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Description of key information

For the registered substance 2-(1,1-dimethylethyl)-6-[[3-(1,1-dimethylethyl)-2-hydroxy-5-methylphenyl]methyl]-4-methylphenyl acrylate (CAS 61167-58-6) an oral absorption potential via micellular solubilisation by bile acids was predicted. However, considering toxicological data, an absorption is considered to be low.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

There are no studies available in which the toxicokinetic behaviour of 2-(1,1-dimethylethyl)-6-[[3-(1,1-dimethylethyl)-2-hydroxy-5-methylphenyl]methyl]-4-methylphenyl acrylate (CAS 61167-58-6) has been investigated.

Therefore, in accordance with Annex VIII, Column 1, Section 8.8.1, 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 2-(1,1-dimethylethyl)-6-[[3-(1,1-dimethylethyl)-2-hydroxy-5-methylphenyl]methyl]-4-methylphenyl acrylate (CAS 61167-58-6) is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physico-chemical and toxicological properties according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017) and taking into account further available information on structural analogue substances.

2-(1,1-dimethylethyl)-6-[[3-(1,1-dimethylethyl)-2-hydroxy-5-methylphenyl]methyl]-4-methylphenyl acrylate (CAS 61167-58-6) is a solid at 20°C which has a molecular weight of 394.55 g/mol and a water solubility of 0.123 µg/L. The experimentally determined log Pow value is 7.25 (HPLC method) and the vapour pressure is calculated to be 2.58 x 10E-7 Pa at 25 °C (EPI Suite, MPBWIN v. 1.43).

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2014).

 

Oral

In general, molecular weights below 500 and log Pow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). Lipophilic compounds may be taken up by micellar solubilisation by bile salts, but this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), in particular for those that are poorly soluble in water (≤ 1 mg/L) as these would otherwise be poorly absorbed (Aungst and Shen, 1986; ECHA, 2017).

The low water solubility (< 0.1 mg/L) and the high log Pow value of 7.25 of the compound indicate that absorption may be limited by the inability to dissolve into GI fluids. However, micellular solubilisation by bile salts may enhance absorption, a mechanism which is especially of importance for highly lipophilic substances with log Pow > 4 and low water solubility (Aungst and Shen, 1986). Thus, in consideration of the molecular weight of 394.55 g/mol absorption following oral administration is predicted.

However, studies on acute oral toxicity with 2-(1,1-dimethylethyl)-6-[[3-(1,1-dimethylethyl)-2-hydroxy-5-methylphenyl]methyl]-4-methylphenyl acrylate (CAS 61167-58-6) showed no signs of systemic toxicity resulting in a LD50 value greater than 5000 mg/kg bw (Miyamoto, 1982). Furthermore, available data on subacute and subchronic oral toxicity with the registered substance (CAS 61167-58-6) showed no adverse systemic effects resulting in a NOAEL ≥ 2792 mg/kg bw/day and a NOAEL ≥ 2193.3 mg/kg bw/day (Hagiwara, 1984), respectively. Considering these results, absorption through micellular solubilisation by bile acids is anticipated to be low.

Dermal

There are no data available on dermal absorption of 2-(1,1-dimethylethyl)-6-[[3-(1,1-dimethylethyl)-2-hydroxy-5-methylphenyl]methyl]-4-methylphenyl acrylate (CAS 61167-58-6). On the basis of the following considerations, the dermal absorption of the substance is considered to be low.

To partition from the stratum corneum into the epidermis, a substance must be sufficiently soluble in water. Thus, with a water solubility < 1 µg/L, dermal uptake of the substance is likely to be low. In addition, for substances having an octanol/water partition coefficient above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and thus limit absorption across the skin. Furthermore, uptake into the stratum corneum itself may be slow. In addition, as the test substance is a solid, hindered dermal absorption has to be considered as dry particulates first have to dissolve into the surface moisture of the skin before uptake vie the skin is possible (ECHA, 2017).

The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) applying the following equation described in US EPA (2014):

log(Kp) = -2.80 + 0.66 log Pow – 0.0056 MW

The Kp was calculated for 2-(1,1-dimethylethyl)-6-[[3-(1,1-dimethylethyl)-2-hydroxy-5-methylphenyl]methyl]-4-methylphenyl acrylate (CAS 61167-58-6) (please refer to Table 1). QSAR calculations confirmed this assumption, as low dermal flux rates ranging of 2.71E-05 mg/cm2 per h was calculated indicating only very low dermal absorption potential for the compound (please refer to Table 1, Dermwin v2.02, EpiSuite 4.1).

Table 1: Dermal absorption value for 2-(1,1-dimethylethyl)-6-[[3-(1,1-dimethylethyl)-2-hydroxy-5-methylphenyl]methyl]-4-methylphenyl acrylate (CAS 61167-58-6) (calculated with Dermwin v 2.02, Epiweb 4.1)

Component

Structural formula

Flux (mg/cm2/h)

2-(1,1-dimethylethyl)-6-[[3-(1,1-dimethylethyl)-2-hydroxy-5-methylphenyl]methyl]-4-methylphenyl acrylate

C26 H34 O3

2.71E-5

 

In addition, available data on acute dermal toxicity of 2-(1,1-dimethylethyl)-6-[[3-(1,1-dimethylethyl)-2-hydroxy-5-methylphenyl]methyl]-4-methylphenyl acrylate (CAS 61167-58-6) showed no systemic toxicity resulting in LD50 values greater than 2000 mg/kg bw (Tsubokura, 2017).

Overall, taking into account the physico-chemical properties of 2-(1,1-dimethylethyl)-6-[[3-(1,1-dimethylethyl)-2-hydroxy-5-methylphenyl]methyl]-4-methylphenyl acrylate (CAS 61167-58-6), the QSAR calculations and available toxicological data with the test compound, the dermal absorption potential of the substance is anticipated to be low.

 

Inhalation

In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15μm the alveolar region of the respiratory tract (ECHA, 2017).

Inhalation of 2-(1,1-dimethylethyl)-6-[[3-(1,1-dimethylethyl)-2-hydroxy-5-methylphenyl]methyl]-4-methylphenyl acrylate (CAS 61167-58-6) is considered negligible since most of the particles have a size between > 250 µm and < 2000 µm. Thus, the contained particles are far above the inhalable size. Moreover, the test substance has a very low calculated vapour pressure of 2.58 x 10E-7 Pa thus being of low volatility (ECHA, 2017). Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours, gases, or mists is not significant.

Based on the physical state and the physico-chemical properties of 2-(1,1-dimethylethyl)-6-[[3-(1,1-dimethylethyl)-2-hydroxy-5-methylphenyl]methyl]-4-methylphenyl acrylate (CAS 61167-58-6), absorption via the lung is expected as negligible.

 

Distribution and accumulation

No data were found regarding the 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 (log Pow >0), it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA, 2017).

Thus, due to the small molecular weight (394.55 g/mol) and a lipophilic character distribution into cells is assumed and in addition the intracellular concentration may be higher than the extracellular concentration particular in fatty tissue. Lipophilic substances will tend to concentrate in adipose tissue and depending on the conditions of exposure may accumulate. If the interval between exposures is less than 4 times the whole body half-life of the substance then there is the potential for the substance to accumulate. It is generally the case that substances with high log Pow values have long biological half-lives. On this basis, daily exposure to a substance with a log Pow value of around 4 or higher could result in a build-up of that substance within the body. Substances with log Pow values of 3 or less would be unlikely to accumulate 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 depending on the half-life of the substance. If fat reserves are mobilized more rapidly than normal, e.g. if an individual or animal is under stress or during lactation there is the potential for large quantities of the parent compound to be released into the blood (ECHA, 2017). Since no experimental data are available a bioaccumulation potential of 2-(1,1-dimethylethyl)-6-[[3-(1,1-dimethylethyl)-2-hydroxy-5-methylphenyl]methyl]-4-methylphenyl acrylate (CAS 61167-58-6) can be assumed. However, considering a low absorption property, the concern of a bioaccumulation is anticipated to be low under actual exposure conditions.

Metabolism

No data are available regarding metabolism. 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. 17 hepatic and 9 dermal metabolites were predicted for the test substance, respectively. Primarily, cleavage of the acrylate ester and/or hydroxylation of the benzene ring, the methyl or the ethyl group may occur in the liver and in the skin, respectively. These predicted metabolites can be regarded as phase I metabolites which are a common prerequisite for the phase II reactions or conjugation reactions, which transfer functional groups to the phase I metabolites to increase the water solubility and the excretion of the xenobiotic. Phase II metabolism by e.g. uridine 5′-diphospho (UDP)-glucuronosyltransferases and sulfotransferases typically generates excretable hydrophilic metabolites by transferring activated glucuronic acid and sulfate-moiety to hydroxyl groups of the substrate, respectively (Aktories, 2005). Up to 28 metabolites were predicted to result from all kinds of microbiological metabolism for the test substance. Regarding the available data on genetic toxicity, Ames test, Chromosome aberration test and HPRT test, no evidence for a genotoxic potential from the registered substance or the metabolites was observed, since all three tests were negative in the absence and in the presence of a metabolic activation system.

 

Excretion

The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces (via bile and directly from the GI mucosa). Only limited conclusions on excretion of a compound can be drawn based on physico-chemical data. Low molecular weight (below 300 g/mol in rat), good water solubility, and ionization of the molecule at the pH of urine are characteristics favourable for urinary excretion. 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. Thus, based on the available data no final conclusion on the excretion route is possible.

 

References

Aktories K., Förstermann U., Hofmann F. and Starke K. (2005): Allgemeine und spezielle Pharmakologie und Toxikologie. 9. Auflage, Urban & Fischer Verlag

Aungst B. and Shen D.D. (1986): Gastrointestinal absorption of toxic agents. In Rozman K.K. and Hanninen O. Gastrointestinal Toxicology.Elsevier, New York, US.

ECHA (2017): Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Version 3.0, June 2017