(aq)+ H2O <---> H2CO3_(aq).

Both carbon dioxide and carbonic acid could occur at acidic pH as in the stomach. At higher pH, carbonic acid would be in a state of equilibrium in the blood with the bicarbonate ion which has a biochemical role in the physiological pH buffering system in the body (acidic-basic homeostasis). But this of minor importance considering the endogenous production of CO2 by the organism.

Regarding 2-tert-butylcyclohexyl acetate (souce substance), it could be hydrolysed in the stomach (low pH) to 2-tert butyl cyclohexanol and ethanoic acid. Then, acetate might be absorbed for transformation into acetylcoenzyme A which can be oxidised in the carboxyclic acid cycle. Acetate could also be degraded in the route of cetogenesis leading to acetylacetic acide, p-hydroxybutiric and acetone.

Therefore, acetate and carbonic acid/bicarbonate ion are compounds involved in physiological pathways.

For ethanol, the classification provided by companies to ECHA identifies that this substance causes serious eye damage (H319).However, even if ethanol formed by hydrolysis of the target substance, it should be at limited amount. Indeed, no irritation to eyes is observed in the in vivo eye irritation study with the target substance. Moreover, no evidence of systemic toxicity,i.e.neither mortality nor clinical/macroscopic effects (including irritation to the gastro-intestinal tract) are observed (LD50 > 2000 mg/kg bw) in the acute oral toxicity study conducted in male mice.

Therefore the main hydrolysis product of toxicological concern the source and target substances is expected to be the same (2 -tert butylcyclohexanol). Based on its structural similarity of cyclohexanol, it may induce effects by oral route according to cyclohexanol classification for the human health, i.e.harmful by oral (H302) and irritant to skin (H315), to the eyes (H319) and by inhalation (H335). However, no acute oral toxicity including irritation of the gastro-intestinal tract was observed in the study performed with 2-tert-butylcyclohexyl ethyl carbonate or in the study with 2-tert-butylcyclohexyl acetate. It might be possible that the amount of 2-tert cyclohexanol together with the presence of 2-tert group could decrease the potential of adverse effect by comparison with cyclohexanol (analogue).

The combined repeated dose toxicity with the reproduction/developmental screening test conducted with the source substance using the oral route (diet) gave a NOAEL of 500 mg/kg bw/day (highest dose level that could be tested, 7500 ppm). Increased relative liver was considered as an adaptive response to an increase in metabolic demand at the highest dose. A dose related increase in relative kidney weight was observed in mid and high dose males which was related to the observed α2µ-microglobulin nephropathy as it was confirmed by immunocytochemical staining of the α2µ-microglobulin protein in the cortical tubular epithelial cells. Hence, the lack of significant adverse findings following oral dosing showed a very low inherent toxicity of 2-tert-butylcyclohexyl acetate. It is anticipated that the effects obtained in the study conducted with the source substance could be used to predict the effects that could be observed if the same study was conducted with 2-tert-butylcyclohexyl ethyl carbonate. Hence, the same type of effect(s) or absence of effect could be predicted showing oral absorption of the target substance.

 

Regarding the dermal absorption, being lipophilic (log Kow = 4.4), the rate of uptake of 2-tert-butylcyclohexyl ethyl carbonate into the stratum corneum is expected to be high while its low water solubility (10.9 mg/L) is not in favour of a high rate of transfer between the stratum corneum and the epidermis. Although no study was available on 2-tert-butylcyclohexyl ethyl carbonate, these assumptions are supported by the absence of systemic effects in an acute toxicity study by dermal route of the source substance up to 5000 mg/kg bw. This would suggest a limited systemic absorption through cutaneous barriers if water solubility and partition coefficient of both substances (target and source substance) are compared. Moreover, enhanced skin penetration is not expected since 2 -tert-butylcyclohexyl ethyl carbonate is nor skin irritating/corrosive nor skin sensitizing as also demonstrated for 2-tert-butylcyclohexyl acetate (see the read-across justification document).

Moreover, using AIHA’s IH SkinPerm tool (developed by American Industrial Hygiene Association) filled in with the physico-chemical properties described above, the (systemic) dermal absorption in human is low for the substanc estimated 2.1%

at 8 -hours workday with 61,2% of evaporation following instantaneous 1 mg deposition of substance (on 1 cm2).

https://www.aiha.org/publications-and-resources/TheSynergist/AIHANews/Pages/French-Research-Institute-Features-AIHA's-IH-SkinPerm-Tool-Online.aspx

For absorption by inhalation, it is expected that exposure to vapour by inhalation is very limited based on the volatility of 2 -tert-butylcyclohexyl ethyl carbonate (2.2 Pa at 25°C). Therefore, the potential for toxicity by inhalation is not anticipated. Moreover, both the partition coefficient (4.4) and the low water solubility (10.9 mg/L) of 2-tert-butylcyclohexyl ethyl carbonate, are not favourable for absorption by inhalation. In addition, considering that 2-tert-butylcyclohexyl ethyl carbonate is not a skin and eye irritant, no respiratory irritation is anticipated that could increase inhalation absorption.

Distribution

Systemic distribution of 2-tert-butylcyclohexyl ethyl carbonate can be predicted from its physico-chemical characteristics. Considering that the substance is hydrophibic (log Kow 4.4) and slight water soluble, it is suggested that, upon systemic absorption, 2-tert-butylcyclohexyl ethyl carbonate may be transported through the circulatory system in association with a carrier molecule such as a lipoprotein or other macromolecule. Afterwards, based on its hydrophibic character, the substance will readily cross cellular barriers or will be distributed into fatty tissues with a potential of accumulation based on the Log K_ow.

The hydrolysed products from 2-tert-butylcyclohexyl ethyl carbonate, i.e. 2-tert butyl cyclohexanol, carbonate and ethanol could be distributed as metabolites or as transformed products if they are absorbed.

Metabolism

The results of the combined repeated dose toxicity with the reproduction/developmental screening test repeated oral toxicity study in the rat with the source substance 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 2-tert-butylcyclohexyl acetate or its hydrolysed products could be metabolised following gastrointestinal tract absorption. Based on the read-across approach, 2-tert-butylcyclohexyl ethyl carbonate and its hydrolysed products could be also metabolised following gastrointestinal tract absorption. For example, ethanol can be metabolised as acetaldehyde by CYP2E1 in the liver before degraded into acetic acid that can enter in the carboxylic acid cycles.

Elimination

2-tert-butylcyclohexyl ethyl carbonate and its hydrolysed products having a molecular weight lower than 300, it is expected to be mainly excreted in urine and may be slightly excreted in bile. It is expected that they are 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 2-tert-butylcyclohexyl ethyl carbonate, that have penetrated the stratum corneum but not totally penetrated the viable epidermis based on limited rate, be sloughed off with skin cells.

Conclusion

2-tert-butylcyclohexyl ethyl carbonate 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. Based on the read-across approach with the source substance tested in the repeated dose oral toxicity study, 2-tert-butylcyclohexyl ethyl carbonate and its hydrolysed products are expected to be metabolised and mainly excreted in urine as unchanged or as their glucuronide and sulfate conjugates.

The bioavailability of 2-tert-butylcyclohexyl ethyl carbonate and hydrolysis products should be limited following exposure by inhalation and by dermal route (see justification document)