Allyl (cyclohexyloxy)acetate

Endpoint summary

Description of key information

No studies are available. The molecular weight, physicochemical properties incl. water solubility and octanol-water partition coefficient of the substance suggest that oral, inhalative and dermal absorption occur. Based on the moderate lipophilicity of the substance, widely distribution within the water compartment of the body after systemic absorption is not expected. However, the distribution into cells particularly in fatty tissues is likely. Based on its log Pow the test substance is considered to have a low bioaccumulation potential. The test substance might be metabolised after absorption. Excretion predominantly via the urine is expected.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

In accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) No 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), assessment of the toxicokinetic behaviour of the test substance was conducted to the extent that can be derived from the relevant available information on physicochemical and toxicological characteristics. There are no studies available evaluating the toxicokinetic properties of the substance.

The test substance is a clear colourless to light yellow liquid at 20 °C with a molecular weight of 198.26 g/mol and a good water solubility of 1655 mg/L at 20 °C. The substance has a low vapour pressure of 0.52 hPa at 20°C and the log Pow is 2.80 at 24.7 °C.

 

Absorption

The major routes by which the test substance can enter the body are via the lung, the gastrointestinal tract, and the skin. To be absorbed, test substances must transverse across biological membranes either by active transport mechanisms or - as being the case for most compounds - by passive diffusion. The latter is dependent on compound properties such as molecular weight, lipophilicity, or water solubility (ECHA, 2017).

 

Oral

Generally the smaller the molecule the more easily it may be taken up. The molecular weight of the test substance is relatively low with 198.26 g/mol, favouring oral absorption of the compound. This is supported by the determined log Pow value of 2.80, being advantageous for oral absorption. Moreover, water-soluble substances will readily dissolve in the gastrointestinal fluids which favour oral absorption. One other mechanism, by which small water-soluble molecules (molecular weight up to around 200) can be absorbed in the GI tract include the passage through aqueous pores or carriage of such molecules across membranes with the bulk passage of water (Renwick, 1994). Moreover, the observation of systemic toxicity following exposure by any route is an indication for substance absorption; however, this will not provide any quantitative information.

 

In an acute oral toxicity study according to OECD 401 conducted with the test substance in rats (Key, 1984) signs of systemic toxicity were observed. No mortality occurred at 250 mg/kg bw, whereas in the 500 and 750 mg/kg bw dose groups 3 and 5 animals died, respectively. In the 1000 mg/kg bw dose group all animals died. Animals of all dose groups showed clinical signs such as apathy, posture anomalies, ataxia, increased excitability, piloerection, ptosis and dark red coloured urine. The symptoms occurred in surviving animals reaching peak intensity within 20 min and 48 h after administration. Animals which died before study termination showed the clinical signs with constant intensity until exitus. Based on the results of this study, the LD50 value was calculated to be 620.42 mg/kg bw in rats.

In addition, a repeated dose 28-day oral toxicity study (OECD 407; Key, 2017) was conducted, where rats were treated with the test substance in the diet at dose levels of 0.01, 0.03 and 0.1% (equivalent to 11.5, 32.8 and 108.6 mg/kg bw/day for males, and 10.7, 32.2 and 96.0 mg/kg bw/day for females, respectively). Dose levels were selected based on the results of a previously conducted dose range finding study in which a test substance-related decrease in body weight was observed in males and females in the 0.3% groups. In the main study, no mortality occurred and no adverse systemic effects were observed.

 

Based on the results of this study, the systemic NOAEL was ≥ 0.1 % in diet (equivalent to 108.6 and 96.0 mg/kg bw/day in males and females, respectively).

In conclusion, based on the available data from the acute oral toxicity study and the repeated dose range finding study, oral toxicity was observed with the test substance and thus absorption of the test item via the gastrointestinal tract has evidently occurred.

 

Dermal

The dermal uptake of liquids and substances in solution is generally expected to be higher than that of dry particles. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Thus, for the molecular weight level of the test substance dermal uptake can be seen to be moderate. The log Pow value of the test substance is between 2 and 3 and therefore is optimal for dermal absorption. For dermal uptake sufficient water solubility is needed for the partitioning from the stratum corneum into the epidermis. Therefore, if the water solubility is between 100 and 10000 mg/L the dermal absorption is anticipated to be high (ECHA, 2017).

The dermal permeability constant Kp of the substance was estimated to be 0.00877 cm/h using DermwinTM (v.2.01) and taking into account the molecular weight of 198.26 g/mol and the log Pow of 2.80. Thus taking also into account the water solubility of 1655 mg/L, the absorption of the test substance is anticipated to be moderate to high. Data from an acute dermal toxicity limit test (Key, 1999) revealed no clinical signs or mortalities at any dose level. Therefore, the dermal LD50 value was greater than 2000 mg/kg bw. Against the background of the demonstrated toxic potency after oral exposure, the dermal toxicity seems to be of lower magnitude, presumably due to a lower dermal uptake in contrast to oral absorption.

 

Inhalation

Moderate log Pow values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. However, the test substance has a low vapour pressure of 0.52 hPa at 20 °C. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapour can be considered negligible.

 

Distribution

Distribution of a compound within the body depends on the physicochemical properties of the substance, especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA, 2017).

Since the test substance is moderately lipophilic (log Pow 2.80) the distribution into cells is likely and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues, if the substance is absorbed systemically. Substances with log P values of 3 or less would be unlikely to accumulate in adipose tissues with the repeated intermittent exposure patterns normally encountered in the workplace but may accumulate if exposures are continuous. Once exposure to the substance stops, the substance will be gradually eliminated at a rate dependent on the half-life of the substance.

 

Metabolism

No metabolism studies are available with the test substance itself. Prediction of compound metabolism based on physicochemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo. The potential metabolites following enzymatic metabolism were predicted using the QSAR OECD toolbox (v4.1, OECD, 2017). This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. The substance is hydrolysed to (cyclohexyloxy)acetic acid and the respective allyl alcohol. 16 hepatic and 2 dermal metabolites were predicted for the test substance. Primarily, hydroxylation of the substance occurs in the liver, while only hydrolysis occurs in the skin. In general, the hydroxyl groups make the substances more water-soluble and susceptible to metabolism by phase II-enzymes. 78 metabolites were predicted to result from all kinds of microbiological metabolism for the test substance. Most of the metabolites were found to be a consequence of the degradation of the molecule. There was no evidence for differences in genotoxic potencies due to metabolic changes in in vitro genotoxicity tests. The studies performed on genotoxicity (Ames test and HPRT test and micronucleus test in mammalian cells in vitro) were negative, with and without metabolic activation (Key, 1999, Key, 2015, Key, 2016).

 

Excretion

Only limited conclusions on excretion of a compound can be drawn based on physicochemical data. Due to metabolic changes, the finally excreted compound may have few or none of the physicochemical properties of the parent compound. In addition, conjugation of the substance may lead to very different molecular weights of the final product. The molecular weight (< 300 g/mol) and the water solubility of the molecule are properties favouring excretion via urine. Thus, the test substance is expected to be excreted predominantly via the urine.

 

References

ECHA (2017): Guidance on information requirements and chemical safety assessment – Chapter 7c: Endpoint specific guidance. European Chemicals Agency, Helsinki

Renwick, A.G. (1994) Toxicokinetics - pharmacokinetics in toxicology. In Hayes, A.W. (ed.) Principles and Methods of Toxicology. Raven Press, New York, p 103 as cited in ECHA, 2017