Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
expert statement
Type of information:
other: expert statement
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study

Data source

Reference
Reference Type:
other: expert statement
Title:
Unnamed

Materials and methods

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Based on molecular weight, physicochemical properties and experimental in vivo data, TBPEH is expected to become bioavailable after oral administration, either as parent and/or as breakdown products.

Oral absorption is favoured for molecular weights below 500 g/mol. TBPEH is not well soluble in water having a relatively high logPow values ranging between 4.79. It may therefore be taken up by micellular solubilisation due to its more lipophilic properties. When administered orally TBPEH might be expected to undergo hydrolysis, at least to some extent. However, it is noteworthy that acute toxicity of TBPEH is low, with an LD50-value of 10000 mg/kg bw in an acute study with rats. This indicates that the acutely more toxic hydrolysis products are probably not formed rapidly enough or to a sufficient amount following oral administration.
Oral absorption for the potential common biodegradation products and the carboxylic acids is well known.
The subacute (28 days) NOAEL was 316 mg/kg bw/day for males and 100 mg/kg bw/day for females, whereas a subchronic NOAEL in rats was determined to be 450 mg/kg bw/d. Based on findings at 300 mg/kg bw/d administered in an EOGRTS (OECD 443) the NOAEL for fertility was determined to be 100 mg/kg bw/d in female rats.
Dermal absorption might be low to moderate based on water solubility and lipophilic properties of TBPEH. Uptake will be limited to the stratum corneum cross the epidermis will be low. This was confirmed in an acute dermal study resulting in an LD50 value of 14142 mg/kg bw. However, TBPEH was shown to be a potential skin sensitizer, thus at least small amounts of the substance or its metabolites must have reached the subcutaneous layers when applied topically on the skin.
No local toxicity effects such as irritation or corrosion were observed in skin or eye.
Based on the low vapour pressure of 2 Pa as well as the considering the very limited use profile, inhalation exposure to TBPEH is not likely. Thus, the inhalation route is considered not relevant for humans.
Nevertheless, if the substance reaches the lung, TBPEH may be absorbed by micellular solubilisation (see above). The low water solubility may enhance penetration to the lower respiratory tract. TBPEH showed very low toxicity after inhalation administration, in an acute inhalation toxicity study revealing a LC50 of 42.2 mg/L. Together, this indicates low systemic availability after inhalation and if bioavailable, potential toxicity is considered to be low.
Details on distribution in tissues:
When reaching the body TBPEH may be distributed throughout the organism. Possible hydrolysis of TBPEH in the blood leads to formation of its degradation products. Both degradation products have low to moderate BCF values and are thus considered not bioaccumulative. Although TBPEH is expected to be distributed into the interior part of the cells due to its lipophilic properties, no bioaccumulation is expected since TBPEH is expected to be degraded to more hydrophilic metabolites when compared to the parent compound. TBPEH undergoes hydrolysis upon contact with water. Possible hydrolysis products are tert-butanol, tert-butyl hydroperoxide and 2-ethylhexanoic acid. All hydrolysis products have a lower log Pow value than TBPEH itself. Consequently, there is no bioaccumulation expected, neither for the parent nor for its degradation products.
Details on excretion:
Since TBPEH has a molecular weight below 300, renal excretion is expected to be the predominant route. This does also apply to the potential degradation products and /or metabolits. This is supported by findings after subchronic exposure to TBPEH. Increased liver and kidney weights were reported, in association with increased urine volume and decreased pH (in both sexes and different cohorts). This observation indicates an increased metabolizing and excretory activity of the kidney and liver induced by the test item exposure. No other histopathological lesions were seen in both organs, except increased findings of chronic progressive nephropathy in male animals.

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
The metabolism of this peroxyester is could possibly include the following pathways:
- enzymatic and non-enzymatic hydrolysis,
- direct reaction with biomolecules due the reactivity of the peroxyester group of the parent or the hydroperoxide formed during hydrolysis (e. g. TBHP)
Hydrolysis may already occur in the gastrointestinal tract. This might occur spontaneously or might be faciliated by an enzymatic process (e.g. esterases or other enzymatic systems of the intestinal microflora).
If the parent compound reaches the liver, enzymatic cleavage is also expected (e.g. by glutathione peroxidase). Unspecific reactions with biomolecules can take place either in the GI-tract or subsequent to absorption. It is assumed that the parent molecules can react directly or after cleavage to hydroperoxide. TBPEH is a skin sensitizer, reactions with macromolecules has been demonstrated to occur. Free radicals and reactive oxygen species which might be formed during metabolism can be deactivated by non-enzymatic antioxidants abundantly available in the organism (e. g. Vitamin E protecting lipid membranes from being peroxidised, Vitamin C and glutathione). Conjugates of these may be faciliated to become excreted or are re-cycled within the endogenous redox system.

Applicant's summary and conclusion

Conclusions:
Based on physico-chemical characteristics, particularly water solubility, octanol-water partition coefficient and vapour pressure, no or only limited absorption by the dermal and inhalation routes is expected. This is supported by the dermal and inhalation acute toxicity studies results. For the oral route uptake of the hydrolysis products of TBPEH is also taken into account. Bioaccumulation of the parent as well as of the hydrolysis products is not likely to occur based on the physico-chemical properties. Excretion of the parent and/or its metabolites or hydrolysis products is expected to occur mainly via the urine.
Executive summary:

Toxicokinetic analysis of tert.Butylperoxy-2-ethylhexanoate (TBPEH) 

Tert. Butylperoxy-2-ethylhexanoate (TBPEH) is a colorless liquid at room temperature with a molecular weight of 216.3 g/mol. The substance is only slightly soluble in water (46.3 mg/L). The logPow of TBPEH was measured to be 4.79. Based on this log Pow a BCF of 202.4 L/kg was calculated by QSAR estimation. TBPEH has a low vapour pressure of 2 Pa at 20 °C.

TBPEH undergoes hydrolysis upon contact with water. Possible hydrolysis products are tert-butanol, tert-butyl hydroperoxide and 2-ethylhexanoic acid. All hydrolysis products have a lower log Pow value than TBPEH itself. Consequently, there is no bioaccumulation expected, neither for the parent nor for its degradation products.

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

Uptake will be limited to the stratum corneum cross the epidermis will be low. This was confirmed in an acute dermal study resulting in an LD50 value of 14142 mg/kg bw. However, TBPEH was shown to be a potential skin sensitizer, thus at least some amounts of the substance or its metabolites must have reached the subcutaneous layers when applied topically on the skin.
No local toxicity effects such as irritation or corrosion were observed in skin or eye.

Oral absorption is favoured for molecular weights below 500 g/mol. Based on the high logPow of 4.79 and the low water solubility, TBPEH may be taken up by micellular solubilisation. When administered orally TBPEH might be expected to undergo hydrolysis, at least to some extent. However, it is noteworthy that acute toxicity of TBPEH is low, with an LD50-value of 10000 mg/kg bw in an acute study with rats. This indicates that the acutely more toxic hydrolysis products are probably not formed rapidly enough or to a sufficient amount following oral administration. The subacute (28 days) NOAEL was 316 mg/kg bw/day for males and 100 mg/kg bw/day for females, whereas a subchronic NOAEL in rats was determined to be 450 mg/kg bw/d. Based on findings at 300 mg/kg bw/d administered in an EOGRTS the NOAEL for fertility was determined to be 100 mg/kg bw/d in female rats.

Based on the low vapour pressure of 2 Pa inhalation exposure is not likely. Nevertheless, if the substance reaches the lung, TBPEH may be absorbed by micellular solubilisation (see above). The low water solubility may enhance penetration to the lower respiratory tract. TBPEH showed very low toxicity after inhalation administration, in an acute inhalation toxicity study revealing a LC50 of 42.2 mg/L. Together, this indicates low systemic availability after inhalation and if bioavailable, potential toxicity is considered to be low.

When reaching the body, TBPEH may be distributed throughout the organism. Hydrolysis of TBPEH in the blood may lead to formation of its degradation products. Both degradation products have low to moderate BCF values (1.09 L/kg and 66.37 L/kg respectively) and are thus considered not bioaccumulative.

Metabolism of parent compound and hydrolysis products may occur. Enzymatic transformation products include the cytochrome P450 system. Phase I reactions are typically followed by phase II reactions resulting in molecules more polar for extraction.

Excretion is likely to occur mainly via the urine and bile. This is supported by findings after subchronic exposure to TBPEH. Increased liver and kidney weights were reported, in association with increased urine volume and decreased pH (in both sexes and different cohorts). This observation indicates an increased metabolizing and excretory activity of the kidney and liver induced by the test item exposure. No other histopathological lesions were seen in both organs, except increased findings of chronic progressive nephropathy in male animals.