tert-butyl 3,5,5-trimethylperoxyhexanoate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: expert statement

Adequacy of study:

key study

Study period:

2014-03-04

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Data source

Reference

Reference Type:

other: expert statement

Title:

Unnamed

Year:

2014

Report date:

2014

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

tert-butyl 3,5,5-trimethylperoxyhexanoate

EC Number:

236-050-7

EC Name:

tert-butyl 3,5,5-trimethylperoxyhexanoate

Cas Number:

13122-18-4

Molecular formula:

C13H26O3

IUPAC Name:

tert-butyl 3,5,5-trimethylhexaneperoxoate

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Oral absorption is favoured as the molecular weight is below 500 g/mol. Based on the high log Pow of 5.16, TBPIN could be regarded as a lipophilic substance. Such a lipophilic compound may be taken up by micellular solubilisation. This mechanism may be of particular importance for TBPIN, as the substance is only slightly soluble and would otherwise be poorly absorbed.
When TBPIN is administered without a vehicle as in the acute study LD50 values between 12905 and 15486 mg/kg bw/day are obtained. Furthermore, results from long term administration studies (28- and 90-day study, prenatal developmental toxicity study) with TBPIN indicate that the compound, and to a lower amount, its hydrolysis products became bioavailable. Therefore, it could be assumed that only limited direct absorption across the gastrointestinal tract epithelium will occur when applied orally. Furthermore, when administered orally TBPIN will hydrolyse rapidly to tert-butyl hydroperoxide and 3,5,5-trimethylhexanoic acid and both substances will be able to pass the epithelium due to their lower log Pow values.
Based on the low vapour pressure of 3 Pa, inhalation exposure is not likely. Nevertheless, if the substance reaches the lung, TBPIN may be absorbed by micellular solubilisation (see above). The low water solubility may enhance penetration to the lower respiratory tract. TBPIN showed no toxicity after inhalation administration, in an acute inhalation toxicity study when applied at a limit dose of 0.8 mg/L. Together, this indicates low systemic availability after inhalation and if bioavailable, no toxicity effects via this route of administration.
Similarly, based on physical–chemical properties of TBPIN, the substance is not likely to penetrate skin to a large extent as the high log Pow value and low water solubility (between 1 and 100 mg/L) do not favour dermal penetration. For substances with a log Pow between 4 and 6, the rate of penetration is limited by the rate of transfer between the stratum corneum and the epidermis. Only the uptake into the stratum corneum will be high. Furthermore, application of TBPIN to skin of rats and rabbits did not cause irritation or corrosion or systemic effects (mortality) in a skin irritation/corrosion study and in acute dermal toxicity study. Applied to the skin of guinea pigs, sensitising effects were observed, indicating that at least small amounts of the substance become available in the body. However, the effects noted might also be linked to reaction products between TBPIN and/or its hydrolysis products and molecules present in the skin.

Details on distribution in tissues:

When absorbed, TBPIN may be distributed into the cells due to its lipophilic properties and the intracellular concentration might be higher than the extracellular concentration particularly in fatty tissues. Based on its relatively high BCF value TBPIN may be therefore considered to bioaccumulate in the human body. However, it is expected that TBPIN does not reach the blood without hydrolysing to its degradation products. Both degradation products have low BCF values (3.16 respectively) and are thus not bioaccumulative.

Details on excretion:

As discussed above TBPIN will hydrolyse rapidly, and will thus not be excreted in its non-hydrolysed form. The first degradation product tert-butyl hydroperoxide has a low molecular weight of 90.12 g/mol, is miscible in water and is thus excreted rapidly via the urine. The second hydrolysis product 3,5,5-trimethylhexanoic acid has a molecular weight of 158.24 g/mol, is poorly soluble in water and will be thus favourably excreted via the bile. However, in case of glucuronic acid and/or amino acid conjugates renal excretion might be favoured due to their increased water solubility.

Metabolite characterisation studies

Metabolites identified:

not measured

Details on metabolites:

Based on the structure of the molecule, TBPIN may be hydrolysed after being in contact with an aqueous solution as well as enzymatically. The first degradation product tert-butyl hydroperoxide may be converted by glutathione peroxidase into tert-butanol which in turn could be conjugated with glucuronic acid or sulfate to increase the compound’s hydrophilicity (Chance, B. et al. 1979). Oxidation of tert-butanol by alcohol dehydrogenases (ADH) and aldehyde dehydrogenases (AlDH) is an alternative metabolic pathway resulting in 2,2-dimethyl-propionic acid (pivalic acid). Pivalic acid as well as the second hydrolysis product of TBPIN, 3,5,5-trimethylhexanoic acid, are estimated to be conjugated with glucuronic acid, sulphate or amino-acids like glutamine in order to ultimately facilitate excretion. Formation of dicarboxylic acids by ω-oxidation might be an alternative metabolic pathway for increasing water solubility and thus facilitating excretion.
Metabolic conversion into more toxic metabolites cannot be fully excluded as results obtained in the Chromosome aberration tests show only positive effects with S9 activating metabolising system. Since these results are not confirmed by the available in vivo micronucleus assay metabolic activation of TBPIN in vivo is considered unlikely.

Applicant's summary and conclusion

Conclusions:

Based on physical-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, which is further supported by the dermal and inhalation acute toxicity studies results. For the uptake by the oral route the hydrolysis products of TBPIN are more relevant than the parent compound. Bioaccumulation of the hydrolysis products is not likely to occur based on the physical-chemical properties. Hydrolytic and metabolic conversion into tert-butyl hydroperoxide and 3,5,5-trimethylhexanoic acid is expected and conjugation of Phase I-metabolites may further increase hydrophilicity. Metabolites of TBPIN are considered to be less toxic than TBPIN itself in vivo. Excretion of the different hydrolysis products is expected to occur via the urine and the faeces depending on the physical-chemical characteristics of the metabolites and/or degradation products.

Executive summary:

Toxicokinetic analysis of tert-butyl-3,5,5-trimethylperoxyhexanoate (TBPIN)

 

TBPIN is a colourless liquid at room temperature with a molecular weight of 230.3 g/mol. The substance is only slightly soluble in water (14.2 mg/L). The log Pow of TBPIN was measured to be 5.16. Based on this log Pow a BCF of 1179 was calculated. TBPIN has a low vapour pressure of 3 Pa at 303.2 K.

TBPIN is rapidly degraded hydrolytically to tert-butyl hydroperoxide and 3,5,5-trimethylhexanoic acid. Both substances have lower log Pow values than TBPIN itself (0.8 and 3.2 respectively) and lower BCF values compared to TBPIN (3.16 L/kg wet-wt.).

 

Absorption

Oral absorption is favoured as the molecular weight is below 500 g/mol. Based on the high log Pow of 5.16, TBPIN could be regarded as a lipophilic substance. Such a lipophilic compound may be taken up by micellular solubilisation. This mechanism may be of particular importance for TBPIN, as the substance is only slightly soluble and would otherwise be poorly absorbed.

When TBPIN is administered without a vehicle as in the acute study LD50 values between 12905 and 15486 mg/kg bw/day are obtained.Furthermore, results from long term administration studies (28- and 90-day study, prenatal developmental toxicity study) with TBPIN indicate that the compound, and to a lower amount, its hydrolysis products became bioavailable.Therefore, it could be assumed that only limited direct absorption across the gastrointestinal tract epithelium will occur when applied orally. Furthermore, when administered orally TBPIN will hydrolyse rapidly to tert-butyl hydroperoxide and 3,5,5-trimethylhexanoic acid and both substances will be able to pass the epithelium due to their lower log Pow values.

Based on the low vapour pressure of 3 Pa, inhalation exposure is not likely. Nevertheless, if the substance reaches the lung, TBPIN may be absorbed by micellular solubilisation (see above). The low water solubility may enhance penetration to the lower respiratory tract. TBPIN showed no toxicity after inhalation administration, in an acute inhalation toxicity study when applied at a limit dose of 0.8 mg/L. Together, this indicates low systemic availability after inhalation and if bioavailable, no toxicity effects via this route of administration.

Similarly, based on physical–chemical properties of TBPIN, the substance is not likely to penetrate skin to a large extent as the high log Pow value and low water solubility (between 1 and 100 mg/L) do not favour dermal penetration. For substances with a log Pow between 4 and 6, the rate of penetration is limited by the rate of transfer between the stratum corneum and the epidermis. Only the uptake into the stratum corneum will be high. Furthermore, application of TBPIN to skin of rats and rabbits did not cause irritation or corrosion or systemic effects (mortality) in a skin irritation/corrosion study and in acute dermal toxicity study. Applied to the skin of guinea pigs, sensitising effects were observed, indicating that at least small amounts of the substance become available in the body. However, the effects noted might also be linked to reaction products between TBPIN and/or its hydrolysis products and molecules present in the skin.

 

Distribution

When absorbed, TBPIN may be distributed into the cells due to its lipophilic properties and the intracellular concentration might be higher than the extracellular concentration particularly in fatty tissues. Based on its relatively high BCF value TBPIN may be therefore considered to bioaccumulate in the human body. However, it is expected that TBPIN does not reach the blood without hydrolysing to its degradation products. Both degradation products have low BCF values (3.16 respectively) and are thus not bioaccumulative.

 

Metabolism

Based on the structure of the molecule, TBPIN may be hydrolysed after being in contact with an aqueous solution as well as enzymatically. The first degradation product tert-butyl hydroperoxide may be converted by glutathione peroxidase into tert-butanol which in turn could be conjugated with glucuronic acid or sulfate to increase the compound’s hydrophilicity (Chance, B. et al. 1979). Oxidation of tert-butanol by alcohol dehydrogenases (ADH) and aldehyde dehydrogenases (AlDH) is an alternative metabolic pathway resulting in 2,2-dimethyl-propionic acid (pivalic acid). Pivalic acid as well as the second hydrolysis product of TBPIN, 3,5,5-trimethylhexanoic acid, are estimated to be conjugated with glucuronic acid, sulphate or amino-acids like glutamine in order to ultimately facilitate excretion. Formation of dicarboxylic acids by ω-oxidation might be an alternative metabolic pathway for increasing water solubility and thus facilitating excretion.

Metabolic conversion into more toxic metabolites cannot be fully excluded asresults obtained in the Chromosome aberration tests show only positive effects with S9 activating metabolising system.Since these results are not confirmed by the available in vivo micronucleus assay metabolic activation of TBPIN in vivo is considered unlikely.

 

Excretion

As discussed above TBPIN will hydrolyse rapidly, and will thus not be excreted in its non-hydrolysed form. The first degradation product tert-butyl hydroperoxide has a low molecular weight of 90.12 g/mol, is miscible in water and is thus excreted rapidly via the urine. The second hydrolysis product 3,5,5-trimethylhexanoic acid has a molecular weight of 158.24 g/mol, is poorly soluble in water and will be thus favourably excreted via the bile. However, in case of glucuronic acid and/or amino acid conjugates renal excretion might be favoured due to their increased water solubility.