OO-tert-butyl O-(2-ethylhexyl) peroxycarbonate

Endpoint summary

Description of key information

The absorption/excretion, toxicokinetics, metabolism and distribution data of TBEC were evaluated from the available toxicological data and the physicochemical properties as suggested by the REACH Guidance Chapter R.7c.

TBEC is a clear colorless liquid at room temperature with a molecular weight of 246.3 g/mol. The substance is only very slightly soluble in water (5.39 mg/L). The logKow of TBEC was measured to be 5.2. Based on this log Kow a logBCF of 3.1 was calculated. TBEC (without its impurities) has a very low vapor pressure of 4 10e-7 Pa at 20 °C.

 

Absorption

Oral

TBEC is at least partially degraded hydrolytically to 2-ethylhexanol at 25 °C, with half-live of 19.4, 83.0, 131.3 and 98.0 h at pH 9, 8, 7 and 4, respectively. Tert-butanol was not detected during the hydrolysis tests. The half-life of TBEC hydrolysis decreases when increasing the temperature at pH 9: t1/2 is 19.4 h at 25 °C, 4.7 h at 37 °C, and 1.4 h at 50 °C. In addition, hydrolysis occurs at pH 4 (rat stomach pH), with a half-life of 12.9 hours at 37°C. Regarding these data, it can be expected that hydrolysis at pH 1.2 (human stomach pH) and 37 °C is possible but relatively limited.

This means that following oral exposure, mainly TBEC (and not its possible hydrolysis by products) will be absorbed both in human and in rats.

Oral absorption is favored for molecular weights below 500 g/mol. Based on the high logKow of 5.2 and the water solubility, TBEC may be taken up by micellular solubilisation. When administered orally TBEC may hydrolyze to 2-ethylhexanol but in a relatively small extent. Acute and subacute oral toxicity of TBEC are low.

Using a model to predict either high or low fraction absorbed for an orally administered, passively transported substance, the rates of absorption of TBEC were 100 and 90% for doses of 1 and 1000 mg, respectively (Danish QSAR database). According to the pkCSM method (Pires et al., 2015) for predicting small-molecule pharmacokinetic properties, TBEC is also expected to be readily absorbed (91%) by the oral route. Therefore, for human risk assessment, a default absorption rate of 100% will be used.

 

Dermal

Based on physico–chemical properties of TBEC the substance is not likely to penetrate skin to a large extent as the high logKow value and the low water solubility do not favor dermal penetration.

The dermal absorption of TBEC was estimated with IH SkinPerm v2.04 model (AIHA, 2018). Compared to in vitro data from OECD 428 studies, IH skinPerm allowed the estimation of the dermal absorption rate with a good confidence and a low frequency (ca. 2%) of underestimation for liquids (Arkema’s internal validation study, 2018). According to the data input, IH SkinPerm v2.04 model leads to the following results:

 

	Instantaneous deposition	Deposition over time End time observation 8 hr
Total deposition (mg) or deposition rate (mg/cm²/hr	1000	1
Fraction absorbed (%)	2.94	0.367
Amount absorbed (mg)	29.4
Lag time stratum corneum (min)	7.28
Max. derm. abs. (mg/cm²/h)	0.00184

 

Uptake across the epidermis is expected to be low (2.94%). This was confirmed in an acute dermal toxicity study resulting in an LD0 value of more than 2000 mg/kg bw (with no associated clinical signs). In addition, TBEC was not shown to be a skin sensitizer and is only slightly to moderately irritating for skin. The skin absorption rate is therefore limited and considered at 10% for risk assessment.

 

Inhalation

Based on the low vapour pressure of 4 10e-7 Pa, inhalation exposure is very unlikely. Nevertheless, if the substance reaches the lung, TBEC may be absorbed by micellular solubilisation. The low water solubility may enhance penetration to the lower respiratory tract.

Distribution

Once absorbed via the gastrointestinal tract it is likely that TBEC will be distributed systemically into cells due to its lipophilic properties and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues.

According to the pkCSM method (Pires et al., 2015) for predicting small-molecule pharmacokinetic properties, TBEC is expected to have a high steady state volume of distribution, a low fraction unbound to serum proteins, and to readily cross the blood-brain barrier and penetrate the CNS.

Metabolism

The metabolism of TBEC by cytP450 was evaluated by the Xenosite P450 Metabolism 1.0 software. XenoSite is able to predict the site of metabolism (SOM) of a molecule for cytP4501A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 CYP isoforms (Pires et al., 2015). Xenosite computes a probability score varying between 0 and 1 (a high probability to be a SOM is characterized by a high score), which reflects both the confidence of the model that a particular atom is metabolised and the statistical likelihood that its prediction for that atom is correct, but they do not explicit model selectivity (which molecules are substrates of a given CYP enzyme). According to the cyt P450 isoforms and the substance isomers, TBEC is preferentially metabolized by cytP4502C9 on the hexyl radical.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100