2-ethylhexyl benzoate

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

10

Additional information

There are no studies available in which the toxicokinetic behaviour of 2-ethylhexyl benzoate has been investigated.

Therefore, the assessment of toxicokinetics of 2-ethylhexyl benzoate is conducted on a qualitative basis taking into account data on benzoic acid esters and the information on substance identity and physiochemical parameters according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2008).

 

Absorption

The test substance is a mono-constituent substance with a purity of > 90%. The molecular weight of the substance is 234.33 g/mol and is therefore in a range suggestive of absorption from the gastro-intestinal tract. The log P value of the substance (log P = 6,21; Butler, 2012) indicates, that the substance is highly lipophilic and therefore may be taken up by micellular solubilisation in particular as the substance is poorly soluble in water (water solubility = 0.4 mg/L at 20 °C; Frischmann 2012). The absorption of the test material in the gastrointestinal (GI) tract may be limited by the inability of the test material to dissolve into GI fluids. However, solubilisation processes by e.g. bile salts may enhance the micellular solubilisation.

Oral

Data on the acute oral toxicity of 2-ethylhexyl benzoate are available. The test substance has been tested in an acute oral toxicity study, resulting in a LD50 value greater than 2500 mg/kg bw. At the dose of 5000 mg/kg bw acute oral toxicity was apparent in the test animals; therefore bioavailability of 2-ethylhexyl benzoate after oral administration is indicated (Blanchard, 2000).

Inhalation

Based on the physicochemical properties of 2-ethylhexyl benzoate, in a conservative approach the absorption via the lung is expected to be equal to oral absorption. The test material has a very low vapor pressure (37 Pa at 20°C, Younis, 2012) and a boiling point of 303°C at 1013hPa (Croda, 2011). Furthermore, the log P values of the test material (log P = 6.21, Butler, 2012 ) do not favour absorption directly across the respiratory tract epithelium by passive diffusion. A possible absorption by micellular solubilisation for highly lipophilic compounds (log P > 4), with a poor water solubility (1 mg/L or less) is possible. Furthermore, due to the above discussed toxicity after oral absorption it is likely that the substance will also be absorbed if it is inhaled.

Dermal

On the basis of the following considerations, the dermal absorption of 2-ethylhexyl benzoate is considered to be moderate to low. The physicochemical parameters, especially the very low water solubility of the test substance and the high log P, indicate a limited dermal uptake. Substances with log P > 6 and low water solubility are not able to partition from the stratum corneum into the epidermis. The rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Furthermore, QSAR calculation using EPIwebv4.1 confirmed this assumption, resulting in a low Dermal Flux of 6.54 x 10 ^-4 mg/cm² per h.

Furthermore, an acute dermal toxicity study with the test material is available indicating a LD50 value > 5000 mg/kg bw after dermal application (Blanchard, 2000). In the study, no systemic signs of toxicity were noted in any animal, thus supporting the assumption of a low dermal absorption. The relevant skin irritation study indicated that 2-ethylhexyl benzoate is not skin irritating and therefore no enhanced penetration of the substance through damaged skin is possible (Johnson, 2001). Furthermore, in the skin irritation study no systemic toxicologically relevant effects were observed. Skin sensitisation studies showed no skin sensitisation properties of 2 -ethylhexyl benzoate, thus confirming the previous notions, as well (Coleman, 2000; Johnson, 2001). Taking the physiochemical parameters, the QSAR calculation and the relevant toxicological test data together, the dermal absorption potential of the test substance cannot completely be excluded but is presumably moderate to low.

Distribution

No toxicokinetic studies investigating the distribution of 2-ethyl hexyl benzoate are available. Regarding the physicochemical parameters of the substance, due to the molecular weight of 234.33 g/mol a distribution is possible. The log P value of (log P = 6.21, Butler, 2012) suggests a distribution into cells and intracellular concentration may be higher than extracellular concentration particularly in fatty tissues.

Metabolism

After absorption, benzyl derivates have been shown to be metabolized in the liver. The ester bond within the molecule is expected to be enzymatically hydrolysed in vivo yielding the corresponding alcohol and benzoic acid (Jones, 1956). For example, in a study with Wistar rats, the metabolism of ethyl para-hydroxybenzoate after oral administration was observed. In the study, the excretion of mainly free 4-hydroxybenzoic acid and its glucuronic and glycine conjugates was noted (Derache and Gourdon, 1963). An in-vivo study in mice and rats with radiolabelled benzyl acetate also confirmed a rapid hydrolysis. In the study, more than 90% radioactivity was demonstrated in the urine as benzoic acid and hippuric acid (Abdo, 1985). Furthermore, a metabolism study with the respective alcohol 2-ethylhexanol, which may result from the ester hydrolysis, have been shown a rapid elimination via the urine after oral administration. The urinary metabolites were predominantly glucuronides of oxidized metabolites of 2-ethylhexanol (Deisinger, 1994).

The predictions of metabolism using the OECD toolbox vs. 2.3 confirmed the generation of different metabolites. The liver metabolism simulator predicted 4 metabolites and the skin metabolism simulator provided 10 metabolites. However, most of the simulated metabolites were generated from the microbial simulator with 56 metabolites of 2-ethyl hexyl benzoate. This metabolites were predominantly the hydrolysis products of the parental substance.

Accumulation and Excretion

After absorption, the test substance is supposed to be metabolized to benzoic acid and the alcohol 2-ethylhexanol (Jones, 1956). Benzoic acid and 2-ethylhexanol are supposed to be rapidly metabolized and excreted (Deisinger, 1994; Abdo, 1985). Therefore, no potential for bioaccumulation is to be expected.

 

References:

Abdo K.M., Huff J.E., Hasseman J.K., Boorman G.A., Eustis S.L., Matthews H.B., Burka L.T., Prejean J.D. and Thompson R.B. (1985) Benzyl acetate carcinogenicity, metabolism and disposition in Fischer 344 rats and B5C3F1 mice. Toxicology, 37, 159-170.

Deisinger. P.J., Boatman. R.J., Guest. D. (1994) Metabolism of 2-ethylhexanol administered orally and dermally to the female Fischer 344 rat. Xenobiotica, 24(5),429-40.

Derache, R., Gourdon, J., 1963. Metabolism of a food preservative: p-hydroxybenzoic acid and its esters. Food Cosmet. Toxicol. 1, 189-195.

Jones P. S., Thigpen D., Morrison J. L., and Richardson A.P. (1956) p-hydroxybenzoic acid esters as preservatives. III. The physiological disposition of p-hydroxybenzoic acid and its esters.J. of the Amer. Pharm. Assoc., 45(1),268-273.