[2-(1-ethoxyethoxy)ethyl]benzene

Endpoint summary

Description of key information

No experimental toxico-kinetic data are available for assessing adsorption, distribution, metabolisation and excretion of the substance. Based on effects seen in the human health toxicity studies and physico-chemical parameters, Hyacinth body is expected to be readily absorbed via the oral, dermal and inhalation route. No specific information is available on the extent of absorption and therefore the precautionary principle for route to route extrapolation is used to derive the final absorption percentages: 50% oral absorption, 50% dermal absorption and 100% inhalation absorption.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Toxicokinetic behaviour Hyacinth body (CAS no. 2556-10-7)

Introduction

The toxicokinetic behaviour of Hyacinth body (IUPAC name: 2-(1-Ethoxyethoxy)ethyl]benzene, CAS no. 2556-10-7) is assessed to the extent that can be derived from the relevant available information, as is required at Annex VIII level according to the REACH requirements.

Hyacinth body has a benzyl ring with an ethyl chain to which an acetal is attached and another ethyl chain. Hyacinth body is a liquid with a molecular weight of 194.28, which predicts an unhampered absorption based on its structure and the following experimental physico-chemical information is available for the substance: a log Kow of 3.5 at 25°C, water solubility of 453 mg/L at 24°C and a vapour pressure of 3.1 Pa at 24°C. All these physico-chemical parameters provide useful information regarding the behaviour of a substance in the body.

Absorption

Oral: No specific measurements have been performed on oral absorption rate of Hyacinth body. No effects were seen in systemic toxicity studies that could indicate oral absorption. According to Martinez and Amidon (2002) the optimal log Kow for oral absorption falls within a range of 2-7. Hyacinth body has a log Kow of 3.5, which favours absorption. This is additionally encouraged by the water solubility of 453 mg/L, which indicates that the substance may readily dissolve into the gastrointestinal fluids. Furthermore, the small molecular weight of Hyacinth body (<200) is favourable for absorption of the substance in the GI tract through aqueous pores or carriage of such molecules across membranes with the bulk passage of water. Based on this, oral absorption is expected to be over 50%.

Skin: Based on the physico-chemical properties of Hyacinth body, it is suspected that dermal absorption is likely to occur. The substance is liquid and lipophilicity (log Kow of 3.5) of Hyacinth body would favour dermal absorption into the stratum corneum. Also, the water solubility levels of Hyacinth body may promote transfer of the substance between the stratum corneum and the epidermis, which facilitates dermal absorption. The optimal molecular weight and log Kow for dermal absorption is < 100 and in the range of 1-4, respectively (ECHA guidance, 7.12, Table R.7.12-3). The substance is within or just outside this range. However, in an acute dermal toxicity study in rabbits no systemic effects were observed. Treatment with 5000 mg/kg bw Hyacinth body induced neither mortality, nor symptoms other than slight local dermal effects. Still, the skin absorption is not expected to be below 50%.

Lung: The low volatility of the liquid Hyacinth body (3.1 Pa at 24°C) would limit its availability for absorption through inhalation. When there is exposure the absorption can be estimated with the blood/air (B/A) partition coefficient. Buist et al. 2012 developed a B/A portioning model for humans using the most important and readily available parameters:

Log PBA = 6.96 – 1.04 (Log VP) – 0.533 (Log Kow) – 0.00495 MW.

For Hyacinth body the B/A partition coefficient would result in:

Log P (BA) = 6.96 – 1.04 x (Log3.1) – 0.533 x 3.5 – 0.00495 x 194.28 = 3.6

This means that Hyacinth body has a tendency to go from air into the blood. It should, however, be noted that this regression line is only valid for substances which have a vapour pressure > 100 Pa. Despite Hyacinth body being out of the applicability domain and that the exact B/A portioning may not be fully correct, it provides an indication that the substance can be readily absorbed via the inhalation route. Based on this, inhalation absorption of 100% will be assumed.

 

Distribution

The low molecular weight of Hyacinth body can facilitate wide distribution throughout the body. Since Hyacinth body is somewhat lipophilic (log Kow 3.5), it can pass through biological cell membranes and distribute into cells.

 

Metabolism

There are no experimental data on the metabolism of the substance. In view of the substance being a phenyl-ethyl-acetal it is anticipated that the Hyacinth body will be hydrolysed in the body into phenyl alcohol and the carbon that binds to the acetal oxygen will form an ethyl aldehyde (acetealdehyde) and the ethyl group will form ethanol (see the figure below) (http://www.inchem.org/documents/jecfa/jecmono/v48je17.htm). Phenyl ethanol may get further metabolized to phenyl acetic acid. This phenyl acetic acid has a fairly low pKa (4.31) and this acid may cause irritancy in the gastro-intestinal tract, which is the reason not to use the maximum dose in the repeated dose – reproscreen study (OECD TG 422).

Figure 1. Hydrolysis of Hyacinth body into phenyl alcohol, acetaldehyde and ethanol. Phenyl ethanol may get further metabolized to phenyl acetic acid as shown.

[figure is included in attachment]

 

Excretion

Hyacinth body as such will be excreted via urine based on its characteristics (molecular weight below 300 g/mol and fairly high water solubility). The substance is most likely metabolised into more hydrophilic compounds which will also be excreted via the urine.  

 

Conclusion

Based on the available information, Hyacinth body is expected to be readily absorbed after oral and dermal exposure. The substance is expected to be readily absorbed also via inhalation, although the exposure is expected to be low based on the low vapour pressure. No specific information is available on the extent of absorption, therefore the default final absorption percentages as provided by ECHA will be used: 100% inhalation absorption, 50% oral absorption and 50% dermal absorption. Hyacinth body is predicted to be metabolised and its metabolites are expected to be mainly excreted via the urine. Overall, the assessment indicates no potential for bioaccumulation.

Oral to dermal extrapolation: Hyacinth body is absorbed orally and dermally. Using the asymmetric handling of uncertainty, the oral absorption will be considered 50% (though likely to be higher) and the dermal absorption will not exceed oral absorption.

Oral to inhalation extrapolation: The inhalation exposure will be considered. It can be expected that 100% of the inhaled vapour is bioavailable. For inhalation absorption 100% will be used for route to route extrapolation, because this will be precautionary for the inhalation route.

 

References

- Martinez, M.N., And Amidon, G.L., 2002, Mechanistic approach to understanding the factors affecting drug absorption: a review of fundament, J. Clinical Pharmacol., 42, 620-643.

- IGHRC, 2006, Guidelines on route to route extrapolation of toxicity data when assessing health risks of chemicals, http://ieh.cranfield.ac.uk/ighrc/cr12[1].pdf

- Buist, H.E., Wit-Bos de, L., Bouwman, T., Vaes, W.H.J., 2012, Predicting blood:air partition coefficient using basic physico-chemical properties, Regul. Toxicol. Pharmacol., 62, 23-28.