tert-butyl peracetate

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert statement

Adequacy of study:

key study

Study period:

2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert Statement in accordance with ECHA Guidance Document on IR & CSA Chapter R7c.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Expert Statement in accordance with ECHA Guidance Document on Information Requirements and Chemical Safety Assessment Chapter R7c.

GLP compliance:

no

Details on absorption:

As the hydrolysis rate was shown to be very low, absorption in the gastro intestinal tract (GIT) will mainly be limited to the parent compound. Generally, oral absorption is favored for molecular weights below 500 g/mol. Further, the test item is well soluble in water and is thus expected to be well absorbed by bulk water passage through the intestinal walls. The test item has a logPow 1.6 and is thus in the range of -1 to 4 which is expected to favor GI absorption.
The above considerations are supported by experimental toxicity data. In acute and repeated oral toxicity studies performed with the test item clear signs of systemic toxicity were observed indicating the bioavailability of the test item after oral administration in rats.
Due to its low vapour pressure (2 Pa), the test item is considered to be of low volatility. Therefore, exposure with the substance via the inhalation route is unlikely, also taking into account that the test item decomposes at temperatures above 70 °C. Thus, the test item is not expected to be available as vapor or gas.
However, if the substance would reach the respiratory tract in its vapour or gaseous state, the small molecular size, well water solubility and low logPow of the test item would probably favor absorption through the mucous membranes of the lung. This is confirmed by fatal findings in acute inhalation studies leading to classification as toxic if inhaled (Cat. 3) according to CLP.
Similarly, based on its physico–chemical properties, the test item is likely to penetrate skin easily as the logPow value and well water solubility favor dermal penetration. It is generally accepted that if a compound’s water solubility is between 100-1000 mg/L, absorption can be anticipated to be moderate to high. Substances with a logPow value between -1 and 4 will be well absorbed through skin as the rate of transfer between the stratum corneum and the epidermis is favored. This is confirmed by mortalities observed after dermal application in the rabbit at high doses of 8000 mg/kg and above. Moreover, the substance classified as skin sensitizer indicating that it passes through the skin.

Details on distribution in tissues:

Assuming that the test item becomes bioavailable following oral intake, it may be widely distributed by body fluids and into the intercellular concentration may be higher than extracellular concentration. It is expected that the test item starts to hydrolyse to a low extent during and after absorption.
The results from the OECD 422 compliant study indicate histopathological effects in stomach and small intestine, liver, bone marrow, spleen, lymphatic organs, and in the males reproductive organs at 500 mg/kg bw/day, being in line with the above considerations. The stomach was also affected in animals at 150 and 50 mg/kg bw/day, the duodenum and jejunum in animals at 150 mg/kg/day and the duodenum in females at 50 mg/kg bw/day. No developmental effects were observed in the offspring that could provide indications of a distribution through the placenta and umbilical cord.
Based on the low logPow value of the test item (1.6) it is of no concern regarding bioaccumulating potential due to lipophilicity.

Details on excretion:

As discussed in the metabolism section, the test item will be metabolised either as parent or its hydrolysis products facilitating increased hydrophilicity. The first hydrolysis product tert-butyl alcohol has a low molecular weight of 74.12 g/mol, is miscible in water and thus may either be directly excreted or further metabolised by Phase II enzymes before excretion. Further potential but not confirmed hydrolysis products are acetic acid and tert-butyl hydroperoxide. Both are of low molecular weight (60.05 and 90.1 g/mol) and well soluble in water and are therefore considered to be excreted via urine.

Details on metabolites:

Based on the structure of the molecule, the test item may be metabolized by Phase I enzymes undergoing functionalization reactions aiming to increase hydrophilicity. Here, metabolism to more toxic metabolites cannot completely be ruled out in the organism. However, available in vitro test data of studies conducted with and without metabolizing system do not give indication of increased toxicity due to metabolic activation. 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) might be expected. Hydrolysis may already occur in the gastrointestinal tract. However, hydrolysis half-life of the test item was determined to be slow at any pH. Thus, it is rather expected to 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 of the peroxyester bond is also expected (e.g. by glutathione peroxidase), resulting in tert-butyl alcohol and acetic acid. Both are of smaller molecular size and have an even lower logPow than the test item. Thus, both cleavage products are expected to become easily excreted or even included into the endogenous metabolic pathways (citric acid cycle). 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. The test item is a skin sensitiser, indicating that reactions with macromolecules are likely 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.

Conclusions:

Based on the physicochemical properties of the test item, particularly its water solubility, octanol-water partition coefficient and vapour pressure, some absorption via the oral and limited absorption via the dermal route is expected. This assumption is further supported by the results of the dermal and oral acute toxicity studies. The test item is considered to be readily metabolized by Phase I and Phase II enzymes. Further it may partially undergo hydrolysis being dissolved in body fluids. Hydrolysis products are readily metabolised or excreted via the urine as such since their molecular weight and logPow is lower and water solubility is higher than for the test item itself. Based on these considerations the test item as well as its hydrolysis products is of no concern regarding bioaccumulation.

Description of key information

Based on the physicochemical properties of the test item, particularly its water solubility, octanol-water partition coefficient and vapour pressure, some absorption via the oral and limited absorption via the dermal route is expected. This assumption is further supported by the results of the dermal and oral acute toxicity studies. The test item is considered to be readily metabolized by Phase I and Phase II enzymes. Further it may partially undergo hydrolysis being dissolved in body fluids. Hydrolysis products are readily metabolised or excreted via the urine as such since their molecular weight and logPow is lower and water solubility is higher than for the test item itself. Based on these considerations the test item as well as its hydrolysis products is of no concern regarding bioaccumulation.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Toxicological profile of tert-butyl peracetate / tert-butyl ethaneperoxoate (TBPA) 

An acute oral toxicity study with the test substance revealed an LD50 > 2000 mg/kg bw in the rat.
In an acute dermal toxicity study conducted in the rabbit an LD50 > 2000 mg/kg bw was observed.

Acute inhalation studies revealed LC50 of 9.2 mg/L for aerosol and vapours of the test item, thus the test item is classified as acutely toxic if inhaled (Cat 3) according to CLP.
Furthermore, the substance was tested for its irritating properties to skin and eyes. The studies were performed with rats and rabbits. As a result, the test item was found to be not irritating to the skin but irritating the eye and thus classified as eye irritant (Cat. 2) according to CLP.

In a guinea pig maximization test the substance was further shown to induce skin sensitisation leading to classification as skin sensitizer (Cat 1) according to CLP.

Data obtained from the Combined Repeated-Dose and Reproduction / Developmental Screening Study in rats revealed a subacute oral NOAEL of 50 mg/kg bw/day calculated as peroxide for parental effects. Therefore, the NOAEL is expected to be 100 mg/kg/ bw day for the test material (50% act. ingr. in Shellsol T).

A sub-acute inhalation study in rats indicates a NOAEC value of 280 mg/cubic meter for the active ingredient. The NOAEC is calculated to be 560 mg/cubic meter for the test material (50% tert-butyl peroxyacetate in Shellsol T).

Tert-butyl peracetate is considered mutagenic in the absence and presence of exogenous metabolic activation in the bacterial reverse mutation assay (Ames test). However, the test item did not induce increases in mutant frequency in the in vitro HPRT test, when tested up to cytotoxic concentrations. The Micronucleus test in vivo also revealed negative results. Therefore, in conclusion, the test item is not considered to be genotoxic.

 

 

Toxicokinetic analysis

 

The test item is a colorless liquid with a pungent odor at room temperature with a molecular weight of 132.16 g/mol. The substance is well soluble in water (3878 mg/L at 25°C). The logPow of 1.6 at 25 °C was determined using the HPLC method according to the OECD guideline 117 and EU method A.8. The test item has a low vapour pressure of 2 Pa and is thus considered as non-volatile. Moreover, boiling point could not be determined since the test item undergoes decomposition at temperatures above 70 °C. Thus, no vapour formation is expected for the test item. Upon contact with water the test item undergoes hydrolysis but very slow (half-life = 784 h at 20°C and pH 7). Thus, hydrolysis products are not considered relevant regarding exposure to the organism.

 

Absorption

As the hydrolysis rate was shown to be very low, absorption in the gastro intestinal tract (GIT) will mainly be limited to the parent compound. Generally, oral absorption is favored for molecular weights below 500 g/mol. Further, the test item is well soluble in water and is thus expected to be well absorbed by bulk water passage through the intestinal walls. The test item has a logPow 1.6 and is thus in the range of -1 to 4 which is expected to favor GI absorption.

The above considerations are supported by experimental toxicity data. In acute and repeated oral toxicity studies performed with the test item clear signs of systemic toxicity were observed indicating the bioavailability of the test item after oral administration in rats.

Due to its low vapour pressure (2 Pa), the test item is considered to be of low volatility. Therefore, exposure with the substance via the inhalation route is unlikely, also taking into account that the test item decomposes at temperatures above 70 °C. Thus, the test item is not expected to be available as vapor or gas. However, if the substance would reach the respiratory tract in its vapour or gaseous state, the small molecular size, well water solubility and low logPow of the test item would probably favor absorption through the mucous membranes of the lung. This is confirmed by fatal findings in acute inhalation studies leading to classification as toxic if inhaled (Cat. 3) according to CLP. Similarly, based on its physico–chemical properties, the test item is likely to penetrate skin easily as the logPow value and well water solubility favor dermal penetration. It is generally accepted that if a compound’s water solubility is between 100-1000 mg/L, absorption can be anticipated to be moderate to high. Substances with a logPow value between -1 and 4 will be well absorbed through skin as the rate of transfer between the stratum corneum and the epidermis is favored. This is confirmed by mortalities observed after dermal application in the rabbit at high doses of 8000 mg/kg and above. Moreover, the substance classified as skin sensitizer indicating that it passes through the skin.

 

Distribution

Assuming that the test item becomes bioavailable following oral intake, it may be widely distributed by body fluids and into the intercellular concentration may be higher than extracellular concentration. It is expected that the test item starts to hydrolyse to a low extent during and after absorption. The results from the OECD 422 compliant study indicate histopathological effects in stomach and small intestine, liver, bone marrow, spleen, lymphatic organs, and in the males reproductive organs at 500 mg/kg bw/day, being in line with the above considerations. The stomach was also affected in animals at 150 and 50 mg/kg bw/day, the duodenum and jejunum in animals at 150 mg/kg/day and the duodenum in females at 50 mg/kg bw/day. No developmental effects were observed in the offspring that could provide indications of a distribution through the placenta and umbilical cord. Based on the low logPow value of the test item (1.6) it is of no concern regarding bioaccumulating potential due to lipophilicity.

 

Metabolism

Based on the structure of the molecule, the test item may be metabolized by Phase I enzymes undergoing functionalization reactions aiming to increase hydrophilicity. Here, metabolism to more toxic metabolites cannot completely be ruled out in the organism. However, available in vitro test data of studies conducted with and without metabolizing system do not give indication of increased toxicity due to metabolic activation. 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) might be expected. Hydrolysis may already occur in the gastrointestinal tract. However, hydrolysis half-life of the test item was determined to be slow at any pH. Thus, it is rather expected to 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 of the peroxyester bond is also expected (e.g. by glutathione peroxidase), resulting in tert-butyl alcohol and acetic acid. Both are of smaller molecular size and have an even lower logPow than the test item. Thus, both cleavage products are expected to become easily excreted or even included into the endogenous metabolic pathways (citric acid cycle). 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. The test item is a skin sensitiser, indicating that reactions with macromolecules are likely 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.

 

Excretion

As discussed above, the test item will be metabolised either as parent or its hydrolysis products facilitating increased hydrophilicity. The first hydrolysis product tert-butyl alcohol has a low molecular weight of 74.12 g/mol, is miscible in water and thus may either be directly excreted or further metabolised by Phase II enzymes before excretion. Further potential but not confirmed hydrolysis products are acetic acid and tert-butyl hydroperoxide. Both are of low molecular weight (60.05 and 90.1 g/mol) and well soluble in water and are therefore considered to be excreted via urine.

 

 

Summary

Based on the physicochemical properties of the test item, particularly its water solubility, octanol-water partition coefficient and vapour pressure, some absorption via the oral and limited absorption via the dermal route is expected. This assumption is further supported by the results of the dermal and oral acute toxicity studies. The test item is considered to be readily metabolized by Phase I and Phase II enzymes. Further it may partially undergo hydrolysis being dissolved in body fluids. Hydrolysis products are readily metabolised or excreted via the urine as such since their molecular weight and logPow is lower and water solubility is higher than for the test item itself. Based on these considerations the test item as well as its hydrolysis products is of no concern regarding bioaccumulation.