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Administrative data

Link to relevant study record(s)

Reference
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
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.
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.
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.

Description of key information

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.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

General

Tert-butyl 3,5,5-trimethylperoxyhexanoate is produced at different EU manufacturing sites. The substance represents a basic industrial chemical used as initiator to start chain reactions in the synthesis of polymers.

 

Toxicological profile of TBPIN

An acute oral toxicity study with rats revealed a LD50-value of 12905 - 15486 mg/kg bw. An acute inhalation toxicity study with rats revealed a LC50-value of > 0.8 mg/L (the highest technically achievable concentration). In an acute dermal toxicity study with rabbits a LD50 of > 2000 mg/kg bw was determined. A skin irritation study with rabbits revealed no skin irritating or corrosive effects leading to classification according to GHS. An eye irritation test also showed that TBPIN is not irritating to the rabbit’s eye. A guinea pig maximisation test revealed that TBPIN has the potential to cause skin sensitisation. TBPIN was not mutagenic in a bacterial mutagenicity test (a reverse mutation test - Ames test) and in an in vitro mouse lymphoma assay both in the presence and absence of metabolic activation. In one chromosome aberration test in cultured human lymphocytes positive results were obtained with and without metabolic activation. In another in vitro chromosome aberration test positive results were obtained only with metabolic activation. To clarify the positive response in the chromosome aberrations assays TBPIN was tested in an in vivo micronucleus assay on mice. The single oral administration of 500, 1000 and 2000 mg/kg bw did not induce biologically or statistically significant increase in the frequency of MPCEs in male mice at either 24 or 48 hours after the treatment compared to the concurrent control group. The test substance is considered not to be genotoxic in vivo.

 

A 28-day oral (gavage) toxicity study was performed with TBPIN in male and female Fischer, F344/DuCrj rats. The test item was administered at 50, 160 and 500 mg/kg bw/day dose levels. The vehicle was corn oil. Significant alterations were observed in blood cells (haemoglobin and haematocrit), liver (fats and enzyme induction), kidney (in the tubuli) and in the stomach (gastric changes were only mild and of limited importance). There was a clear sex difference in the response to the test substance with different effects in both sexes and a higher susceptibility of the males. Based on the fact, that indications for a possible renal toxicity were present exclusively in the males, an involvement of α2u-globulin was suggested, implying that the observed effects in the kidney are of no relevance to humans. A NOEL of < 50 mg/kg bw/day in males and a NOAEL of 50 mg/kg bw/day in both sexes was determined for TBPIN.

 

In order to assess reversibility, persistence or delayed occurrence of potential toxicological effects a 90-day toxicity study followed by a 28-day recovery period was performed with TBPIN. The test item was administered orally (by gavage) to Hsd.Brl.Han: Wistar rats once a day at 0 (vehicle control), 160, 40 and 10 mg/kg bw/day doses. There was no test item related mortality. Toxic signs related to the test item were not detected at any dose level at the daily and detailed weekly clinical observations and in the course of the functional observation battery. Salivation was observed in the male and female animals of the 160 or 40 mg/kg bw/day groups with variable frequency within a group but in a dose related manner regarding the incidence and onset. The body weight development and the daily mean food consumption of male and female animals was not affected by the test item. A test item influence on the estrous cycle was not detected. No test item-related changes were observed in investigated hematology or blood coagulation parameters. Clinical chemistry examinations did not reveal any pathologic changes in the examined parameters.

 

Although statistical significant increases of mean liver weights in male animals of all dose groups and of mean kidney weights in male animals of 160 and 40 mg/kg bw/day group were noted, all values remained within the historical control ranges. Sperm analysis did not reveal test item influence on the sperm cells (count, motility and morphology) at 160 mg/kg bw/day dose. Histopathology investigations revealed test item related hyaline–like droplets in the epithel cells of some proximal convoluted tubules in the kidney of male animals treated with 160, 40 and 10 mg/kg bw/day, which was accompanied by dilatation of tubuli in the distal area, at the border of cortical – medullary region at 160 and 40 mg/kg bw/day. The renal lesion was not present at the end of the recovery period and no additional renal lesions or increased cell turnover were determined. Based on immunohistochemistry examinations hyaline-like droplets at 160, 40 and 10 mg/kg bw/day doses in male rats could not be caused by α2u-globulin. However, in accordance with literature data (ECETOC, 2002) the isolated and reversible finding hyaline-like droplets in male rats has to be considered as a toxicological relevant, but not adverse effect. A NOEL of < 10 mg/kg bw/day for male animals and 10 mg/kg bw/day for female animals and a NOAEL of 160 mg/kg bw/day for male and female animals was determined for TBPIN.

 

A Reproduction/Developmental Toxicity Screening Test with the test item TBPIN was performed according to OECD guideline 421. TBPIN was administered once daily orally (by gavage) at dosages of 0, 50, 160, 400 mg/kg/day to male rats for 41 days in total and to female rats throughout the pre-pairing, the pairing, the gestation and the lactation periods until day 3 post partum (last dosing). Maternal mortality was observed at 160 mg/kg bw/day and 400 mg/kg bw/day dose levels at the end of pregnancy and at early lactation due to acute-subacute tubular damage in the kidneys and related pulmonary alterations. Reproductive performance of males was unaffected by the treatment. Effects on female reproduction parameters were observed at dose levels where maternal toxicity occurred. In the offspring generation, the higher mortality, clinical signs and decreased body weight were linked to severe maternal toxicity. Although, it seemed that the female reproduction parameters and the toxicity effects observed in the offspring generation (developmental toxicity) were a result of the maternal toxicity, the NOAEL for female reproduction performance and developmental toxicity was determined to be 50 mg/kg bw/day.

 

In a prenatal development toxicity study groups of 24 sperm-positive female Hsd. Brl. Han: WISTAR rats were treated with TBPIN by oral administration daily at three dose levels of 20, 50 and 150 mg/kg bw/day from day 6 up to and including day 19 post coitum. A control group of 25 sperm positive females was included and the animals were given the vehicle sunflower oil. A Caesarean section and gross pathology were performed on gestational day 20.

In total, there were 19, 20, 21 and 22 evaluated litters in the control, 20, 50 and 150 mg/kg groups, respectively. Two pregnant females died in the course of the study, one female in the 50 mg/kg bw/day group on gestational day (GD) 17 and one in the 150 mg/kg bw/day group on GD 9. The death and clinical signs were considered to be likely without a relationship with an effect of the test item.

There were no clinical signs and necropsy findings recorded for the survived dams in the experimental groups. There was no indication of an effect of the test item on body weight, corrected body weight and food consumption of the dams in the 20, 50, 150 mg/kg bw/day dose groups. There was no effect indicated related to the administration of TBPIN in the intrauterine mortality of the conceptuses, the number of implantations, viable fetuses and their sex distribution. The mean fetal weight was similar in the control and 20 mg/kg bw/day groups. The slight but statistically significant reduction in the bodyweight of the fetuses in the 50 and 150 mg/kg bw/day dose groups might be attributed to an effect of the test item. Relative placental weight was similar in all experimental groups.

The visceral malformations were considered to be incidental and were not attributed to the administration of the test item to the dams. The incidence of visceral variations was similar to the vehicle control level.

Skeletal malformations in two fetuses of the low dose group and in one fetus of the control group were without a relationship to the test item. Statistically significant skeletal variations were seen in the 20 and in the 150 mg/kg bw/day dose group when the ossification of sternum (3 or less ossified sternebra) was evaluated. Considering that there was no dose response indicated between the low and mid dose group and that the mean percent of the high dose group was slightly above the laboratory´s historical control level, this variation was judged to be in the biological variations. Incomplete ossification of the skull-bones (marked and less marked) was evaluated as variation during skeletal examination. Incomplete ossification of the skull bones correlated with the slightly lower mean fetal weight observed at 50 and 150 mg/kg bw/day dose groups, which was below the mean value seen in the laboratory´s historical control data. Overall, incomplete ossification of the skull bones (marked and less marked) seen at 50 mg/kg bw/day and at 150 mg/kg bw/day is considered to be non-adverse. Based on these observations a No Observed Effect Level (NOEL) for maternal toxicity of 150 mg/kg bw/day and developmental toxicity of 20 mg/kg bw/day and a No Observed Adverse Effect Level (NOAEL) for maternal toxicity of 150 mg/kg bw/day and for developmental toxicity of 150 mg/kg bw/day was determined.

 

Toxicokinetic analysis of 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.

 

Summary

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.

 

 

References

 

- ECHA (2008),Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance

- Marquardt H., et al., (1999). Toxicology.Academic Press, 1999

- ECETOC Guidance (2002) Recognition of and Differentiation between, Adverse and Non-adverse effects in Toxicoloigal studies. Technical Report No. 85.

- Chance, B., Sies, H. and Boveris, A. (1979) Hydroperoxide Metabolism in Mammalian Organs, Phys. reviews 59(3): 527-605.